Emergency Medicine

A 43-year-old woman presents to the emergency department with substernal chest pressure of moderate intensity that started approximately 6 hours ago. The pressure radiates to both arms and is accompanied by nausea. She says she has had no emesis, diaphoresis, fevers, chills, shortness of breath, abdominal pain, melena, dysuria, weight loss, headaches, change in vision, seizures, joint pain, or skin rashes. She also says she has had no prior similar episodes and has no history of myocardial infarction (MI) or stroke.

The patient has a history of gastroesophageal reflux disease and uterine fibroids. She has had three pregnancies, one ending in spontaneous abortion at 12 weeks and two ending with healthy children delivered by cesarean section. She does not take any daily medications. She has smoked one pack per day over the last 25 years. She denies using alcohol or illicit drugs.

The patient’s mother had idiopathic deep vein thrombosis (DVT) at age 46, her father had an MI at age 65, and her sister had an MI at age 43.

On examination, she is in mild distress but is alert and oriented. Her temperature is 99.0°F (37.2°C), blood pressure 98/66 mm Hg, heart rate 65 beats per minute, respiratory rate 18 breaths per minute, and oxygen saturation 99% on room air. Her body mass index is 19.5 (normal range 18.5–24.9). Her skin appears normal. Her head and neck show no obvious abnormalities, lymphadenopathy, thyromegaly, or bruits. Her heart, lungs, and abdomen are normal, as are her strength, sensation, reflexes, and gait.

Laboratory values at the time of admission:

• White blood cell count 12.58 × 10⁹/L (reference range 4.0–11.0)
• Hemoglobin 15.4 g/dL (12.0–16.0)
• Platelet count 122 × 10⁹/L (150–400)
• International normalized ratio (INR) 1.1 (0.9–1.1)
• Activated partial thromboplastin time 29.1 seconds (24.6–34).

A heart attack, and then a stroke

An initial electrocardiogram shows normal sinus rhythm, left anterior hemiblock, and nonspecific T-wave abnormalities. Cardiac enzymes are measured at intervals: her troponin T level is less than 0.01 ng/mL at the time of admission but rises to 0.75 ng/mL 3 hours later (normal range 0.0–0.1 ng/mL). Similarly, her creatine kinase-MB level is 3.3 ng/mL at admission but rises to 71.9 ng/mL 3 hours later (normal range 0.0–8.0 ng/mL).

The patient is diagnosed with non-ST-elevation MI. An intravenous heparin drip is started, and she is sent for urgent cardiac catheterization, which shows a total occlusion in a lateral obtuse marginal branch of the left circumflex artery due to a thrombus in the vessel. Otherwise, her coronary arteries are angiographically free of disease. The heparin drip is continued, and treatment is started with abciximab (ReoPro) and tissue plasminogen activator (Alteplase). She is sent to the cardiac intensive care unit for recovery, where she is placed on continuous cardiac monitoring, with no evidence of arrhythmia.

One day later, the left side of her face is drooping, her left arm is weak, and her speech is slurred. Magnetic resonance imaging of the brain shows an acute ischemic infarct in the right temporoparietal area and multiple areas of subacute to chronic ischemia. Magnetic resonance angiography of the brain indicates patent vessels. Both transthoracic and transesophageal echocardiography are performed and indicate normal left ventricular size, ejection fraction of 55%, valves without thrombus or vegetations, aorta with mild atheroma, and no patent foramen ovale by Doppler flow or agitated saline contrast study. Carotid artery Doppler ultrasonography shows 40% to 59% stenosis bilaterally.

ARTERIAL THROMBOSIS

1. Which of the following is a risk factor for arterial thrombosis?

• Atherosclerosis
• Protein C deficiency
• Use of oral contraceptive pills
• The factor V Leiden mutation

Protein C deficiency, the use of oral contraceptives, and the factor V Leiden mutation are typically associated with venous thrombosis¹; they have been documented as a cause of arterial thrombosis only in some case reports. In contrast, atherosclerosis is a well-established risk factor for arterial thrombosis.

Arterial occlusion can be due to thrombosis, embolism, or trauma

The causes of arterial occlusion can be categorized as thrombotic, embolic, or traumatic (Table 1).

Atherosclerosis is a risk factor for thrombosis and can be a source of emboli. Atherosclerotic plaque rupture may release inflammatory mediators, which also predispose to thrombosis.² This patient’s coronary arteries are essentially free of atherosclerotic disease per angiography. However, studies of intravascular ultrasonography have shown that coronary angiography may not detect all atherosclerotic plaques, as angiography can show only the lumen of the artery and not the plaque itself.³ For that reason, atherosclerosis has not been ruled out completely, and further workup is needed to evaluate other possible causes of her thrombotic events.

Embolism is the most likely cause of her stroke, however. Cases of arterial embolism can be classified on the basis of the origin of the thrombus, ie, the heart, an artery, or the venous system via a patent foramen ovale (paradoxical embolism). This patient’s echocardiogram reveals mild aortic atheroma, which can be a source of emboli, especially soon after intervention.

Case continues: Acute and recurrent DVT

While recovering from her MI and stroke, the patient develops edema and pain in both legs. Doppler ultrasonography is performed, which reveals acute DVT in the right gastrocnemius and posterior tibial veins and left soleal vein, despite her continued heparin therapy.

Her platelet count is 189 × 10⁹/L, so heparin-induced thrombocytopenia is not suspected; the new DVT is thought to be due to her hospitalization. Several days later, oral warfarin (Coumadin) is started and titrated to an INR of 2.0 to 3.0, the heparin is phased out, and the patient is sent home.

In the first few months after discharge, the patient presents to the emergency department three times with severe leg pain, and each time she is found to have extensive DVT in various leg veins even though she is complying with her warfarin therapy. At each visit, her INR is in the range of 2.5 to 3.1.

Comment. Her recurrent DVT warrants further evaluation for risk factors for venous thrombosis, which can be divided into hereditary and acquired factors.

Hereditary risk factors include the factor V Leiden mutation, the prothrombin gene mutation, hyperhomocysteinemia, dysfibrinogenemia, and deficiencies of protein C, protein S, and antithrombin.

Acquired risk factors include the antiphospholipid antibody syndrome, cancer, immobilization, surgery, congestive heart failure, pregnancy, use of hormonal contraceptives, hormone replacement therapy, nephrotic syndrome, trauma, and infection.^1,4

TESTING FOR HYPERCOAGULABLE STATES

2. In view of our patient’s recurrent thrombotic episodes, should she be tested for hypercoagulable states?

• Yes
• No

Testing for hypercoagulable conditions is warranted if it will affect the patient’s management or outcome. Some authorities recommend testing patients who are clinically characterized as “strongly” thrombophilic,⁵ ie, those who present with DVT and are younger than age 50, have recurrent thrombotic episodes, have a first-degree relative with documented thromboembolism before age 50, or have thrombotic episodes despite warfarin therapy.

This patient should be tested for hypercoagulable conditions because her initial DVT occurred before age 50 (at age 43), she has had recurrent, apparently idiopathic thrombotic episodes, she has a family history of thromboembolism, and she had clots while on therapeutic warfarin therapy, all of which suggest a hypercoagulable state. Furthermore, the confirmation of her diagnosis may affect her medical management, as it may determine if further testing and therapies are needed.

Case continues: Tests are negative

Laboratory tests for hypercoagulable conditions are performed and are negative for the factor V Leiden mutation, the prothrombin gene mutation, antithrombin deficiency, and protein C and S deficiencies. A screen for antiphospholipid antibodies is indeterminate.

TREATMENT AFFECTS TEST RESULTS

3. If a patient is on warfarin therapy, which test results may be affected?

• Antithrombin levels
• Protein C and S levels
• Factor V Leiden mutation

Warfarin decreases the levels of proteins C and S; therefore, the levels of these substances cannot be accurately interpreted in a patient taking warfarin.

All anticoagulants prolong the clotting time and may affect the results of assays based on the clotting time, such as the prothrombin time, the partial thromboplastin time, the dilute Russell’s viper venom time (DRVVT), the hexagonal phase phospholipid neutralization assay, the thrombin time, and clottable protein C and protein S. Heparin reduces the level of antithrombin; however, laboratories now have heparin-binding agents that reduce the effect of heparin in clotting studies.

Acute thrombotic states lower the levels of antithrombin and proteins C and S.

Assays not based on the clotting time (immunogenic or genetic tests such as those for anticardiolipin antibodies and the factor V Leiden and prothrombin gene mutations) are not affected by anticoagulant use.⁵

However, the presence or absence of a hypercoagulable state should not affect the treatment of acute DVT, and a full 6- to 12-month course of anticoagulation should be completed.^6,7 If possible, lupus anticoagulant testing should be repeated 2 weeks after anticoagulation is stopped.⁸

This patient needs lifelong anticoagulation because of her repeated thrombotic episodes. Stopping the medication for 2 weeks for testing would increase the risk of rethrombosis in this patient, and most experts would not advise it.

In summary, testing for hypercoagulable conditions is not recommended during an acute thrombotic episode and is preferably performed while the patient is not on anticoagulation therapy. If the patient is already on anticoagulation, the results of tests for hypercoagulable conditions should be interpreted with caution.

Case continues: Another stroke

During the subsequent year, the patient’s primary care physician monitors her warfarin use and sends her for age-appropriate cancer screening, including a breast examination, Papanicolaou smear, and mammography. Also, given her history of smoking, a chest radiograph is ordered. All of these studies are normal. In addition, evaluations for hematologic disorders such as myelodysplastic syndrome, polycythemia vera, and Waldenström macroglobulinema reveal normal complete blood counts and normal results on serum and urine protein electrophoresis.

Later that year, she returns to the emergency department with complete aphasia and total right-sided paralysis. Magnetic resonance imaging shows an acute infarct in the left frontal operculum, a subacute infarct in the right cerebellum, and multiple chronic cortical and subcortical infarcts throughout the brain. Ultrasonography shows an extensive new DVT in her right leg. Her INR at this time is 3.1.

WHAT CONDITIONS CAUSE BOTH ARTERIAL AND VENOUS THROMBOSIS?

4. Given that the patient has evidence of both recurrent arterial and venous thromboses, which of the following conditions is likely?

• Antiphospholipid antibody syndrome
• Heparin-induced thrombocytopenia
• Malignancy
• All of the above

Conditions associated with both arterial and venous thrombosis include antiphospholipid antibody syndrome, heparin-induced thrombocytopenia, malignancy, paradoxical embolism, hyperhomocysteinemia, myeloproliferative disorders, myelodysplastic disorder, paraproteinemia, vasculitis, and paroxysmal nocturnal hemoglobinuria.^1,4

At present, the exact mechanism that causes Trousseau syndrome is unknown. Some hypotheses implicate mucin (produced by the cancer),¹⁰ tissue factor,¹¹ tumor-associated cysteine proteinase,¹² tumor hypoxia,¹³ and oncogene activation as plausible triggers for this syndrome.

DOES SHE HAVE ANTIPHOSPHOLIPID ANTIBODY SYNDROME?

5. The patient is positive for lupus anticoagulant. Does she have antiphospholipid antibody syndrome?

• Yes
• No
• Repeat testing is needed to meet the diagnostic criteria

The Sapporo criteria¹⁵ indicate that antiphospholipid antibody syndrome is present if at least one clinical criterion and one laboratory criterion are met. The clinical criteria are one or more episodes of arterial or venous thrombosis or pregnancy-related morbidity, ie:

• Unexplained intrauterine fetal death at 10 weeks gestation or later with no apparent fetal abnormality
• Premature births of a morphologically normal fetus at less than 34 weeks of gestation due to preeclampsia, eclampsia, or placental insufficiency
• Three or more spontaneous abortions at 10 weeks of gestation or earlier, with no known paternal chromosomal abnormalities or maternal hormonal abnormalities and normal maternal anatomy.

The laboratory criteria are:

• Lupus anticoagulant present
• Anticardiolipin antibody (IgG or IgM) titer greater than 40 IgG antiphospholipid units (GPL) or IgM antiphospholipid units (MPL) or higher than the 99th percentile of the testing laboratory normal reference range
• Anti-beta-2 glycoprotein-I antibody (IgG or IgM) titer greater than 20 GPL or MPL or higher than the 99th percentile of the testing laboratory normal reference range.

The patient likely has antiphospholipid antibody syndrome because her lupus anticoagulant screen is positive and she meets the clinical criteria of thrombosis, and she should continue to be treated accordingly. However, to officially meet the revised Sapporo criteria, she would need to have laboratory tests that are positive on two or more occasions at least 12 weeks apart.

Case continues: Lung cancer is found

The patient reports that she has lost 10 pounds in 4 months. Since age-appropriate cancer testing was previously performed, a more extensive evaluation for weight loss is undertaken, with computed tomography of the chest, abdomen, and pelvis. These tests reveal a nodule in the right upper lobe of the lung, scarring in the right middle and left lower lung lobes, and hilar lymphadenopathy. Bronchoscopy with transbronchial biopsy confirms that she has adenocarcinoma of the lung.

6. What is suggested as a sufficient workup for malignancy in patients with idiopathic venous thromboembolism?

• Computed tomography of the chest, abdomen, and pelvis for every patient with idiopathic venous thromboembolism
• Positron emission tomography and tumor marker levels
• A comprehensive history and physical examination, routine laboratory tests, chest radiography, age- and sex-specific cancer screening, and patient-specific testing as indicated clinically

To date, there is no evidence to support a cancer evaluation beyond a comprehensive medical history and physical examination, routine laboratory testing, chest radiography, and age- and sex-specific cancer screening unless it is dictated by the patient’s clinical presentation. A study by Cornuz et al¹⁶ suggested that this approach is appropriate for detecting cancer in patients with idiopathic venous thromboembolism.

A 2004 study¹⁷ attempted to answer the question of what to do about patients who have idiopathic venous thromboembolism but no other signs or symptoms that raise any clinical suspicion of cancer. This study randomized patients with idiopathic venous thromboembolism to undergo either routine medical management or an extensive malignancy evaluation. The evaluation included ultrasonography of the abdomen and pelvis, computed tomography of the abdomen and pelvis, gastroscopy or a double-contrast barium swallow study, colonoscopy or sigmoidoscopy followed by a barium enema, stool occult blood testing, and sputum cytology. Women were also tested for the tumor markers carcinoembryonic antigen, alpha-fetoprotein, and CA-125, and they underwent mammography and Papanicolaou testing; men were tested for prostate-specific antigen and underwent ultrasonography of the prostate. The results of the study did not reveal a statistically significant survival benefit in the group that underwent extensive cancer evaluation.

These studies indicate that the decision to test for cancer should be guided by clinical suspicion. Our patient lost 10 pounds in 4 months, smokes, and has had recurrent venous thromboembolism, so testing was appropriate.

After her diagnosis with adenocarcinoma of the lung, the patient has yet another DVT despite an INR of 3.1 and treatment with warfarin and aspirin.

LOW-MOLECULAR-WEIGHT HEPARIN FOR PATIENTS WITH CANCER?

7. True or false? Low-molecular-weight heparin is more effective than warfarin in preventing DVT in cancer patients without increasing the bleeding risk.

• True
• False

This statement is true. The American College of Chest Physicians (ACCP) recommends immediate treatment of DVT with low-molecular-weight heparin for 6 to 12 months after a thrombotic event in a patient with malignancy.^6,18

Two major studies provide evidence for these recommendations: the Comparison of Low-Molecular-Weight Heparin Versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients With Cancer (CLOT)¹⁹ and the Trial of the Effect of Low-Molecular-Weight Heparin Versus Warfarin on Mortality in the Long-Term Treatment of Proximal Deep Vein Thrombosis (LITE)²⁰ studies.

The CLOT¹⁹ study showed that dalteparin (Fragmin) 200 IU/kg subcutaneously once daily for l month and then 150 IU/kg once daily was more effective than oral warfarin titrated to an INR of 2.5 and did not increase the risk of bleeding.

The LITE trial²⁰ showed the efficacy of tinzaparin (Innohep) 175 IU/kg subcutaneously daily, which can be used as an alternative.

Enoxaparin sodium (Lovenox) 1.5 mg/kg once daily has also been used. However, if low-molecular-weight heparin is not available, warfarin titrated to an INR of 2 to 3 is also acceptable.¹⁸

The ACCP consensus panel recommends giving anticoagulation for an initial 6 to 12 months and continuing it as long as there is evidence of active malignancy.⁶ The American Society for Clinical Oncology also recommends placement of an inferior vena cava filter for patients who have contraindications to anticoagulation or for whom low-molecular-weight heparin fails.¹⁸

Case continues: Summing up

In conclusion, our patient had an underlying malignancy, causing Trousseau syndrome. Before her cancer was diagnosed, she also had test results that suggested antiphospholipid antibody syndrome. Both of these conditions likely contributed to her hypercoagulable state, increasing her propensity for clotting and causing her recurrent thrombosis. The patient is currently on low-molecular-weight heparin and is undergoing palliative chemotherapy for metastatic adenocarcinoma of the lung. To this date, she has not had any new thrombotic events.

TAKE-HOME POINTS

• Risk factors for arterial occlusion can be divided into thrombotic, embolic, and traumatic categories.
• Risk factors for venous thrombosis can be divided into hereditary and acquired categories.
• Evaluation for hypercoagulable conditions is recommended if it will affect patient management or outcome. Patients to be considered for testing include those with idiopathic DVT and who are under age 50, those with a history of recurrent thrombosis, and those with a first-degree relative with documented venous thromboembolism before age 50.
• Evaluation for hypercoagulable conditions should ideally be performed either before starting anticoagulation therapy or 2 weeks after completing it.
• Potential causes of both arterial and venous thrombosis include antiphospholipid antibody syndrome, cancer, hyperhomocysteinemia, heparin-induced thrombocytopenia, paradoxical emboli, myeloproliferative disorders, myelodysplastic syndrome, paraproteinemia, vasculitis, and paroxysmal nocturnal hemoglobinuria.
• Current evidence does not support an extensive cancer evaluation in patients with idiopathic venous thromboembolism, unless dictated by the patient’s clinical condition.
• In patients with venous thromboembolism and active malignancy, anticoagulation is recommended for at least 6 to 12 months and as long as there is evidence of active malignancy.

A 43-year-old woman presents to the emergency department with substernal chest pressure of moderate intensity that started approximately 6 hours ago. The pressure radiates to both arms and is accompanied by nausea. She says she has had no emesis, diaphoresis, fevers, chills, shortness of breath, abdominal pain, melena, dysuria, weight loss, headaches, change in vision, seizures, joint pain, or skin rashes. She also says she has had no prior similar episodes and has no history of myocardial infarction (MI) or stroke.

The patient has a history of gastroesophageal reflux disease and uterine fibroids. She has had three pregnancies, one ending in spontaneous abortion at 12 weeks and two ending with healthy children delivered by cesarean section. She does not take any daily medications. She has smoked one pack per day over the last 25 years. She denies using alcohol or illicit drugs.

The patient’s mother had idiopathic deep vein thrombosis (DVT) at age 46, her father had an MI at age 65, and her sister had an MI at age 43.

On examination, she is in mild distress but is alert and oriented. Her temperature is 99.0°F (37.2°C), blood pressure 98/66 mm Hg, heart rate 65 beats per minute, respiratory rate 18 breaths per minute, and oxygen saturation 99% on room air. Her body mass index is 19.5 (normal range 18.5–24.9). Her skin appears normal. Her head and neck show no obvious abnormalities, lymphadenopathy, thyromegaly, or bruits. Her heart, lungs, and abdomen are normal, as are her strength, sensation, reflexes, and gait.

Laboratory values at the time of admission:

• White blood cell count 12.58 × 10⁹/L (reference range 4.0–11.0)
• Hemoglobin 15.4 g/dL (12.0–16.0)
• Platelet count 122 × 10⁹/L (150–400)
• International normalized ratio (INR) 1.1 (0.9–1.1)
• Activated partial thromboplastin time 29.1 seconds (24.6–34).

A heart attack, and then a stroke

An initial electrocardiogram shows normal sinus rhythm, left anterior hemiblock, and nonspecific T-wave abnormalities. Cardiac enzymes are measured at intervals: her troponin T level is less than 0.01 ng/mL at the time of admission but rises to 0.75 ng/mL 3 hours later (normal range 0.0–0.1 ng/mL). Similarly, her creatine kinase-MB level is 3.3 ng/mL at admission but rises to 71.9 ng/mL 3 hours later (normal range 0.0–8.0 ng/mL).

The patient is diagnosed with non-ST-elevation MI. An intravenous heparin drip is started, and she is sent for urgent cardiac catheterization, which shows a total occlusion in a lateral obtuse marginal branch of the left circumflex artery due to a thrombus in the vessel. Otherwise, her coronary arteries are angiographically free of disease. The heparin drip is continued, and treatment is started with abciximab (ReoPro) and tissue plasminogen activator (Alteplase). She is sent to the cardiac intensive care unit for recovery, where she is placed on continuous cardiac monitoring, with no evidence of arrhythmia.

One day later, the left side of her face is drooping, her left arm is weak, and her speech is slurred. Magnetic resonance imaging of the brain shows an acute ischemic infarct in the right temporoparietal area and multiple areas of subacute to chronic ischemia. Magnetic resonance angiography of the brain indicates patent vessels. Both transthoracic and transesophageal echocardiography are performed and indicate normal left ventricular size, ejection fraction of 55%, valves without thrombus or vegetations, aorta with mild atheroma, and no patent foramen ovale by Doppler flow or agitated saline contrast study. Carotid artery Doppler ultrasonography shows 40% to 59% stenosis bilaterally.

ARTERIAL THROMBOSIS

1. Which of the following is a risk factor for arterial thrombosis?

• Atherosclerosis
• Protein C deficiency
• Use of oral contraceptive pills
• The factor V Leiden mutation

Protein C deficiency, the use of oral contraceptives, and the factor V Leiden mutation are typically associated with venous thrombosis¹; they have been documented as a cause of arterial thrombosis only in some case reports. In contrast, atherosclerosis is a well-established risk factor for arterial thrombosis.

Arterial occlusion can be due to thrombosis, embolism, or trauma

The causes of arterial occlusion can be categorized as thrombotic, embolic, or traumatic (Table 1).

Atherosclerosis is a risk factor for thrombosis and can be a source of emboli. Atherosclerotic plaque rupture may release inflammatory mediators, which also predispose to thrombosis.² This patient’s coronary arteries are essentially free of atherosclerotic disease per angiography. However, studies of intravascular ultrasonography have shown that coronary angiography may not detect all atherosclerotic plaques, as angiography can show only the lumen of the artery and not the plaque itself.³ For that reason, atherosclerosis has not been ruled out completely, and further workup is needed to evaluate other possible causes of her thrombotic events.

Embolism is the most likely cause of her stroke, however. Cases of arterial embolism can be classified on the basis of the origin of the thrombus, ie, the heart, an artery, or the venous system via a patent foramen ovale (paradoxical embolism). This patient’s echocardiogram reveals mild aortic atheroma, which can be a source of emboli, especially soon after intervention.

Case continues: Acute and recurrent DVT

While recovering from her MI and stroke, the patient develops edema and pain in both legs. Doppler ultrasonography is performed, which reveals acute DVT in the right gastrocnemius and posterior tibial veins and left soleal vein, despite her continued heparin therapy.

Her platelet count is 189 × 10⁹/L, so heparin-induced thrombocytopenia is not suspected; the new DVT is thought to be due to her hospitalization. Several days later, oral warfarin (Coumadin) is started and titrated to an INR of 2.0 to 3.0, the heparin is phased out, and the patient is sent home.

In the first few months after discharge, the patient presents to the emergency department three times with severe leg pain, and each time she is found to have extensive DVT in various leg veins even though she is complying with her warfarin therapy. At each visit, her INR is in the range of 2.5 to 3.1.

Comment. Her recurrent DVT warrants further evaluation for risk factors for venous thrombosis, which can be divided into hereditary and acquired factors.

Hereditary risk factors include the factor V Leiden mutation, the prothrombin gene mutation, hyperhomocysteinemia, dysfibrinogenemia, and deficiencies of protein C, protein S, and antithrombin.

Acquired risk factors include the antiphospholipid antibody syndrome, cancer, immobilization, surgery, congestive heart failure, pregnancy, use of hormonal contraceptives, hormone replacement therapy, nephrotic syndrome, trauma, and infection.^1,4

TESTING FOR HYPERCOAGULABLE STATES

2. In view of our patient’s recurrent thrombotic episodes, should she be tested for hypercoagulable states?

• Yes
• No

Testing for hypercoagulable conditions is warranted if it will affect the patient’s management or outcome. Some authorities recommend testing patients who are clinically characterized as “strongly” thrombophilic,⁵ ie, those who present with DVT and are younger than age 50, have recurrent thrombotic episodes, have a first-degree relative with documented thromboembolism before age 50, or have thrombotic episodes despite warfarin therapy.

This patient should be tested for hypercoagulable conditions because her initial DVT occurred before age 50 (at age 43), she has had recurrent, apparently idiopathic thrombotic episodes, she has a family history of thromboembolism, and she had clots while on therapeutic warfarin therapy, all of which suggest a hypercoagulable state. Furthermore, the confirmation of her diagnosis may affect her medical management, as it may determine if further testing and therapies are needed.

Case continues: Tests are negative

Laboratory tests for hypercoagulable conditions are performed and are negative for the factor V Leiden mutation, the prothrombin gene mutation, antithrombin deficiency, and protein C and S deficiencies. A screen for antiphospholipid antibodies is indeterminate.

TREATMENT AFFECTS TEST RESULTS

3. If a patient is on warfarin therapy, which test results may be affected?

• Antithrombin levels
• Protein C and S levels
• Factor V Leiden mutation

Warfarin decreases the levels of proteins C and S; therefore, the levels of these substances cannot be accurately interpreted in a patient taking warfarin.

All anticoagulants prolong the clotting time and may affect the results of assays based on the clotting time, such as the prothrombin time, the partial thromboplastin time, the dilute Russell’s viper venom time (DRVVT), the hexagonal phase phospholipid neutralization assay, the thrombin time, and clottable protein C and protein S. Heparin reduces the level of antithrombin; however, laboratories now have heparin-binding agents that reduce the effect of heparin in clotting studies.

Acute thrombotic states lower the levels of antithrombin and proteins C and S.

Assays not based on the clotting time (immunogenic or genetic tests such as those for anticardiolipin antibodies and the factor V Leiden and prothrombin gene mutations) are not affected by anticoagulant use.⁵

However, the presence or absence of a hypercoagulable state should not affect the treatment of acute DVT, and a full 6- to 12-month course of anticoagulation should be completed.^6,7 If possible, lupus anticoagulant testing should be repeated 2 weeks after anticoagulation is stopped.⁸

This patient needs lifelong anticoagulation because of her repeated thrombotic episodes. Stopping the medication for 2 weeks for testing would increase the risk of rethrombosis in this patient, and most experts would not advise it.

In summary, testing for hypercoagulable conditions is not recommended during an acute thrombotic episode and is preferably performed while the patient is not on anticoagulation therapy. If the patient is already on anticoagulation, the results of tests for hypercoagulable conditions should be interpreted with caution.

Case continues: Another stroke

During the subsequent year, the patient’s primary care physician monitors her warfarin use and sends her for age-appropriate cancer screening, including a breast examination, Papanicolaou smear, and mammography. Also, given her history of smoking, a chest radiograph is ordered. All of these studies are normal. In addition, evaluations for hematologic disorders such as myelodysplastic syndrome, polycythemia vera, and Waldenström macroglobulinema reveal normal complete blood counts and normal results on serum and urine protein electrophoresis.

Later that year, she returns to the emergency department with complete aphasia and total right-sided paralysis. Magnetic resonance imaging shows an acute infarct in the left frontal operculum, a subacute infarct in the right cerebellum, and multiple chronic cortical and subcortical infarcts throughout the brain. Ultrasonography shows an extensive new DVT in her right leg. Her INR at this time is 3.1.

WHAT CONDITIONS CAUSE BOTH ARTERIAL AND VENOUS THROMBOSIS?

4. Given that the patient has evidence of both recurrent arterial and venous thromboses, which of the following conditions is likely?

• Antiphospholipid antibody syndrome
• Heparin-induced thrombocytopenia
• Malignancy
• All of the above

Conditions associated with both arterial and venous thrombosis include antiphospholipid antibody syndrome, heparin-induced thrombocytopenia, malignancy, paradoxical embolism, hyperhomocysteinemia, myeloproliferative disorders, myelodysplastic disorder, paraproteinemia, vasculitis, and paroxysmal nocturnal hemoglobinuria.^1,4

At present, the exact mechanism that causes Trousseau syndrome is unknown. Some hypotheses implicate mucin (produced by the cancer),¹⁰ tissue factor,¹¹ tumor-associated cysteine proteinase,¹² tumor hypoxia,¹³ and oncogene activation as plausible triggers for this syndrome.

DOES SHE HAVE ANTIPHOSPHOLIPID ANTIBODY SYNDROME?

5. The patient is positive for lupus anticoagulant. Does she have antiphospholipid antibody syndrome?

• Yes
• No
• Repeat testing is needed to meet the diagnostic criteria

The Sapporo criteria¹⁵ indicate that antiphospholipid antibody syndrome is present if at least one clinical criterion and one laboratory criterion are met. The clinical criteria are one or more episodes of arterial or venous thrombosis or pregnancy-related morbidity, ie:

• Unexplained intrauterine fetal death at 10 weeks gestation or later with no apparent fetal abnormality
• Premature births of a morphologically normal fetus at less than 34 weeks of gestation due to preeclampsia, eclampsia, or placental insufficiency
• Three or more spontaneous abortions at 10 weeks of gestation or earlier, with no known paternal chromosomal abnormalities or maternal hormonal abnormalities and normal maternal anatomy.

The laboratory criteria are:

• Lupus anticoagulant present
• Anticardiolipin antibody (IgG or IgM) titer greater than 40 IgG antiphospholipid units (GPL) or IgM antiphospholipid units (MPL) or higher than the 99th percentile of the testing laboratory normal reference range
• Anti-beta-2 glycoprotein-I antibody (IgG or IgM) titer greater than 20 GPL or MPL or higher than the 99th percentile of the testing laboratory normal reference range.

The patient likely has antiphospholipid antibody syndrome because her lupus anticoagulant screen is positive and she meets the clinical criteria of thrombosis, and she should continue to be treated accordingly. However, to officially meet the revised Sapporo criteria, she would need to have laboratory tests that are positive on two or more occasions at least 12 weeks apart.

Case continues: Lung cancer is found

The patient reports that she has lost 10 pounds in 4 months. Since age-appropriate cancer testing was previously performed, a more extensive evaluation for weight loss is undertaken, with computed tomography of the chest, abdomen, and pelvis. These tests reveal a nodule in the right upper lobe of the lung, scarring in the right middle and left lower lung lobes, and hilar lymphadenopathy. Bronchoscopy with transbronchial biopsy confirms that she has adenocarcinoma of the lung.

6. What is suggested as a sufficient workup for malignancy in patients with idiopathic venous thromboembolism?

• Computed tomography of the chest, abdomen, and pelvis for every patient with idiopathic venous thromboembolism
• Positron emission tomography and tumor marker levels
• A comprehensive history and physical examination, routine laboratory tests, chest radiography, age- and sex-specific cancer screening, and patient-specific testing as indicated clinically

To date, there is no evidence to support a cancer evaluation beyond a comprehensive medical history and physical examination, routine laboratory testing, chest radiography, and age- and sex-specific cancer screening unless it is dictated by the patient’s clinical presentation. A study by Cornuz et al¹⁶ suggested that this approach is appropriate for detecting cancer in patients with idiopathic venous thromboembolism.

A 2004 study¹⁷ attempted to answer the question of what to do about patients who have idiopathic venous thromboembolism but no other signs or symptoms that raise any clinical suspicion of cancer. This study randomized patients with idiopathic venous thromboembolism to undergo either routine medical management or an extensive malignancy evaluation. The evaluation included ultrasonography of the abdomen and pelvis, computed tomography of the abdomen and pelvis, gastroscopy or a double-contrast barium swallow study, colonoscopy or sigmoidoscopy followed by a barium enema, stool occult blood testing, and sputum cytology. Women were also tested for the tumor markers carcinoembryonic antigen, alpha-fetoprotein, and CA-125, and they underwent mammography and Papanicolaou testing; men were tested for prostate-specific antigen and underwent ultrasonography of the prostate. The results of the study did not reveal a statistically significant survival benefit in the group that underwent extensive cancer evaluation.

These studies indicate that the decision to test for cancer should be guided by clinical suspicion. Our patient lost 10 pounds in 4 months, smokes, and has had recurrent venous thromboembolism, so testing was appropriate.

After her diagnosis with adenocarcinoma of the lung, the patient has yet another DVT despite an INR of 3.1 and treatment with warfarin and aspirin.

LOW-MOLECULAR-WEIGHT HEPARIN FOR PATIENTS WITH CANCER?

7. True or false? Low-molecular-weight heparin is more effective than warfarin in preventing DVT in cancer patients without increasing the bleeding risk.

• True
• False

This statement is true. The American College of Chest Physicians (ACCP) recommends immediate treatment of DVT with low-molecular-weight heparin for 6 to 12 months after a thrombotic event in a patient with malignancy.^6,18

Two major studies provide evidence for these recommendations: the Comparison of Low-Molecular-Weight Heparin Versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients With Cancer (CLOT)¹⁹ and the Trial of the Effect of Low-Molecular-Weight Heparin Versus Warfarin on Mortality in the Long-Term Treatment of Proximal Deep Vein Thrombosis (LITE)²⁰ studies.

The CLOT¹⁹ study showed that dalteparin (Fragmin) 200 IU/kg subcutaneously once daily for l month and then 150 IU/kg once daily was more effective than oral warfarin titrated to an INR of 2.5 and did not increase the risk of bleeding.

The LITE trial²⁰ showed the efficacy of tinzaparin (Innohep) 175 IU/kg subcutaneously daily, which can be used as an alternative.

Enoxaparin sodium (Lovenox) 1.5 mg/kg once daily has also been used. However, if low-molecular-weight heparin is not available, warfarin titrated to an INR of 2 to 3 is also acceptable.¹⁸

The ACCP consensus panel recommends giving anticoagulation for an initial 6 to 12 months and continuing it as long as there is evidence of active malignancy.⁶ The American Society for Clinical Oncology also recommends placement of an inferior vena cava filter for patients who have contraindications to anticoagulation or for whom low-molecular-weight heparin fails.¹⁸

Case continues: Summing up

In conclusion, our patient had an underlying malignancy, causing Trousseau syndrome. Before her cancer was diagnosed, she also had test results that suggested antiphospholipid antibody syndrome. Both of these conditions likely contributed to her hypercoagulable state, increasing her propensity for clotting and causing her recurrent thrombosis. The patient is currently on low-molecular-weight heparin and is undergoing palliative chemotherapy for metastatic adenocarcinoma of the lung. To this date, she has not had any new thrombotic events.

TAKE-HOME POINTS

• Risk factors for arterial occlusion can be divided into thrombotic, embolic, and traumatic categories.
• Risk factors for venous thrombosis can be divided into hereditary and acquired categories.
• Evaluation for hypercoagulable conditions is recommended if it will affect patient management or outcome. Patients to be considered for testing include those with idiopathic DVT and who are under age 50, those with a history of recurrent thrombosis, and those with a first-degree relative with documented venous thromboembolism before age 50.
• Evaluation for hypercoagulable conditions should ideally be performed either before starting anticoagulation therapy or 2 weeks after completing it.
• Potential causes of both arterial and venous thrombosis include antiphospholipid antibody syndrome, cancer, hyperhomocysteinemia, heparin-induced thrombocytopenia, paradoxical emboli, myeloproliferative disorders, myelodysplastic syndrome, paraproteinemia, vasculitis, and paroxysmal nocturnal hemoglobinuria.
• Current evidence does not support an extensive cancer evaluation in patients with idiopathic venous thromboembolism, unless dictated by the patient’s clinical condition.
• In patients with venous thromboembolism and active malignancy, anticoagulation is recommended for at least 6 to 12 months and as long as there is evidence of active malignancy.

A 43-year-old woman presents to the emergency department with substernal chest pressure of moderate intensity that started approximately 6 hours ago. The pressure radiates to both arms and is accompanied by nausea. She says she has had no emesis, diaphoresis, fevers, chills, shortness of breath, abdominal pain, melena, dysuria, weight loss, headaches, change in vision, seizures, joint pain, or skin rashes. She also says she has had no prior similar episodes and has no history of myocardial infarction (MI) or stroke.

The patient has a history of gastroesophageal reflux disease and uterine fibroids. She has had three pregnancies, one ending in spontaneous abortion at 12 weeks and two ending with healthy children delivered by cesarean section. She does not take any daily medications. She has smoked one pack per day over the last 25 years. She denies using alcohol or illicit drugs.

The patient’s mother had idiopathic deep vein thrombosis (DVT) at age 46, her father had an MI at age 65, and her sister had an MI at age 43.

On examination, she is in mild distress but is alert and oriented. Her temperature is 99.0°F (37.2°C), blood pressure 98/66 mm Hg, heart rate 65 beats per minute, respiratory rate 18 breaths per minute, and oxygen saturation 99% on room air. Her body mass index is 19.5 (normal range 18.5–24.9). Her skin appears normal. Her head and neck show no obvious abnormalities, lymphadenopathy, thyromegaly, or bruits. Her heart, lungs, and abdomen are normal, as are her strength, sensation, reflexes, and gait.

Laboratory values at the time of admission:

• White blood cell count 12.58 × 10⁹/L (reference range 4.0–11.0)
• Hemoglobin 15.4 g/dL (12.0–16.0)
• Platelet count 122 × 10⁹/L (150–400)
• International normalized ratio (INR) 1.1 (0.9–1.1)
• Activated partial thromboplastin time 29.1 seconds (24.6–34).

A heart attack, and then a stroke

An initial electrocardiogram shows normal sinus rhythm, left anterior hemiblock, and nonspecific T-wave abnormalities. Cardiac enzymes are measured at intervals: her troponin T level is less than 0.01 ng/mL at the time of admission but rises to 0.75 ng/mL 3 hours later (normal range 0.0–0.1 ng/mL). Similarly, her creatine kinase-MB level is 3.3 ng/mL at admission but rises to 71.9 ng/mL 3 hours later (normal range 0.0–8.0 ng/mL).

The patient is diagnosed with non-ST-elevation MI. An intravenous heparin drip is started, and she is sent for urgent cardiac catheterization, which shows a total occlusion in a lateral obtuse marginal branch of the left circumflex artery due to a thrombus in the vessel. Otherwise, her coronary arteries are angiographically free of disease. The heparin drip is continued, and treatment is started with abciximab (ReoPro) and tissue plasminogen activator (Alteplase). She is sent to the cardiac intensive care unit for recovery, where she is placed on continuous cardiac monitoring, with no evidence of arrhythmia.

One day later, the left side of her face is drooping, her left arm is weak, and her speech is slurred. Magnetic resonance imaging of the brain shows an acute ischemic infarct in the right temporoparietal area and multiple areas of subacute to chronic ischemia. Magnetic resonance angiography of the brain indicates patent vessels. Both transthoracic and transesophageal echocardiography are performed and indicate normal left ventricular size, ejection fraction of 55%, valves without thrombus or vegetations, aorta with mild atheroma, and no patent foramen ovale by Doppler flow or agitated saline contrast study. Carotid artery Doppler ultrasonography shows 40% to 59% stenosis bilaterally.

ARTERIAL THROMBOSIS

1. Which of the following is a risk factor for arterial thrombosis?

• Atherosclerosis
• Protein C deficiency
• Use of oral contraceptive pills
• The factor V Leiden mutation

Protein C deficiency, the use of oral contraceptives, and the factor V Leiden mutation are typically associated with venous thrombosis¹; they have been documented as a cause of arterial thrombosis only in some case reports. In contrast, atherosclerosis is a well-established risk factor for arterial thrombosis.

Arterial occlusion can be due to thrombosis, embolism, or trauma

The causes of arterial occlusion can be categorized as thrombotic, embolic, or traumatic (Table 1).

Atherosclerosis is a risk factor for thrombosis and can be a source of emboli. Atherosclerotic plaque rupture may release inflammatory mediators, which also predispose to thrombosis.² This patient’s coronary arteries are essentially free of atherosclerotic disease per angiography. However, studies of intravascular ultrasonography have shown that coronary angiography may not detect all atherosclerotic plaques, as angiography can show only the lumen of the artery and not the plaque itself.³ For that reason, atherosclerosis has not been ruled out completely, and further workup is needed to evaluate other possible causes of her thrombotic events.

Embolism is the most likely cause of her stroke, however. Cases of arterial embolism can be classified on the basis of the origin of the thrombus, ie, the heart, an artery, or the venous system via a patent foramen ovale (paradoxical embolism). This patient’s echocardiogram reveals mild aortic atheroma, which can be a source of emboli, especially soon after intervention.

Case continues: Acute and recurrent DVT

While recovering from her MI and stroke, the patient develops edema and pain in both legs. Doppler ultrasonography is performed, which reveals acute DVT in the right gastrocnemius and posterior tibial veins and left soleal vein, despite her continued heparin therapy.

Her platelet count is 189 × 10⁹/L, so heparin-induced thrombocytopenia is not suspected; the new DVT is thought to be due to her hospitalization. Several days later, oral warfarin (Coumadin) is started and titrated to an INR of 2.0 to 3.0, the heparin is phased out, and the patient is sent home.

In the first few months after discharge, the patient presents to the emergency department three times with severe leg pain, and each time she is found to have extensive DVT in various leg veins even though she is complying with her warfarin therapy. At each visit, her INR is in the range of 2.5 to 3.1.

Comment. Her recurrent DVT warrants further evaluation for risk factors for venous thrombosis, which can be divided into hereditary and acquired factors.

Hereditary risk factors include the factor V Leiden mutation, the prothrombin gene mutation, hyperhomocysteinemia, dysfibrinogenemia, and deficiencies of protein C, protein S, and antithrombin.

Acquired risk factors include the antiphospholipid antibody syndrome, cancer, immobilization, surgery, congestive heart failure, pregnancy, use of hormonal contraceptives, hormone replacement therapy, nephrotic syndrome, trauma, and infection.^1,4

TESTING FOR HYPERCOAGULABLE STATES

2. In view of our patient’s recurrent thrombotic episodes, should she be tested for hypercoagulable states?

• Yes
• No

Testing for hypercoagulable conditions is warranted if it will affect the patient’s management or outcome. Some authorities recommend testing patients who are clinically characterized as “strongly” thrombophilic,⁵ ie, those who present with DVT and are younger than age 50, have recurrent thrombotic episodes, have a first-degree relative with documented thromboembolism before age 50, or have thrombotic episodes despite warfarin therapy.

This patient should be tested for hypercoagulable conditions because her initial DVT occurred before age 50 (at age 43), she has had recurrent, apparently idiopathic thrombotic episodes, she has a family history of thromboembolism, and she had clots while on therapeutic warfarin therapy, all of which suggest a hypercoagulable state. Furthermore, the confirmation of her diagnosis may affect her medical management, as it may determine if further testing and therapies are needed.

Case continues: Tests are negative

Laboratory tests for hypercoagulable conditions are performed and are negative for the factor V Leiden mutation, the prothrombin gene mutation, antithrombin deficiency, and protein C and S deficiencies. A screen for antiphospholipid antibodies is indeterminate.

TREATMENT AFFECTS TEST RESULTS

3. If a patient is on warfarin therapy, which test results may be affected?

• Antithrombin levels
• Protein C and S levels
• Factor V Leiden mutation

Warfarin decreases the levels of proteins C and S; therefore, the levels of these substances cannot be accurately interpreted in a patient taking warfarin.

All anticoagulants prolong the clotting time and may affect the results of assays based on the clotting time, such as the prothrombin time, the partial thromboplastin time, the dilute Russell’s viper venom time (DRVVT), the hexagonal phase phospholipid neutralization assay, the thrombin time, and clottable protein C and protein S. Heparin reduces the level of antithrombin; however, laboratories now have heparin-binding agents that reduce the effect of heparin in clotting studies.

Acute thrombotic states lower the levels of antithrombin and proteins C and S.

Assays not based on the clotting time (immunogenic or genetic tests such as those for anticardiolipin antibodies and the factor V Leiden and prothrombin gene mutations) are not affected by anticoagulant use.⁵

However, the presence or absence of a hypercoagulable state should not affect the treatment of acute DVT, and a full 6- to 12-month course of anticoagulation should be completed.^6,7 If possible, lupus anticoagulant testing should be repeated 2 weeks after anticoagulation is stopped.⁸

This patient needs lifelong anticoagulation because of her repeated thrombotic episodes. Stopping the medication for 2 weeks for testing would increase the risk of rethrombosis in this patient, and most experts would not advise it.

In summary, testing for hypercoagulable conditions is not recommended during an acute thrombotic episode and is preferably performed while the patient is not on anticoagulation therapy. If the patient is already on anticoagulation, the results of tests for hypercoagulable conditions should be interpreted with caution.

Case continues: Another stroke

During the subsequent year, the patient’s primary care physician monitors her warfarin use and sends her for age-appropriate cancer screening, including a breast examination, Papanicolaou smear, and mammography. Also, given her history of smoking, a chest radiograph is ordered. All of these studies are normal. In addition, evaluations for hematologic disorders such as myelodysplastic syndrome, polycythemia vera, and Waldenström macroglobulinema reveal normal complete blood counts and normal results on serum and urine protein electrophoresis.

Later that year, she returns to the emergency department with complete aphasia and total right-sided paralysis. Magnetic resonance imaging shows an acute infarct in the left frontal operculum, a subacute infarct in the right cerebellum, and multiple chronic cortical and subcortical infarcts throughout the brain. Ultrasonography shows an extensive new DVT in her right leg. Her INR at this time is 3.1.

WHAT CONDITIONS CAUSE BOTH ARTERIAL AND VENOUS THROMBOSIS?

4. Given that the patient has evidence of both recurrent arterial and venous thromboses, which of the following conditions is likely?

• Antiphospholipid antibody syndrome
• Heparin-induced thrombocytopenia
• Malignancy
• All of the above

Conditions associated with both arterial and venous thrombosis include antiphospholipid antibody syndrome, heparin-induced thrombocytopenia, malignancy, paradoxical embolism, hyperhomocysteinemia, myeloproliferative disorders, myelodysplastic disorder, paraproteinemia, vasculitis, and paroxysmal nocturnal hemoglobinuria.^1,4

At present, the exact mechanism that causes Trousseau syndrome is unknown. Some hypotheses implicate mucin (produced by the cancer),¹⁰ tissue factor,¹¹ tumor-associated cysteine proteinase,¹² tumor hypoxia,¹³ and oncogene activation as plausible triggers for this syndrome.

DOES SHE HAVE ANTIPHOSPHOLIPID ANTIBODY SYNDROME?

5. The patient is positive for lupus anticoagulant. Does she have antiphospholipid antibody syndrome?

• Yes
• No
• Repeat testing is needed to meet the diagnostic criteria

The Sapporo criteria¹⁵ indicate that antiphospholipid antibody syndrome is present if at least one clinical criterion and one laboratory criterion are met. The clinical criteria are one or more episodes of arterial or venous thrombosis or pregnancy-related morbidity, ie:

• Unexplained intrauterine fetal death at 10 weeks gestation or later with no apparent fetal abnormality
• Premature births of a morphologically normal fetus at less than 34 weeks of gestation due to preeclampsia, eclampsia, or placental insufficiency
• Three or more spontaneous abortions at 10 weeks of gestation or earlier, with no known paternal chromosomal abnormalities or maternal hormonal abnormalities and normal maternal anatomy.

The laboratory criteria are:

• Lupus anticoagulant present
• Anticardiolipin antibody (IgG or IgM) titer greater than 40 IgG antiphospholipid units (GPL) or IgM antiphospholipid units (MPL) or higher than the 99th percentile of the testing laboratory normal reference range
• Anti-beta-2 glycoprotein-I antibody (IgG or IgM) titer greater than 20 GPL or MPL or higher than the 99th percentile of the testing laboratory normal reference range.

The patient likely has antiphospholipid antibody syndrome because her lupus anticoagulant screen is positive and she meets the clinical criteria of thrombosis, and she should continue to be treated accordingly. However, to officially meet the revised Sapporo criteria, she would need to have laboratory tests that are positive on two or more occasions at least 12 weeks apart.

Case continues: Lung cancer is found

The patient reports that she has lost 10 pounds in 4 months. Since age-appropriate cancer testing was previously performed, a more extensive evaluation for weight loss is undertaken, with computed tomography of the chest, abdomen, and pelvis. These tests reveal a nodule in the right upper lobe of the lung, scarring in the right middle and left lower lung lobes, and hilar lymphadenopathy. Bronchoscopy with transbronchial biopsy confirms that she has adenocarcinoma of the lung.

6. What is suggested as a sufficient workup for malignancy in patients with idiopathic venous thromboembolism?

• Computed tomography of the chest, abdomen, and pelvis for every patient with idiopathic venous thromboembolism
• Positron emission tomography and tumor marker levels
• A comprehensive history and physical examination, routine laboratory tests, chest radiography, age- and sex-specific cancer screening, and patient-specific testing as indicated clinically

To date, there is no evidence to support a cancer evaluation beyond a comprehensive medical history and physical examination, routine laboratory testing, chest radiography, and age- and sex-specific cancer screening unless it is dictated by the patient’s clinical presentation. A study by Cornuz et al¹⁶ suggested that this approach is appropriate for detecting cancer in patients with idiopathic venous thromboembolism.

A 2004 study¹⁷ attempted to answer the question of what to do about patients who have idiopathic venous thromboembolism but no other signs or symptoms that raise any clinical suspicion of cancer. This study randomized patients with idiopathic venous thromboembolism to undergo either routine medical management or an extensive malignancy evaluation. The evaluation included ultrasonography of the abdomen and pelvis, computed tomography of the abdomen and pelvis, gastroscopy or a double-contrast barium swallow study, colonoscopy or sigmoidoscopy followed by a barium enema, stool occult blood testing, and sputum cytology. Women were also tested for the tumor markers carcinoembryonic antigen, alpha-fetoprotein, and CA-125, and they underwent mammography and Papanicolaou testing; men were tested for prostate-specific antigen and underwent ultrasonography of the prostate. The results of the study did not reveal a statistically significant survival benefit in the group that underwent extensive cancer evaluation.

These studies indicate that the decision to test for cancer should be guided by clinical suspicion. Our patient lost 10 pounds in 4 months, smokes, and has had recurrent venous thromboembolism, so testing was appropriate.

After her diagnosis with adenocarcinoma of the lung, the patient has yet another DVT despite an INR of 3.1 and treatment with warfarin and aspirin.

LOW-MOLECULAR-WEIGHT HEPARIN FOR PATIENTS WITH CANCER?

7. True or false? Low-molecular-weight heparin is more effective than warfarin in preventing DVT in cancer patients without increasing the bleeding risk.

• True
• False

This statement is true. The American College of Chest Physicians (ACCP) recommends immediate treatment of DVT with low-molecular-weight heparin for 6 to 12 months after a thrombotic event in a patient with malignancy.^6,18

Two major studies provide evidence for these recommendations: the Comparison of Low-Molecular-Weight Heparin Versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients With Cancer (CLOT)¹⁹ and the Trial of the Effect of Low-Molecular-Weight Heparin Versus Warfarin on Mortality in the Long-Term Treatment of Proximal Deep Vein Thrombosis (LITE)²⁰ studies.

The CLOT¹⁹ study showed that dalteparin (Fragmin) 200 IU/kg subcutaneously once daily for l month and then 150 IU/kg once daily was more effective than oral warfarin titrated to an INR of 2.5 and did not increase the risk of bleeding.

The LITE trial²⁰ showed the efficacy of tinzaparin (Innohep) 175 IU/kg subcutaneously daily, which can be used as an alternative.

Enoxaparin sodium (Lovenox) 1.5 mg/kg once daily has also been used. However, if low-molecular-weight heparin is not available, warfarin titrated to an INR of 2 to 3 is also acceptable.¹⁸

The ACCP consensus panel recommends giving anticoagulation for an initial 6 to 12 months and continuing it as long as there is evidence of active malignancy.⁶ The American Society for Clinical Oncology also recommends placement of an inferior vena cava filter for patients who have contraindications to anticoagulation or for whom low-molecular-weight heparin fails.¹⁸

Case continues: Summing up

In conclusion, our patient had an underlying malignancy, causing Trousseau syndrome. Before her cancer was diagnosed, she also had test results that suggested antiphospholipid antibody syndrome. Both of these conditions likely contributed to her hypercoagulable state, increasing her propensity for clotting and causing her recurrent thrombosis. The patient is currently on low-molecular-weight heparin and is undergoing palliative chemotherapy for metastatic adenocarcinoma of the lung. To this date, she has not had any new thrombotic events.

TAKE-HOME POINTS

• Risk factors for arterial occlusion can be divided into thrombotic, embolic, and traumatic categories.
• Risk factors for venous thrombosis can be divided into hereditary and acquired categories.
• Evaluation for hypercoagulable conditions is recommended if it will affect patient management or outcome. Patients to be considered for testing include those with idiopathic DVT and who are under age 50, those with a history of recurrent thrombosis, and those with a first-degree relative with documented venous thromboembolism before age 50.
• Evaluation for hypercoagulable conditions should ideally be performed either before starting anticoagulation therapy or 2 weeks after completing it.
• Potential causes of both arterial and venous thrombosis include antiphospholipid antibody syndrome, cancer, hyperhomocysteinemia, heparin-induced thrombocytopenia, paradoxical emboli, myeloproliferative disorders, myelodysplastic syndrome, paraproteinemia, vasculitis, and paroxysmal nocturnal hemoglobinuria.
• Current evidence does not support an extensive cancer evaluation in patients with idiopathic venous thromboembolism, unless dictated by the patient’s clinical condition.
• In patients with venous thromboembolism and active malignancy, anticoagulation is recommended for at least 6 to 12 months and as long as there is evidence of active malignancy.

An 82-year-old man presented to his primary care provider complaining of headaches for the past week. At the time of presentation, he reported persistent, nonthrobbing pain behind his right eye. Previously, he had experienced pain on the top and right side of his head.

The patient denied any recent visual changes. His last eye examination had taken place four weeks earlier. He was prescribed new eyeglasses, but he had not yet filled the prescription. He denied having symptoms of transient ischemic attack or stroke. He denied any nasal drainage, fever, or chills and reported no prior history of headaches. For the current headache, he had been taking acetaminophen intermittently and said it provided some relief.

The patient’s prior diagnoses included type 2 diabetes, hypertension, dyslipidemia, gout, metabolic syndrome, osteoarthritis, leg edema, and atrial fibrillation. His current medications were allopurinol, diltiazem, glipizide, hydrochlorothiazide, rosiglitazone, valsartan, vardenafil, and warfarin.

His most recent international normalized ratio (INR), measured five days earlier, was 3.34. Fifteen days earlier, however, his INR had been measured at 4.6.

The patient described himself as active, riding his bicycle 50 miles each week. He denied using tobacco but admitted to having “a couple of cocktails” before dinner each evening. He was a widower who lived alone. He owned an advertising company and was involved in its day-to-day operation.

On examination, the patient was alert and oriented. He had an irregularly irregular heart rate with a controlled ventricular response. Cranial nerves II through XII were intact. No papilledema was noted.

The patient was given a diagnosis of headaches of unknown etiology. He was told that he could continue using acetaminophen and was scheduled for head CT with and without contrast the following day.

CT revealed a 2.3-cm, right-sided subacute (mixed-density) subdural hematoma (SDH) with midline shift of 1.8 cm (see Figure 1). The patient’s provider was notified of the CT results, and the patient was sent directly from radiology to the emergency department. His INR was 2.7. The patient was given a partial dose of recombinant factor VIIa (rFVIIa), then emergently transferred to another facility for neurosurgical care.

Upon his arrival there, the patient was noted to be drowsy but oriented, without any focal neurologic deficits. The dose of rFVIIa was completed, and he was given 5 mg of vitamin K. He underwent an emergency craniotomy for clot evacuation. Intraoperatively, his INR was measured at 1.5, and he was given two units of fresh frozen plasma (FFP) to further reverse his coagulopathy.

Repeat head CT the following morning revealed nearly complete removal of the clot, with reexpansion of the brain (see Figure 2). The patient’s INR was 1.1. Additional doses of FFP or rFVIIa were deemed unnecessary. The patient recovered and was discharged from the hospital four days after his surgery. When he was seen at the clinic one month later, he had no neurologic deficits. Head CT was found stable with only a thin rim of residual subdural fluid noted (see Figure 3). He was followed as an outpatient with serial head CTs until all the subdural fluid completely resolved. At that time, he was allowed to restart warfarin.

Discussion
Use of anticoagulation therapy will become increasingly common as our population ages. While anticoagulants are important for preventing thromboembolic events that may result from use of mechanical heart valves, atrial fibrillation, and other conditions, their use is not without risk. The most significant and potentially lethal complication is hemorrhage.

Warfarin-Associated Hemorrhage
In patients who take warfarin, hemorrhage can occur in a variety of areas—most commonly, cerebral and gastrointestinal sites, the nose, the airways, the urinary tract, muscle, and skin.^1,2 The site of hemorrhage that carries the highest risk of mortality and morbidity is cerebral.^3-5 Among anticoagulated patients experiencing intracranial hemorrhage, a fourfold to fivefold increase in mortality has been reported.⁶ Among study patients who experienced intracranial hemorrhages while taking warfarin, only 14% were able to return to living independently.⁴

Excessive Anticoagulation
Recent studies have led to the conclusion that excessive anticoagulation, not anticoagulation targeting specific therapeutic levels, is associated with major bleeding events.^7,8 In a review of 2,460 patients from 2000 to 2003 at Brigham and Women’s Hospital in Boston, Fanikos et al⁸ found that 83% of major bleeding events occurred in patients with an INR exceeding 3.0.

In addition, excessive anticoagulation has been associated with increased morbidity and mortality.^5,9,10 Pieracci et al⁹ found that among patients who experienced a traumatic intracranial hemorrhage with an INR exceeding 3.5, the mortality rate was nearly 75%.

Intracranial Hemorrhage
Subdural hematoma is one of the most common types of intracranial hemorrhage. SDHs are classified based on radiographic findings and age. Acute SDHs are those less than three days old, subacute (mixed-density) SDHs are three to 20 days old, and chronic SDHs (CSDHs) are at least 21 days old.

Acute hemorrhages are more dense and appear white on CT, whereas CSDHs are hypodense and appear darker than the brain parenchyma. Subacute SDHs may have features of both acute SDHs and CSDHs or may appear isodense. While acute SDHs are often associated with trauma and are readily diagnosed, chronic and subacute SDHs present a greater diagnostic challenge. Clinically, subacute SDHs act like CSDHs and are treated similarly.¹¹ For the purposes of this discussion, the case patient’s SDH will be considered a form of CSDH.

Pathophysiology of Chronic Subdural Hematomas
Chronic subdural hematomas form in a number of ways. Major causes are related to brain atrophy resulting from advanced age, alcoholism, brain injury, stroke, or other conditions.¹¹ Atrophy of the brain causes the size of the subdural space to increase. This increased space causes the bridging veins between the cortical surface of the brain and the dura to become stretched and easily torn. As a result, seemingly minor trauma can easily lead to hemorrhage.

Over time, these small, acute hemorrhages in the subdural space may liquefy into CSDHs. Bleeding triggers an inflammatory response, and gradually, blood begins to break down, as with any bruise. Unlike most blood clots, however, blood in the subdural space is affected by fluid dynamics, fibrinolysis, and the formation of neomembranes.^11,12 As a result, the blood may not be completely reabsorbed and may actually expand, causing patients to experience symptoms.

Potentially, SDHs can also be caused by subdural hygromas, low intracranial pressure, dehydration, or overdrainage of cerebrospinal fluid during lumbar puncture, spinal anesthesia, or shunting.¹³

Epidemiology
The annual incidence of CSDH is one to two cases per 100,000 persons. Incidence increases to seven cases per 100,000 among persons older than 70.¹³ The mortality rate for SDH is 31% to 36%.^14,15 The mortality rate for CSDH is approximately 6%. For patients older than 60, the rate increases to 8.8%.¹⁶ Rates of morbidity (ie, severe disability or persistent vegetative state) associated with CSDHs have been reported at about 10%.^16,17

Men are affected more commonly than are women (accounting for 61% to 70% of cases), and median ages between 71 and 78 have been reported.^4,12,18,19

The risk factors for CSDH are listed in Table 1.^4,10 SDHs frequently occur in the context of trauma, but they can occur spontaneously, especially in coagulopathic patients. Among patients with CSDHs who are taking warfarin, 45.5% to 52% deny recent experiences of trauma.^4,14

Signs and Symptoms of Chronic Subdural Hematomas
The clinical onset of CSDH is insidious. Possible presenting symptoms are listed in Table 2.^14,18,20,21 Frequently, the neurologic examination fails to reveal any focal deficits. Many of the symptoms are vague and nonspecific and may mimic those of other conditions that are common in the elderly, thus making diagnosis difficult. Despite clinical suspicion, the definitive diagnosis of SDH is based on CT results.

Reversing Warfarin-Induced Coagulopathy
In all patients with intracranial hemorrhages who are taking warfarin, the coagulopathy must be reversed. The agents commonly used to reverse the effects of warfarin include vitamin K, FFP, and rFVIIa.^9,22-24 The choice of agents depends on the timing of intervention.

Vitamin K is commonly given to patients either intravenously or orally in combination with FFP and/or rFVIIa to promote the reversal of warfarin-induced coagulopathy. Vitamin K is seldom used alone, as its effects may not be seen for 24 hours or longer, and may not completely reverse the effects of warfarin.²⁵

Another frequently used product is FFP. Unfortunately, FFP has been associated with complications such as fluid overload, infectious disease transmission, and anaphylaxis. Additionally, FFP too reverses coagulopathy very slowly. Boulis et al²⁶ found that in patients given FFP with single-dose vitamin K, INR reduction averaged 0.18/hour. At this rate, it would take approximately 11 hours to correct an INR of 3.0 to the desired target of 1.0.

In contrast, rFVIIa, used off-label, has proved highly effective in rapidly reversing coagulopathy and allowing patients to safely undergo immediate surgical treatment.^23,24 To its disadvantage, rFVIIa increases the risk of thromboembolism and is significantly more expensive than FFP. Compared with $105 for one unit of FFP, the cost of an 80-mcg/kg dose of rFVIIa for a patient weighing 80 kg is about $6,400.²⁷

Factors Predicting Outcome for Subdural Hematomas
A number of factors determine post-SDH outcome. Rozzelle et al¹⁴ found that a Glasgow Coma Scale score below 7, age greater than 80, more acute hemorrhages, and hemorrhages requiring craniotomy rather than burr-hole drainage were associated with significantly higher mortality rates than when these factors were absent.

Other studies have revealed that patients with poor clinical status and larger hematomas with more midline shift are also prone to higher mortality rates.^20,28 Merlicco et al²⁹ found that younger, nonalcoholic patients without severe trauma whose hematomas were under high pressure had better chances for full recovery than other patients.

Patient Outcome
This case study illustrates the importance of patient education. The patient described here was aware of his excessive anticoagulation and told his provider that he was concerned about bleeding in the brain. Because the patient had been educated about the potential risks of warfarin therapy, he was able to alert his provider when he experienced symptoms of a possible complication. As a result, his condition was quickly diagnosed and treated, with an excellent outcome.

Conclusion
Intracranial hemorrhage is a serious and potentially life-threatening complication of warfarin therapy. CSDHs in particular are a significant cause of mortality and morbidity in older patients. The risk of death or disability increases in patients who are undergoing anticoagulation therapy. In addition, patients with an INR elevated above therapeutic levels face a significantly higher risk for major bleeding events. For this reason, it is important that anticoagulation be tightly controlled within the therapeutic range. It is equally important to educate patients and their families about anticoagulation’s potential risks and complications.

Making the diagnosis of CSDH can be difficult because its symptoms are so often nonspecific and a concomitant illness may be present. Thus, providers must maintain a low threshold for evaluating even minor patient complaints that may signal a complication of warfarin therapy. All too often, minor signs and symptoms go unrecognized, sometimes leading to devastating consequences.

Although many factors predict outcomes for CSDHs, the most important can be controlled by patients and their providers. If patients are well educated and providers listen to their patients, then early diagnosis of SDH can lead to early intervention and improved outcomes.    

An 82-year-old man presented to his primary care provider complaining of headaches for the past week. At the time of presentation, he reported persistent, nonthrobbing pain behind his right eye. Previously, he had experienced pain on the top and right side of his head.

The patient denied any recent visual changes. His last eye examination had taken place four weeks earlier. He was prescribed new eyeglasses, but he had not yet filled the prescription. He denied having symptoms of transient ischemic attack or stroke. He denied any nasal drainage, fever, or chills and reported no prior history of headaches. For the current headache, he had been taking acetaminophen intermittently and said it provided some relief.

The patient’s prior diagnoses included type 2 diabetes, hypertension, dyslipidemia, gout, metabolic syndrome, osteoarthritis, leg edema, and atrial fibrillation. His current medications were allopurinol, diltiazem, glipizide, hydrochlorothiazide, rosiglitazone, valsartan, vardenafil, and warfarin.

His most recent international normalized ratio (INR), measured five days earlier, was 3.34. Fifteen days earlier, however, his INR had been measured at 4.6.

The patient described himself as active, riding his bicycle 50 miles each week. He denied using tobacco but admitted to having “a couple of cocktails” before dinner each evening. He was a widower who lived alone. He owned an advertising company and was involved in its day-to-day operation.

On examination, the patient was alert and oriented. He had an irregularly irregular heart rate with a controlled ventricular response. Cranial nerves II through XII were intact. No papilledema was noted.

The patient was given a diagnosis of headaches of unknown etiology. He was told that he could continue using acetaminophen and was scheduled for head CT with and without contrast the following day.

CT revealed a 2.3-cm, right-sided subacute (mixed-density) subdural hematoma (SDH) with midline shift of 1.8 cm (see Figure 1). The patient’s provider was notified of the CT results, and the patient was sent directly from radiology to the emergency department. His INR was 2.7. The patient was given a partial dose of recombinant factor VIIa (rFVIIa), then emergently transferred to another facility for neurosurgical care.

Upon his arrival there, the patient was noted to be drowsy but oriented, without any focal neurologic deficits. The dose of rFVIIa was completed, and he was given 5 mg of vitamin K. He underwent an emergency craniotomy for clot evacuation. Intraoperatively, his INR was measured at 1.5, and he was given two units of fresh frozen plasma (FFP) to further reverse his coagulopathy.

Repeat head CT the following morning revealed nearly complete removal of the clot, with reexpansion of the brain (see Figure 2). The patient’s INR was 1.1. Additional doses of FFP or rFVIIa were deemed unnecessary. The patient recovered and was discharged from the hospital four days after his surgery. When he was seen at the clinic one month later, he had no neurologic deficits. Head CT was found stable with only a thin rim of residual subdural fluid noted (see Figure 3). He was followed as an outpatient with serial head CTs until all the subdural fluid completely resolved. At that time, he was allowed to restart warfarin.

Discussion
Use of anticoagulation therapy will become increasingly common as our population ages. While anticoagulants are important for preventing thromboembolic events that may result from use of mechanical heart valves, atrial fibrillation, and other conditions, their use is not without risk. The most significant and potentially lethal complication is hemorrhage.

Warfarin-Associated Hemorrhage
In patients who take warfarin, hemorrhage can occur in a variety of areas—most commonly, cerebral and gastrointestinal sites, the nose, the airways, the urinary tract, muscle, and skin.^1,2 The site of hemorrhage that carries the highest risk of mortality and morbidity is cerebral.^3-5 Among anticoagulated patients experiencing intracranial hemorrhage, a fourfold to fivefold increase in mortality has been reported.⁶ Among study patients who experienced intracranial hemorrhages while taking warfarin, only 14% were able to return to living independently.⁴

Excessive Anticoagulation
Recent studies have led to the conclusion that excessive anticoagulation, not anticoagulation targeting specific therapeutic levels, is associated with major bleeding events.^7,8 In a review of 2,460 patients from 2000 to 2003 at Brigham and Women’s Hospital in Boston, Fanikos et al⁸ found that 83% of major bleeding events occurred in patients with an INR exceeding 3.0.

In addition, excessive anticoagulation has been associated with increased morbidity and mortality.^5,9,10 Pieracci et al⁹ found that among patients who experienced a traumatic intracranial hemorrhage with an INR exceeding 3.5, the mortality rate was nearly 75%.

Intracranial Hemorrhage
Subdural hematoma is one of the most common types of intracranial hemorrhage. SDHs are classified based on radiographic findings and age. Acute SDHs are those less than three days old, subacute (mixed-density) SDHs are three to 20 days old, and chronic SDHs (CSDHs) are at least 21 days old.

Acute hemorrhages are more dense and appear white on CT, whereas CSDHs are hypodense and appear darker than the brain parenchyma. Subacute SDHs may have features of both acute SDHs and CSDHs or may appear isodense. While acute SDHs are often associated with trauma and are readily diagnosed, chronic and subacute SDHs present a greater diagnostic challenge. Clinically, subacute SDHs act like CSDHs and are treated similarly.¹¹ For the purposes of this discussion, the case patient’s SDH will be considered a form of CSDH.

Pathophysiology of Chronic Subdural Hematomas
Chronic subdural hematomas form in a number of ways. Major causes are related to brain atrophy resulting from advanced age, alcoholism, brain injury, stroke, or other conditions.¹¹ Atrophy of the brain causes the size of the subdural space to increase. This increased space causes the bridging veins between the cortical surface of the brain and the dura to become stretched and easily torn. As a result, seemingly minor trauma can easily lead to hemorrhage.

Over time, these small, acute hemorrhages in the subdural space may liquefy into CSDHs. Bleeding triggers an inflammatory response, and gradually, blood begins to break down, as with any bruise. Unlike most blood clots, however, blood in the subdural space is affected by fluid dynamics, fibrinolysis, and the formation of neomembranes.^11,12 As a result, the blood may not be completely reabsorbed and may actually expand, causing patients to experience symptoms.

Potentially, SDHs can also be caused by subdural hygromas, low intracranial pressure, dehydration, or overdrainage of cerebrospinal fluid during lumbar puncture, spinal anesthesia, or shunting.¹³

Epidemiology
The annual incidence of CSDH is one to two cases per 100,000 persons. Incidence increases to seven cases per 100,000 among persons older than 70.¹³ The mortality rate for SDH is 31% to 36%.^14,15 The mortality rate for CSDH is approximately 6%. For patients older than 60, the rate increases to 8.8%.¹⁶ Rates of morbidity (ie, severe disability or persistent vegetative state) associated with CSDHs have been reported at about 10%.^16,17

Men are affected more commonly than are women (accounting for 61% to 70% of cases), and median ages between 71 and 78 have been reported.^4,12,18,19

The risk factors for CSDH are listed in Table 1.^4,10 SDHs frequently occur in the context of trauma, but they can occur spontaneously, especially in coagulopathic patients. Among patients with CSDHs who are taking warfarin, 45.5% to 52% deny recent experiences of trauma.^4,14

Signs and Symptoms of Chronic Subdural Hematomas
The clinical onset of CSDH is insidious. Possible presenting symptoms are listed in Table 2.^14,18,20,21 Frequently, the neurologic examination fails to reveal any focal deficits. Many of the symptoms are vague and nonspecific and may mimic those of other conditions that are common in the elderly, thus making diagnosis difficult. Despite clinical suspicion, the definitive diagnosis of SDH is based on CT results.

Reversing Warfarin-Induced Coagulopathy
In all patients with intracranial hemorrhages who are taking warfarin, the coagulopathy must be reversed. The agents commonly used to reverse the effects of warfarin include vitamin K, FFP, and rFVIIa.^9,22-24 The choice of agents depends on the timing of intervention.

Vitamin K is commonly given to patients either intravenously or orally in combination with FFP and/or rFVIIa to promote the reversal of warfarin-induced coagulopathy. Vitamin K is seldom used alone, as its effects may not be seen for 24 hours or longer, and may not completely reverse the effects of warfarin.²⁵

Another frequently used product is FFP. Unfortunately, FFP has been associated with complications such as fluid overload, infectious disease transmission, and anaphylaxis. Additionally, FFP too reverses coagulopathy very slowly. Boulis et al²⁶ found that in patients given FFP with single-dose vitamin K, INR reduction averaged 0.18/hour. At this rate, it would take approximately 11 hours to correct an INR of 3.0 to the desired target of 1.0.

In contrast, rFVIIa, used off-label, has proved highly effective in rapidly reversing coagulopathy and allowing patients to safely undergo immediate surgical treatment.^23,24 To its disadvantage, rFVIIa increases the risk of thromboembolism and is significantly more expensive than FFP. Compared with $105 for one unit of FFP, the cost of an 80-mcg/kg dose of rFVIIa for a patient weighing 80 kg is about $6,400.²⁷

Factors Predicting Outcome for Subdural Hematomas
A number of factors determine post-SDH outcome. Rozzelle et al¹⁴ found that a Glasgow Coma Scale score below 7, age greater than 80, more acute hemorrhages, and hemorrhages requiring craniotomy rather than burr-hole drainage were associated with significantly higher mortality rates than when these factors were absent.

Other studies have revealed that patients with poor clinical status and larger hematomas with more midline shift are also prone to higher mortality rates.^20,28 Merlicco et al²⁹ found that younger, nonalcoholic patients without severe trauma whose hematomas were under high pressure had better chances for full recovery than other patients.

Patient Outcome
This case study illustrates the importance of patient education. The patient described here was aware of his excessive anticoagulation and told his provider that he was concerned about bleeding in the brain. Because the patient had been educated about the potential risks of warfarin therapy, he was able to alert his provider when he experienced symptoms of a possible complication. As a result, his condition was quickly diagnosed and treated, with an excellent outcome.

Conclusion
Intracranial hemorrhage is a serious and potentially life-threatening complication of warfarin therapy. CSDHs in particular are a significant cause of mortality and morbidity in older patients. The risk of death or disability increases in patients who are undergoing anticoagulation therapy. In addition, patients with an INR elevated above therapeutic levels face a significantly higher risk for major bleeding events. For this reason, it is important that anticoagulation be tightly controlled within the therapeutic range. It is equally important to educate patients and their families about anticoagulation’s potential risks and complications.

Making the diagnosis of CSDH can be difficult because its symptoms are so often nonspecific and a concomitant illness may be present. Thus, providers must maintain a low threshold for evaluating even minor patient complaints that may signal a complication of warfarin therapy. All too often, minor signs and symptoms go unrecognized, sometimes leading to devastating consequences.

Although many factors predict outcomes for CSDHs, the most important can be controlled by patients and their providers. If patients are well educated and providers listen to their patients, then early diagnosis of SDH can lead to early intervention and improved outcomes.    

An 82-year-old man presented to his primary care provider complaining of headaches for the past week. At the time of presentation, he reported persistent, nonthrobbing pain behind his right eye. Previously, he had experienced pain on the top and right side of his head.

The patient denied any recent visual changes. His last eye examination had taken place four weeks earlier. He was prescribed new eyeglasses, but he had not yet filled the prescription. He denied having symptoms of transient ischemic attack or stroke. He denied any nasal drainage, fever, or chills and reported no prior history of headaches. For the current headache, he had been taking acetaminophen intermittently and said it provided some relief.

The patient’s prior diagnoses included type 2 diabetes, hypertension, dyslipidemia, gout, metabolic syndrome, osteoarthritis, leg edema, and atrial fibrillation. His current medications were allopurinol, diltiazem, glipizide, hydrochlorothiazide, rosiglitazone, valsartan, vardenafil, and warfarin.

His most recent international normalized ratio (INR), measured five days earlier, was 3.34. Fifteen days earlier, however, his INR had been measured at 4.6.

The patient described himself as active, riding his bicycle 50 miles each week. He denied using tobacco but admitted to having “a couple of cocktails” before dinner each evening. He was a widower who lived alone. He owned an advertising company and was involved in its day-to-day operation.

On examination, the patient was alert and oriented. He had an irregularly irregular heart rate with a controlled ventricular response. Cranial nerves II through XII were intact. No papilledema was noted.

The patient was given a diagnosis of headaches of unknown etiology. He was told that he could continue using acetaminophen and was scheduled for head CT with and without contrast the following day.

CT revealed a 2.3-cm, right-sided subacute (mixed-density) subdural hematoma (SDH) with midline shift of 1.8 cm (see Figure 1). The patient’s provider was notified of the CT results, and the patient was sent directly from radiology to the emergency department. His INR was 2.7. The patient was given a partial dose of recombinant factor VIIa (rFVIIa), then emergently transferred to another facility for neurosurgical care.

Upon his arrival there, the patient was noted to be drowsy but oriented, without any focal neurologic deficits. The dose of rFVIIa was completed, and he was given 5 mg of vitamin K. He underwent an emergency craniotomy for clot evacuation. Intraoperatively, his INR was measured at 1.5, and he was given two units of fresh frozen plasma (FFP) to further reverse his coagulopathy.

Repeat head CT the following morning revealed nearly complete removal of the clot, with reexpansion of the brain (see Figure 2). The patient’s INR was 1.1. Additional doses of FFP or rFVIIa were deemed unnecessary. The patient recovered and was discharged from the hospital four days after his surgery. When he was seen at the clinic one month later, he had no neurologic deficits. Head CT was found stable with only a thin rim of residual subdural fluid noted (see Figure 3). He was followed as an outpatient with serial head CTs until all the subdural fluid completely resolved. At that time, he was allowed to restart warfarin.

Discussion
Use of anticoagulation therapy will become increasingly common as our population ages. While anticoagulants are important for preventing thromboembolic events that may result from use of mechanical heart valves, atrial fibrillation, and other conditions, their use is not without risk. The most significant and potentially lethal complication is hemorrhage.

Warfarin-Associated Hemorrhage
In patients who take warfarin, hemorrhage can occur in a variety of areas—most commonly, cerebral and gastrointestinal sites, the nose, the airways, the urinary tract, muscle, and skin.^1,2 The site of hemorrhage that carries the highest risk of mortality and morbidity is cerebral.^3-5 Among anticoagulated patients experiencing intracranial hemorrhage, a fourfold to fivefold increase in mortality has been reported.⁶ Among study patients who experienced intracranial hemorrhages while taking warfarin, only 14% were able to return to living independently.⁴

Excessive Anticoagulation
Recent studies have led to the conclusion that excessive anticoagulation, not anticoagulation targeting specific therapeutic levels, is associated with major bleeding events.^7,8 In a review of 2,460 patients from 2000 to 2003 at Brigham and Women’s Hospital in Boston, Fanikos et al⁸ found that 83% of major bleeding events occurred in patients with an INR exceeding 3.0.

In addition, excessive anticoagulation has been associated with increased morbidity and mortality.^5,9,10 Pieracci et al⁹ found that among patients who experienced a traumatic intracranial hemorrhage with an INR exceeding 3.5, the mortality rate was nearly 75%.

Intracranial Hemorrhage
Subdural hematoma is one of the most common types of intracranial hemorrhage. SDHs are classified based on radiographic findings and age. Acute SDHs are those less than three days old, subacute (mixed-density) SDHs are three to 20 days old, and chronic SDHs (CSDHs) are at least 21 days old.

Acute hemorrhages are more dense and appear white on CT, whereas CSDHs are hypodense and appear darker than the brain parenchyma. Subacute SDHs may have features of both acute SDHs and CSDHs or may appear isodense. While acute SDHs are often associated with trauma and are readily diagnosed, chronic and subacute SDHs present a greater diagnostic challenge. Clinically, subacute SDHs act like CSDHs and are treated similarly.¹¹ For the purposes of this discussion, the case patient’s SDH will be considered a form of CSDH.

Pathophysiology of Chronic Subdural Hematomas
Chronic subdural hematomas form in a number of ways. Major causes are related to brain atrophy resulting from advanced age, alcoholism, brain injury, stroke, or other conditions.¹¹ Atrophy of the brain causes the size of the subdural space to increase. This increased space causes the bridging veins between the cortical surface of the brain and the dura to become stretched and easily torn. As a result, seemingly minor trauma can easily lead to hemorrhage.

Over time, these small, acute hemorrhages in the subdural space may liquefy into CSDHs. Bleeding triggers an inflammatory response, and gradually, blood begins to break down, as with any bruise. Unlike most blood clots, however, blood in the subdural space is affected by fluid dynamics, fibrinolysis, and the formation of neomembranes.^11,12 As a result, the blood may not be completely reabsorbed and may actually expand, causing patients to experience symptoms.

Potentially, SDHs can also be caused by subdural hygromas, low intracranial pressure, dehydration, or overdrainage of cerebrospinal fluid during lumbar puncture, spinal anesthesia, or shunting.¹³

Epidemiology
The annual incidence of CSDH is one to two cases per 100,000 persons. Incidence increases to seven cases per 100,000 among persons older than 70.¹³ The mortality rate for SDH is 31% to 36%.^14,15 The mortality rate for CSDH is approximately 6%. For patients older than 60, the rate increases to 8.8%.¹⁶ Rates of morbidity (ie, severe disability or persistent vegetative state) associated with CSDHs have been reported at about 10%.^16,17

Men are affected more commonly than are women (accounting for 61% to 70% of cases), and median ages between 71 and 78 have been reported.^4,12,18,19

The risk factors for CSDH are listed in Table 1.^4,10 SDHs frequently occur in the context of trauma, but they can occur spontaneously, especially in coagulopathic patients. Among patients with CSDHs who are taking warfarin, 45.5% to 52% deny recent experiences of trauma.^4,14

Signs and Symptoms of Chronic Subdural Hematomas
The clinical onset of CSDH is insidious. Possible presenting symptoms are listed in Table 2.^14,18,20,21 Frequently, the neurologic examination fails to reveal any focal deficits. Many of the symptoms are vague and nonspecific and may mimic those of other conditions that are common in the elderly, thus making diagnosis difficult. Despite clinical suspicion, the definitive diagnosis of SDH is based on CT results.

Reversing Warfarin-Induced Coagulopathy
In all patients with intracranial hemorrhages who are taking warfarin, the coagulopathy must be reversed. The agents commonly used to reverse the effects of warfarin include vitamin K, FFP, and rFVIIa.^9,22-24 The choice of agents depends on the timing of intervention.

Vitamin K is commonly given to patients either intravenously or orally in combination with FFP and/or rFVIIa to promote the reversal of warfarin-induced coagulopathy. Vitamin K is seldom used alone, as its effects may not be seen for 24 hours or longer, and may not completely reverse the effects of warfarin.²⁵

Another frequently used product is FFP. Unfortunately, FFP has been associated with complications such as fluid overload, infectious disease transmission, and anaphylaxis. Additionally, FFP too reverses coagulopathy very slowly. Boulis et al²⁶ found that in patients given FFP with single-dose vitamin K, INR reduction averaged 0.18/hour. At this rate, it would take approximately 11 hours to correct an INR of 3.0 to the desired target of 1.0.

In contrast, rFVIIa, used off-label, has proved highly effective in rapidly reversing coagulopathy and allowing patients to safely undergo immediate surgical treatment.^23,24 To its disadvantage, rFVIIa increases the risk of thromboembolism and is significantly more expensive than FFP. Compared with $105 for one unit of FFP, the cost of an 80-mcg/kg dose of rFVIIa for a patient weighing 80 kg is about $6,400.²⁷

Factors Predicting Outcome for Subdural Hematomas
A number of factors determine post-SDH outcome. Rozzelle et al¹⁴ found that a Glasgow Coma Scale score below 7, age greater than 80, more acute hemorrhages, and hemorrhages requiring craniotomy rather than burr-hole drainage were associated with significantly higher mortality rates than when these factors were absent.

Other studies have revealed that patients with poor clinical status and larger hematomas with more midline shift are also prone to higher mortality rates.^20,28 Merlicco et al²⁹ found that younger, nonalcoholic patients without severe trauma whose hematomas were under high pressure had better chances for full recovery than other patients.

Patient Outcome
This case study illustrates the importance of patient education. The patient described here was aware of his excessive anticoagulation and told his provider that he was concerned about bleeding in the brain. Because the patient had been educated about the potential risks of warfarin therapy, he was able to alert his provider when he experienced symptoms of a possible complication. As a result, his condition was quickly diagnosed and treated, with an excellent outcome.

Conclusion
Intracranial hemorrhage is a serious and potentially life-threatening complication of warfarin therapy. CSDHs in particular are a significant cause of mortality and morbidity in older patients. The risk of death or disability increases in patients who are undergoing anticoagulation therapy. In addition, patients with an INR elevated above therapeutic levels face a significantly higher risk for major bleeding events. For this reason, it is important that anticoagulation be tightly controlled within the therapeutic range. It is equally important to educate patients and their families about anticoagulation’s potential risks and complications.

Making the diagnosis of CSDH can be difficult because its symptoms are so often nonspecific and a concomitant illness may be present. Thus, providers must maintain a low threshold for evaluating even minor patient complaints that may signal a complication of warfarin therapy. All too often, minor signs and symptoms go unrecognized, sometimes leading to devastating consequences.

Although many factors predict outcomes for CSDHs, the most important can be controlled by patients and their providers. If patients are well educated and providers listen to their patients, then early diagnosis of SDH can lead to early intervention and improved outcomes.    

A 21-year-old woman who is 12 weeks pregnant according to the date of her last menstrual period comes to the emergency department with shortness of breath and chest pain.

One week ago she began experiencing pre-syncope and shortness of breath on minimal exertion and then even at rest on most days. The shortness of breath worsened throughout the week, eventually limiting her daily activities to such a degree that she restricted herself to bed rest.

Her chest pain started today while she was sitting in church, without any apparent provocation. It is right-sided, sharp, and focal, and it does not radiate. At the same time, her shortness of breath was more severe than before, so she immediately came to the emergency department.

This is her third pregnancy; she has had one live birth and one abortion. Her last pregnancy was full-term, with routine prenatal care and no complications. However, so far during this pregnancy, she has had no prenatal care, she has not taken prenatal vitamins, and she has been unable to maintain adequate nutrition because of persistent emesis, which began early in her pregnancy and continues to occur as often as two or three times daily. She has lost 20 pounds over the past 12 weeks.

She says she has no close contacts who are sick, and she has had no fever, diarrhea, dysuria, urinary frequency or urgency, palpitations, swelling of the legs or feet, blurry vision, or increase in neck girth. She says she does not smoke or use alcohol or illicit substances. Her only previous surgery was laser-assisted in situ keratoplasty (LASIK) eye surgery in 1998. She is allergic to seafood only. She has not eaten at any new places recently. She is up to date with her childhood vaccinations. She has no family history of hypercoagulability or venous thrombotic events.

PHYSICAL EXAMINATION

She is breathing rapidly—as fast as 45 breaths per minute. Her temperature is 37.2°C (98.9°F), blood pressure 95/60 mm Hg, oxygen saturation 100% while on 10 L of oxygen using a nonrebreather mask, pulse 102 beats per minute, and weight 55.9 kg (123.2 pounds). She appears alert, oriented, and comfortable, with a thin body habitus. She has no jugular venous distention, neck mass, or thyromegaly. Her lungs are clear to auscultation, with no wheezes or rales. The cardiovascular examination is normal. She has a regular heart rate and rhythm, normal S1 and S2 sounds, and no rubs, clicks, or murmurs. Pulses in the extremities are normal, and she has no peripheral edema. The neurologic examination is normal.

Electrocardiography shows sinus tachycardia with first-degree atrioventricular block.

DIFFERENTIAL DIAGNOSIS

1. At this point, which is the most probable cause of her symptoms?

• Pulmonary embolism
• Peripartum cardiomyopathy
• Acute coronary syndrome
• Aortic dissection
• Expected physiologic changes of pregnancy

Pulmonary embolism would be the most probable diagnosis, given the patient’s pregnancy, shortness of breath, and tachycardia and the pleuritic quality of her chest pain.

Peripartum cardiomyopathy is also a possible cause, as it may present with profound shortness of breath and markedly decreased cardiac function. But it is much less likely in this patient because she is early in her pregnancy, and peripartum cardiomyopathy usually is seen during the last month of gestation or the first months after delivery.

Acute coronary syndrome is unlikely, given her young age and the lack of significant risk factors or a supporting history.

Aortic dissection is unlikely in view of her medical history.

Physiologic changes of pregnancy. Many pregnant women experience a sensation of not being able to catch their breath or expand their lungs fully, as the diaphragm is limited by the gravid abdomen. They also present with dyspnea, fatigue, reduced exercise capacity, peripheral edema, or volume overload.¹ However, these changes tend to occur gradually and worsen over time. This patient’s degree of shortness of breath and its sudden onset do not seem like normal physiologic changes of pregnancy.

Other possible causes of dyspnea in a pregnant woman include asthma, pleural empyema, pneumonia, and severe anemia. Asthma should be considered in anyone with a history of wheezing, cough, and dyspnea. Fever and sputum production would support a diagnosis of pneumonia or empyema. In addition, maternal heart disease (eg, endocarditis, pulmonary hypertension) complicates 0.2% to 3% of pregnancies.¹

CASE CONTINUED

The emergency department staff decide to evaluate the patient for heart failure and pulmonary embolism.

Bedside echocardiography reveals an ejection fraction of 55% (normal range 50%–75%), normal heart function and size, and no valvular abnormalities.

Chest radiography is normal.

Lower-extremity duplex ultrasonography is negative for deep-vein thrombosis.

The D-dimer level is 380 ng/mL (normal range < 500 ng/mL).

The medical intensive care unit is consulted about the patient’s continued tachypnea and the possible need for intubation. A ventilation-perfusion scan is performed to screen for pulmonary embolism, and it is negative.

An obstetric team performs Doppler ultrasonography at the bedside; a fetal heartbeat can be heard, thus confirming a viable pregnancy.

The patient has normal serum levels of the cardiac enzymes troponin T and creatine kinase-MB fraction, thus all but ruling out myocardial ischemia.

The patient is admitted to the hospital the next day, and a cardiology consult is obtained.

RULING OUT PULMONARY EMBOLISM

2. Has pulmonary embolism been definitively ruled out at this point?

• Yes
• No

The answer is no. The negative ventilation-perfusion scan and normal D-dimer test in this patient are not enough to rule out pulmonary embolism. The diagnosis of pulmonary embolism should be based on the clinician’s estimation of the pretest probability of pulmonary embolism (which is based on presenting signs and symptoms), as well as on a variety of tests, including spiral computed tomography (CT), ventilation-perfusion lung scanning, and serum D-dimer testing. Signs and symptoms that may guide the clinician are chest pain (present in 70% of patients with pulmonary embolism), tachypnea (70%), cough (40%), shortness of breath (25%), and tachycardia (33%).² A history of pregnancy, malignancy, immobility, or recent surgery may also increase the pretest probability of pulmonary embolism. In many cases, one’s clinical suspicion is highly predictive and is useful in diagnosing pulmonary embolism.

The accuracy of the tests varies widely, depending on the pretest probability of pulmonary embolism. For instance, in a patient with a high pretest probability but a low-probability ventilation-perfusion scan, the true probability of pulmonary embolism is 40%, but in a patient with a low pretest probability and a low-probability scan, the probability is only 4%.

The Wells criteria can be used to calculate the pretest probability of pulmonary embolism. Given this patient’s tachycardia and clinical presentation, her pretest probability according to the Wells criteria indicates increased risk. However, because her D-dimer test, lower-extremity Doppler test, and ventilation-perfusion scan were normal, pulmonary embolism is less likely.³

However, if one’s clinical suspicion is high enough, further investigation of pulmonary embolism would proceed despite the encouraging test results.

CASE CONTINUED

The cardiology consult team notes that her beta human chorionic gonadotropin (beta-hCG) level is much higher than would be expected at 12 weeks of pregnancy, and so they are concerned about the possibility of a molar pregnancy. In addition, her level of thyroid-stimulating hormone (TSH, or thyrotropin) is markedly low.

HYPERTHYROIDISM IN PREGNANCY

3. Which of the following would not explain this patient’s markedly low TSH level?

• Graves disease
• Molar pregnancy
• TSH-secreting pituitary adenoma
• Gestational transient thyrotoxicosis
• Twin pregnancy

Hyperthyroidism (also called thyrotoxicosis) has many causes, including but not limited to Graves disease, pituitary adenoma, struma ovarii (teratoma), hCG-secreting hydatidiform mole, and thyroid carcinoma (which is rare).⁴ In most of these disorders, the TSH level is low while the levels of thyroxine (T₄), triiodothyronine (T₃), or both are high.

Symptoms of hyperthyroidism are the effect of elevated T₄ and T₃ levels on the target organs themselves. Common symptoms include fever, tachycardia, tremor, stare, sweating, and lid lag. Other symptoms include nervousness, delirium, hypersensitivity to heat, flushing, palpitations, fatigue, weight loss, dyspnea, weakness, increased appetite, swelling of the legs, nausea, vomiting, diarrhea, goiter, tremor, atrial fibrillation, and cardiac failure.⁴ In its extreme form, called thyroid storm, thyrotoxicosis can be life-threatening. The likelihood of an impending thyroid storm can be assessed by clinical variables such as the patient’s temperature and heart rate and whether he or she has heart failure or gastrointestinal manifestations.⁵

Graves disease, the most common cause of hyperthyroidism in pregnancy, is due to stimulation of TSH receptors by antibodies against these receptors. Graves disease is possible in this patient, but a subsequent TSH receptor antibody test is negative.

Pituitary adenomas are one of the few causes of hyperthyroidism in which the TSH level is high, not low. Therefore, this is the correct answer.

Gestational transient thyrotoxicosis is a nonautoimmune condition that results in transient hyperthyroidism of variable severity.⁶ Usually, it occurs in otherwise normal pregnancies without complications, but the initial manifestation is hyper- emesis.⁶ It can be differentiated from Graves disease by the absence of TSH receptor antibodies and by no history of thyroid disorder.⁷ Common symptoms of gestational transient thyrotoxicosis include weight loss (or failure to gain weight), tachycardia, and fatigue.

The reason for the transient rise in ^T4 may be that beta-hCG is structurally similar to TSH (and also to luteinizing hormone and follicle-stimulating hormone), so that it has mild thyroid-stimulating effects.⁷ Sustained high levels of beta-hCG may in time give rise to the manifestations of thyrotoxicosis.

Molar pregnancy also can cause hyper-thyroidism via elevated levels of beta-hCG. However, twin pregnancy is more common and can produce sustained levels of beta-hCG above 100,000 IU/L. In most cases of twin pregnancy, the TSH level is decreased and the T₄ level transiently elevated.⁶ The elevated beta-hCG and the subsequent thyrotropic manifestations are thought to be directly related, and symptoms resolve when beta-hCG levels go down.⁶

In most cases of hyperthyroidism in pregnancy, the acute condition can be managed by a short (≤ 2-month) course of a beta-blocker. In rare cases, propylthiouracil treatment may be required. Gestational transient thyrotoxicosis is not associated with detrimental outcomes.

Case continued

Our patient’s TSH level is low and her free T₄ and T₃ levels are elevated. Her high beta-hCG level may be stimulating the thyroid gland and may account for the low TSH value, as well as for her tachycardia, emesis, shortness of breath, and weight loss.

After an obstetric consult, it is determined that our patient has a viable pregnancy. However, further investigation with transvaginal ultrasonography reveals that she has two viable, single-placenta, intrauterine gestations, separated by a thin chorionic membrane.

Beta-hCG and free T₄ levels are significantly higher in twin pregnancies than in single pregnancies, especially in the early stages.⁶ In our patient, the twin pregnancy led to the elevated beta-hCG, which eventually manifested as thyrotoxicosis, which caused the shortness of breath, hyperemesis, weight loss, tachycardia, and nausea.

Shortness of breath in patients with thyrotoxicosis is well recognized but not well explained. It may be caused by decreased lung compliance, engorged capillaries in the lung, or left ventricular failure, as well as by chest pain due to increased myocardial demand or coronary artery vasospasm.⁴ The dyspnea is present at rest and during exertion, and the high metabolic rate is thought to lead to an inappropriate response of the ventilatory system.^3,8

WHAT TREATMENT?

4. How would you treat this patient at this point?

• No drug therapy, just supportive care
• Propranolol (Inderal)
• Levothyroxine
• Propylthiouracil

Several types of drugs are used to manage hyperthyroidism.

Antithyroid drugs such as propylthiouracil, methimazole (Northyx, Tapazole), and carbimazole block thyroid hormone synthesis by inhibiting thyroid peroxidase. Propylthiouracil also blocks peripheral conversion of T₄ to T₃. Side effects of these agents include abnormal sense of taste, pruritus, urticaria, agranulocytosis, and hepatotoxicity.⁴

Usually, hyperthyroidism is treated with propylthiouracil at the smallest effective dose. This has been proven to be safe to the fetus and mother during pregnancy.⁹ Propylthiouracil and the other drugs in its class cross the placenta, but propylthiouracil crosses at one-quarter the rate of the other two.⁹

Beta-blockers are effective in the acute phase of thyrotoxicosis against tachycardia, hypertension, and atrial fibrillation. They also decrease conversion of T₄ to T₃, which is an added benefit. Beta-blockers can be tapered as thyroid hormone levels decrease.

A short course of a short-acting beta-blocker would be an option for our patient and would decrease her symptoms, although she does not have the typical markedly elevated T₄ or T₃ levels. In the long term, a beta-blocker would present a fetal risk, but short courses can be tolerated without incident.⁹

Radioactive iodine 131 is used in patients with Graves disease. ¹³¹Iodine therapy is safe for most adults, but in pregnancy its use is contraindicated. Fetal thyroid tissue is thought to be present after 10 weeks of gestation and could be damaged by the use of radioactive iodine. Another warning with the use of radioactive iodine is that patients should avoid close contact with other adults for a few days after treatment, and should avoid close contact with children and pregnant women for 2 to 3 weeks after treatment because of the risk of exposure to radiation emanating from the thyroid gland.

Levothyroxine is a treatment for hypothyroidism, not hyperthyroidism.

CASE CONTINUED

Our patient is treated with propranolol and monitored for several days in the hospital, during which her symptoms markedly improve. She is discharged without complications.

TAKE-HOME POINTS

The evaluation of shortness of breath in adult patients can be difficult, given the many possible causes. It is especially challenging in pregnant patients, since normal physiologic changes of pregnancy may produce these symptoms.

In many instances, cardiomyopathy must be suspected if a pregnant patient complains of shortness of breath. However, it is not the only possible cause.

A 21-year-old woman who is 12 weeks pregnant according to the date of her last menstrual period comes to the emergency department with shortness of breath and chest pain.

One week ago she began experiencing pre-syncope and shortness of breath on minimal exertion and then even at rest on most days. The shortness of breath worsened throughout the week, eventually limiting her daily activities to such a degree that she restricted herself to bed rest.

Her chest pain started today while she was sitting in church, without any apparent provocation. It is right-sided, sharp, and focal, and it does not radiate. At the same time, her shortness of breath was more severe than before, so she immediately came to the emergency department.

This is her third pregnancy; she has had one live birth and one abortion. Her last pregnancy was full-term, with routine prenatal care and no complications. However, so far during this pregnancy, she has had no prenatal care, she has not taken prenatal vitamins, and she has been unable to maintain adequate nutrition because of persistent emesis, which began early in her pregnancy and continues to occur as often as two or three times daily. She has lost 20 pounds over the past 12 weeks.

She says she has no close contacts who are sick, and she has had no fever, diarrhea, dysuria, urinary frequency or urgency, palpitations, swelling of the legs or feet, blurry vision, or increase in neck girth. She says she does not smoke or use alcohol or illicit substances. Her only previous surgery was laser-assisted in situ keratoplasty (LASIK) eye surgery in 1998. She is allergic to seafood only. She has not eaten at any new places recently. She is up to date with her childhood vaccinations. She has no family history of hypercoagulability or venous thrombotic events.

PHYSICAL EXAMINATION

She is breathing rapidly—as fast as 45 breaths per minute. Her temperature is 37.2°C (98.9°F), blood pressure 95/60 mm Hg, oxygen saturation 100% while on 10 L of oxygen using a nonrebreather mask, pulse 102 beats per minute, and weight 55.9 kg (123.2 pounds). She appears alert, oriented, and comfortable, with a thin body habitus. She has no jugular venous distention, neck mass, or thyromegaly. Her lungs are clear to auscultation, with no wheezes or rales. The cardiovascular examination is normal. She has a regular heart rate and rhythm, normal S1 and S2 sounds, and no rubs, clicks, or murmurs. Pulses in the extremities are normal, and she has no peripheral edema. The neurologic examination is normal.

Electrocardiography shows sinus tachycardia with first-degree atrioventricular block.

DIFFERENTIAL DIAGNOSIS

1. At this point, which is the most probable cause of her symptoms?

• Pulmonary embolism
• Peripartum cardiomyopathy
• Acute coronary syndrome
• Aortic dissection
• Expected physiologic changes of pregnancy

Pulmonary embolism would be the most probable diagnosis, given the patient’s pregnancy, shortness of breath, and tachycardia and the pleuritic quality of her chest pain.

Peripartum cardiomyopathy is also a possible cause, as it may present with profound shortness of breath and markedly decreased cardiac function. But it is much less likely in this patient because she is early in her pregnancy, and peripartum cardiomyopathy usually is seen during the last month of gestation or the first months after delivery.

Acute coronary syndrome is unlikely, given her young age and the lack of significant risk factors or a supporting history.

Aortic dissection is unlikely in view of her medical history.

Physiologic changes of pregnancy. Many pregnant women experience a sensation of not being able to catch their breath or expand their lungs fully, as the diaphragm is limited by the gravid abdomen. They also present with dyspnea, fatigue, reduced exercise capacity, peripheral edema, or volume overload.¹ However, these changes tend to occur gradually and worsen over time. This patient’s degree of shortness of breath and its sudden onset do not seem like normal physiologic changes of pregnancy.

Other possible causes of dyspnea in a pregnant woman include asthma, pleural empyema, pneumonia, and severe anemia. Asthma should be considered in anyone with a history of wheezing, cough, and dyspnea. Fever and sputum production would support a diagnosis of pneumonia or empyema. In addition, maternal heart disease (eg, endocarditis, pulmonary hypertension) complicates 0.2% to 3% of pregnancies.¹

CASE CONTINUED

The emergency department staff decide to evaluate the patient for heart failure and pulmonary embolism.

Bedside echocardiography reveals an ejection fraction of 55% (normal range 50%–75%), normal heart function and size, and no valvular abnormalities.

Chest radiography is normal.

Lower-extremity duplex ultrasonography is negative for deep-vein thrombosis.

The D-dimer level is 380 ng/mL (normal range < 500 ng/mL).

The medical intensive care unit is consulted about the patient’s continued tachypnea and the possible need for intubation. A ventilation-perfusion scan is performed to screen for pulmonary embolism, and it is negative.

An obstetric team performs Doppler ultrasonography at the bedside; a fetal heartbeat can be heard, thus confirming a viable pregnancy.

The patient has normal serum levels of the cardiac enzymes troponin T and creatine kinase-MB fraction, thus all but ruling out myocardial ischemia.

The patient is admitted to the hospital the next day, and a cardiology consult is obtained.

RULING OUT PULMONARY EMBOLISM

2. Has pulmonary embolism been definitively ruled out at this point?

• Yes
• No

The answer is no. The negative ventilation-perfusion scan and normal D-dimer test in this patient are not enough to rule out pulmonary embolism. The diagnosis of pulmonary embolism should be based on the clinician’s estimation of the pretest probability of pulmonary embolism (which is based on presenting signs and symptoms), as well as on a variety of tests, including spiral computed tomography (CT), ventilation-perfusion lung scanning, and serum D-dimer testing. Signs and symptoms that may guide the clinician are chest pain (present in 70% of patients with pulmonary embolism), tachypnea (70%), cough (40%), shortness of breath (25%), and tachycardia (33%).² A history of pregnancy, malignancy, immobility, or recent surgery may also increase the pretest probability of pulmonary embolism. In many cases, one’s clinical suspicion is highly predictive and is useful in diagnosing pulmonary embolism.

The accuracy of the tests varies widely, depending on the pretest probability of pulmonary embolism. For instance, in a patient with a high pretest probability but a low-probability ventilation-perfusion scan, the true probability of pulmonary embolism is 40%, but in a patient with a low pretest probability and a low-probability scan, the probability is only 4%.

The Wells criteria can be used to calculate the pretest probability of pulmonary embolism. Given this patient’s tachycardia and clinical presentation, her pretest probability according to the Wells criteria indicates increased risk. However, because her D-dimer test, lower-extremity Doppler test, and ventilation-perfusion scan were normal, pulmonary embolism is less likely.³

However, if one’s clinical suspicion is high enough, further investigation of pulmonary embolism would proceed despite the encouraging test results.

CASE CONTINUED

The cardiology consult team notes that her beta human chorionic gonadotropin (beta-hCG) level is much higher than would be expected at 12 weeks of pregnancy, and so they are concerned about the possibility of a molar pregnancy. In addition, her level of thyroid-stimulating hormone (TSH, or thyrotropin) is markedly low.

HYPERTHYROIDISM IN PREGNANCY

3. Which of the following would not explain this patient’s markedly low TSH level?

• Graves disease
• Molar pregnancy
• TSH-secreting pituitary adenoma
• Gestational transient thyrotoxicosis
• Twin pregnancy

Hyperthyroidism (also called thyrotoxicosis) has many causes, including but not limited to Graves disease, pituitary adenoma, struma ovarii (teratoma), hCG-secreting hydatidiform mole, and thyroid carcinoma (which is rare).⁴ In most of these disorders, the TSH level is low while the levels of thyroxine (T₄), triiodothyronine (T₃), or both are high.

Symptoms of hyperthyroidism are the effect of elevated T₄ and T₃ levels on the target organs themselves. Common symptoms include fever, tachycardia, tremor, stare, sweating, and lid lag. Other symptoms include nervousness, delirium, hypersensitivity to heat, flushing, palpitations, fatigue, weight loss, dyspnea, weakness, increased appetite, swelling of the legs, nausea, vomiting, diarrhea, goiter, tremor, atrial fibrillation, and cardiac failure.⁴ In its extreme form, called thyroid storm, thyrotoxicosis can be life-threatening. The likelihood of an impending thyroid storm can be assessed by clinical variables such as the patient’s temperature and heart rate and whether he or she has heart failure or gastrointestinal manifestations.⁵

Graves disease, the most common cause of hyperthyroidism in pregnancy, is due to stimulation of TSH receptors by antibodies against these receptors. Graves disease is possible in this patient, but a subsequent TSH receptor antibody test is negative.

Pituitary adenomas are one of the few causes of hyperthyroidism in which the TSH level is high, not low. Therefore, this is the correct answer.

Gestational transient thyrotoxicosis is a nonautoimmune condition that results in transient hyperthyroidism of variable severity.⁶ Usually, it occurs in otherwise normal pregnancies without complications, but the initial manifestation is hyper- emesis.⁶ It can be differentiated from Graves disease by the absence of TSH receptor antibodies and by no history of thyroid disorder.⁷ Common symptoms of gestational transient thyrotoxicosis include weight loss (or failure to gain weight), tachycardia, and fatigue.

The reason for the transient rise in ^T4 may be that beta-hCG is structurally similar to TSH (and also to luteinizing hormone and follicle-stimulating hormone), so that it has mild thyroid-stimulating effects.⁷ Sustained high levels of beta-hCG may in time give rise to the manifestations of thyrotoxicosis.

Molar pregnancy also can cause hyper-thyroidism via elevated levels of beta-hCG. However, twin pregnancy is more common and can produce sustained levels of beta-hCG above 100,000 IU/L. In most cases of twin pregnancy, the TSH level is decreased and the T₄ level transiently elevated.⁶ The elevated beta-hCG and the subsequent thyrotropic manifestations are thought to be directly related, and symptoms resolve when beta-hCG levels go down.⁶

In most cases of hyperthyroidism in pregnancy, the acute condition can be managed by a short (≤ 2-month) course of a beta-blocker. In rare cases, propylthiouracil treatment may be required. Gestational transient thyrotoxicosis is not associated with detrimental outcomes.

Case continued

Our patient’s TSH level is low and her free T₄ and T₃ levels are elevated. Her high beta-hCG level may be stimulating the thyroid gland and may account for the low TSH value, as well as for her tachycardia, emesis, shortness of breath, and weight loss.

After an obstetric consult, it is determined that our patient has a viable pregnancy. However, further investigation with transvaginal ultrasonography reveals that she has two viable, single-placenta, intrauterine gestations, separated by a thin chorionic membrane.

Beta-hCG and free T₄ levels are significantly higher in twin pregnancies than in single pregnancies, especially in the early stages.⁶ In our patient, the twin pregnancy led to the elevated beta-hCG, which eventually manifested as thyrotoxicosis, which caused the shortness of breath, hyperemesis, weight loss, tachycardia, and nausea.

Shortness of breath in patients with thyrotoxicosis is well recognized but not well explained. It may be caused by decreased lung compliance, engorged capillaries in the lung, or left ventricular failure, as well as by chest pain due to increased myocardial demand or coronary artery vasospasm.⁴ The dyspnea is present at rest and during exertion, and the high metabolic rate is thought to lead to an inappropriate response of the ventilatory system.^3,8

WHAT TREATMENT?

4. How would you treat this patient at this point?

• No drug therapy, just supportive care
• Propranolol (Inderal)
• Levothyroxine
• Propylthiouracil

Several types of drugs are used to manage hyperthyroidism.

Antithyroid drugs such as propylthiouracil, methimazole (Northyx, Tapazole), and carbimazole block thyroid hormone synthesis by inhibiting thyroid peroxidase. Propylthiouracil also blocks peripheral conversion of T₄ to T₃. Side effects of these agents include abnormal sense of taste, pruritus, urticaria, agranulocytosis, and hepatotoxicity.⁴

Usually, hyperthyroidism is treated with propylthiouracil at the smallest effective dose. This has been proven to be safe to the fetus and mother during pregnancy.⁹ Propylthiouracil and the other drugs in its class cross the placenta, but propylthiouracil crosses at one-quarter the rate of the other two.⁹

Beta-blockers are effective in the acute phase of thyrotoxicosis against tachycardia, hypertension, and atrial fibrillation. They also decrease conversion of T₄ to T₃, which is an added benefit. Beta-blockers can be tapered as thyroid hormone levels decrease.

A short course of a short-acting beta-blocker would be an option for our patient and would decrease her symptoms, although she does not have the typical markedly elevated T₄ or T₃ levels. In the long term, a beta-blocker would present a fetal risk, but short courses can be tolerated without incident.⁹

Radioactive iodine 131 is used in patients with Graves disease. ¹³¹Iodine therapy is safe for most adults, but in pregnancy its use is contraindicated. Fetal thyroid tissue is thought to be present after 10 weeks of gestation and could be damaged by the use of radioactive iodine. Another warning with the use of radioactive iodine is that patients should avoid close contact with other adults for a few days after treatment, and should avoid close contact with children and pregnant women for 2 to 3 weeks after treatment because of the risk of exposure to radiation emanating from the thyroid gland.

Levothyroxine is a treatment for hypothyroidism, not hyperthyroidism.

CASE CONTINUED

Our patient is treated with propranolol and monitored for several days in the hospital, during which her symptoms markedly improve. She is discharged without complications.

TAKE-HOME POINTS

The evaluation of shortness of breath in adult patients can be difficult, given the many possible causes. It is especially challenging in pregnant patients, since normal physiologic changes of pregnancy may produce these symptoms.

In many instances, cardiomyopathy must be suspected if a pregnant patient complains of shortness of breath. However, it is not the only possible cause.

A 21-year-old woman who is 12 weeks pregnant according to the date of her last menstrual period comes to the emergency department with shortness of breath and chest pain.

One week ago she began experiencing pre-syncope and shortness of breath on minimal exertion and then even at rest on most days. The shortness of breath worsened throughout the week, eventually limiting her daily activities to such a degree that she restricted herself to bed rest.

Her chest pain started today while she was sitting in church, without any apparent provocation. It is right-sided, sharp, and focal, and it does not radiate. At the same time, her shortness of breath was more severe than before, so she immediately came to the emergency department.

This is her third pregnancy; she has had one live birth and one abortion. Her last pregnancy was full-term, with routine prenatal care and no complications. However, so far during this pregnancy, she has had no prenatal care, she has not taken prenatal vitamins, and she has been unable to maintain adequate nutrition because of persistent emesis, which began early in her pregnancy and continues to occur as often as two or three times daily. She has lost 20 pounds over the past 12 weeks.

She says she has no close contacts who are sick, and she has had no fever, diarrhea, dysuria, urinary frequency or urgency, palpitations, swelling of the legs or feet, blurry vision, or increase in neck girth. She says she does not smoke or use alcohol or illicit substances. Her only previous surgery was laser-assisted in situ keratoplasty (LASIK) eye surgery in 1998. She is allergic to seafood only. She has not eaten at any new places recently. She is up to date with her childhood vaccinations. She has no family history of hypercoagulability or venous thrombotic events.

PHYSICAL EXAMINATION

She is breathing rapidly—as fast as 45 breaths per minute. Her temperature is 37.2°C (98.9°F), blood pressure 95/60 mm Hg, oxygen saturation 100% while on 10 L of oxygen using a nonrebreather mask, pulse 102 beats per minute, and weight 55.9 kg (123.2 pounds). She appears alert, oriented, and comfortable, with a thin body habitus. She has no jugular venous distention, neck mass, or thyromegaly. Her lungs are clear to auscultation, with no wheezes or rales. The cardiovascular examination is normal. She has a regular heart rate and rhythm, normal S1 and S2 sounds, and no rubs, clicks, or murmurs. Pulses in the extremities are normal, and she has no peripheral edema. The neurologic examination is normal.

Electrocardiography shows sinus tachycardia with first-degree atrioventricular block.

DIFFERENTIAL DIAGNOSIS

1. At this point, which is the most probable cause of her symptoms?

• Pulmonary embolism
• Peripartum cardiomyopathy
• Acute coronary syndrome
• Aortic dissection
• Expected physiologic changes of pregnancy

Pulmonary embolism would be the most probable diagnosis, given the patient’s pregnancy, shortness of breath, and tachycardia and the pleuritic quality of her chest pain.

Peripartum cardiomyopathy is also a possible cause, as it may present with profound shortness of breath and markedly decreased cardiac function. But it is much less likely in this patient because she is early in her pregnancy, and peripartum cardiomyopathy usually is seen during the last month of gestation or the first months after delivery.

Acute coronary syndrome is unlikely, given her young age and the lack of significant risk factors or a supporting history.

Aortic dissection is unlikely in view of her medical history.

Physiologic changes of pregnancy. Many pregnant women experience a sensation of not being able to catch their breath or expand their lungs fully, as the diaphragm is limited by the gravid abdomen. They also present with dyspnea, fatigue, reduced exercise capacity, peripheral edema, or volume overload.¹ However, these changes tend to occur gradually and worsen over time. This patient’s degree of shortness of breath and its sudden onset do not seem like normal physiologic changes of pregnancy.

Other possible causes of dyspnea in a pregnant woman include asthma, pleural empyema, pneumonia, and severe anemia. Asthma should be considered in anyone with a history of wheezing, cough, and dyspnea. Fever and sputum production would support a diagnosis of pneumonia or empyema. In addition, maternal heart disease (eg, endocarditis, pulmonary hypertension) complicates 0.2% to 3% of pregnancies.¹

CASE CONTINUED

The emergency department staff decide to evaluate the patient for heart failure and pulmonary embolism.

Bedside echocardiography reveals an ejection fraction of 55% (normal range 50%–75%), normal heart function and size, and no valvular abnormalities.

Chest radiography is normal.

Lower-extremity duplex ultrasonography is negative for deep-vein thrombosis.

The D-dimer level is 380 ng/mL (normal range < 500 ng/mL).

The medical intensive care unit is consulted about the patient’s continued tachypnea and the possible need for intubation. A ventilation-perfusion scan is performed to screen for pulmonary embolism, and it is negative.

An obstetric team performs Doppler ultrasonography at the bedside; a fetal heartbeat can be heard, thus confirming a viable pregnancy.

The patient has normal serum levels of the cardiac enzymes troponin T and creatine kinase-MB fraction, thus all but ruling out myocardial ischemia.

The patient is admitted to the hospital the next day, and a cardiology consult is obtained.

RULING OUT PULMONARY EMBOLISM

2. Has pulmonary embolism been definitively ruled out at this point?

• Yes
• No

The answer is no. The negative ventilation-perfusion scan and normal D-dimer test in this patient are not enough to rule out pulmonary embolism. The diagnosis of pulmonary embolism should be based on the clinician’s estimation of the pretest probability of pulmonary embolism (which is based on presenting signs and symptoms), as well as on a variety of tests, including spiral computed tomography (CT), ventilation-perfusion lung scanning, and serum D-dimer testing. Signs and symptoms that may guide the clinician are chest pain (present in 70% of patients with pulmonary embolism), tachypnea (70%), cough (40%), shortness of breath (25%), and tachycardia (33%).² A history of pregnancy, malignancy, immobility, or recent surgery may also increase the pretest probability of pulmonary embolism. In many cases, one’s clinical suspicion is highly predictive and is useful in diagnosing pulmonary embolism.

The accuracy of the tests varies widely, depending on the pretest probability of pulmonary embolism. For instance, in a patient with a high pretest probability but a low-probability ventilation-perfusion scan, the true probability of pulmonary embolism is 40%, but in a patient with a low pretest probability and a low-probability scan, the probability is only 4%.

The Wells criteria can be used to calculate the pretest probability of pulmonary embolism. Given this patient’s tachycardia and clinical presentation, her pretest probability according to the Wells criteria indicates increased risk. However, because her D-dimer test, lower-extremity Doppler test, and ventilation-perfusion scan were normal, pulmonary embolism is less likely.³

However, if one’s clinical suspicion is high enough, further investigation of pulmonary embolism would proceed despite the encouraging test results.

CASE CONTINUED

The cardiology consult team notes that her beta human chorionic gonadotropin (beta-hCG) level is much higher than would be expected at 12 weeks of pregnancy, and so they are concerned about the possibility of a molar pregnancy. In addition, her level of thyroid-stimulating hormone (TSH, or thyrotropin) is markedly low.

HYPERTHYROIDISM IN PREGNANCY

3. Which of the following would not explain this patient’s markedly low TSH level?

• Graves disease
• Molar pregnancy
• TSH-secreting pituitary adenoma
• Gestational transient thyrotoxicosis
• Twin pregnancy

Hyperthyroidism (also called thyrotoxicosis) has many causes, including but not limited to Graves disease, pituitary adenoma, struma ovarii (teratoma), hCG-secreting hydatidiform mole, and thyroid carcinoma (which is rare).⁴ In most of these disorders, the TSH level is low while the levels of thyroxine (T₄), triiodothyronine (T₃), or both are high.

Symptoms of hyperthyroidism are the effect of elevated T₄ and T₃ levels on the target organs themselves. Common symptoms include fever, tachycardia, tremor, stare, sweating, and lid lag. Other symptoms include nervousness, delirium, hypersensitivity to heat, flushing, palpitations, fatigue, weight loss, dyspnea, weakness, increased appetite, swelling of the legs, nausea, vomiting, diarrhea, goiter, tremor, atrial fibrillation, and cardiac failure.⁴ In its extreme form, called thyroid storm, thyrotoxicosis can be life-threatening. The likelihood of an impending thyroid storm can be assessed by clinical variables such as the patient’s temperature and heart rate and whether he or she has heart failure or gastrointestinal manifestations.⁵

Graves disease, the most common cause of hyperthyroidism in pregnancy, is due to stimulation of TSH receptors by antibodies against these receptors. Graves disease is possible in this patient, but a subsequent TSH receptor antibody test is negative.

Pituitary adenomas are one of the few causes of hyperthyroidism in which the TSH level is high, not low. Therefore, this is the correct answer.

Gestational transient thyrotoxicosis is a nonautoimmune condition that results in transient hyperthyroidism of variable severity.⁶ Usually, it occurs in otherwise normal pregnancies without complications, but the initial manifestation is hyper- emesis.⁶ It can be differentiated from Graves disease by the absence of TSH receptor antibodies and by no history of thyroid disorder.⁷ Common symptoms of gestational transient thyrotoxicosis include weight loss (or failure to gain weight), tachycardia, and fatigue.

The reason for the transient rise in ^T4 may be that beta-hCG is structurally similar to TSH (and also to luteinizing hormone and follicle-stimulating hormone), so that it has mild thyroid-stimulating effects.⁷ Sustained high levels of beta-hCG may in time give rise to the manifestations of thyrotoxicosis.

Molar pregnancy also can cause hyper-thyroidism via elevated levels of beta-hCG. However, twin pregnancy is more common and can produce sustained levels of beta-hCG above 100,000 IU/L. In most cases of twin pregnancy, the TSH level is decreased and the T₄ level transiently elevated.⁶ The elevated beta-hCG and the subsequent thyrotropic manifestations are thought to be directly related, and symptoms resolve when beta-hCG levels go down.⁶

In most cases of hyperthyroidism in pregnancy, the acute condition can be managed by a short (≤ 2-month) course of a beta-blocker. In rare cases, propylthiouracil treatment may be required. Gestational transient thyrotoxicosis is not associated with detrimental outcomes.

Case continued

Our patient’s TSH level is low and her free T₄ and T₃ levels are elevated. Her high beta-hCG level may be stimulating the thyroid gland and may account for the low TSH value, as well as for her tachycardia, emesis, shortness of breath, and weight loss.

After an obstetric consult, it is determined that our patient has a viable pregnancy. However, further investigation with transvaginal ultrasonography reveals that she has two viable, single-placenta, intrauterine gestations, separated by a thin chorionic membrane.

Beta-hCG and free T₄ levels are significantly higher in twin pregnancies than in single pregnancies, especially in the early stages.⁶ In our patient, the twin pregnancy led to the elevated beta-hCG, which eventually manifested as thyrotoxicosis, which caused the shortness of breath, hyperemesis, weight loss, tachycardia, and nausea.

Shortness of breath in patients with thyrotoxicosis is well recognized but not well explained. It may be caused by decreased lung compliance, engorged capillaries in the lung, or left ventricular failure, as well as by chest pain due to increased myocardial demand or coronary artery vasospasm.⁴ The dyspnea is present at rest and during exertion, and the high metabolic rate is thought to lead to an inappropriate response of the ventilatory system.^3,8

WHAT TREATMENT?

4. How would you treat this patient at this point?

• No drug therapy, just supportive care
• Propranolol (Inderal)
• Levothyroxine
• Propylthiouracil

Several types of drugs are used to manage hyperthyroidism.

Antithyroid drugs such as propylthiouracil, methimazole (Northyx, Tapazole), and carbimazole block thyroid hormone synthesis by inhibiting thyroid peroxidase. Propylthiouracil also blocks peripheral conversion of T₄ to T₃. Side effects of these agents include abnormal sense of taste, pruritus, urticaria, agranulocytosis, and hepatotoxicity.⁴

Usually, hyperthyroidism is treated with propylthiouracil at the smallest effective dose. This has been proven to be safe to the fetus and mother during pregnancy.⁹ Propylthiouracil and the other drugs in its class cross the placenta, but propylthiouracil crosses at one-quarter the rate of the other two.⁹

Beta-blockers are effective in the acute phase of thyrotoxicosis against tachycardia, hypertension, and atrial fibrillation. They also decrease conversion of T₄ to T₃, which is an added benefit. Beta-blockers can be tapered as thyroid hormone levels decrease.

A short course of a short-acting beta-blocker would be an option for our patient and would decrease her symptoms, although she does not have the typical markedly elevated T₄ or T₃ levels. In the long term, a beta-blocker would present a fetal risk, but short courses can be tolerated without incident.⁹

Radioactive iodine 131 is used in patients with Graves disease. ¹³¹Iodine therapy is safe for most adults, but in pregnancy its use is contraindicated. Fetal thyroid tissue is thought to be present after 10 weeks of gestation and could be damaged by the use of radioactive iodine. Another warning with the use of radioactive iodine is that patients should avoid close contact with other adults for a few days after treatment, and should avoid close contact with children and pregnant women for 2 to 3 weeks after treatment because of the risk of exposure to radiation emanating from the thyroid gland.

Levothyroxine is a treatment for hypothyroidism, not hyperthyroidism.

CASE CONTINUED

Our patient is treated with propranolol and monitored for several days in the hospital, during which her symptoms markedly improve. She is discharged without complications.

TAKE-HOME POINTS

The evaluation of shortness of breath in adult patients can be difficult, given the many possible causes. It is especially challenging in pregnant patients, since normal physiologic changes of pregnancy may produce these symptoms.

In many instances, cardiomyopathy must be suspected if a pregnant patient complains of shortness of breath. However, it is not the only possible cause.

A 22-year-old African American man with sickle cell disease comes to the in his joints and chest—a presentation similar to those of his previous sickle cell crises. He is given intravenous fluids for dehydration and morphine sulfate for pain via a peripheral line, and he is admitted to the hospital.

Shortly afterward, the peripheral line becomes infiltrated. After failed attempts at peripheral cannulation, central venous cannulation via an internal jugular site is considered.

WHERE IS THE CATHETER TIP?

HAZARDS OF ABERRANT LINE PLACEMENT

Central venous catheters are commonly used to give various infusions (eg, parenteral nutrition), to draw blood, and to monitor the central venous pressure.¹ The internal jugular vein is one of the preferred veins for central venous access.^1,2 Normally, the anatomy of the jugular venous system and the design of the catheter facilitate proper insertion. Occasionally, however, despite proper technique, the tip of the catheter may not terminate at the desired level, resulting in aberrant placement in the internal thoracic vein, superior vena cava, azygos vein, accessory hemiazygos vein, or axillary vein.^1–8

The use of chest radiographs to establish the correct placement of internal jugular and subclavian lines has been advocated and is routinely practiced.^6,7 Obtaining a chest x-ray to confirm line placement is particularly important in patients with prior multiple and difficult catheterizations. The lateral view is seldom obtained when confirming central neck line placement, but when the anteroposterior view is not reassuring, it may be prudent to obtain this alternate view.

In a large retrospective analysis,⁹ cannulation of the azygos arch occurred in about 1.2% of insertions, and the rate was about seven times higher when the left jugular vein was used than when the right one was used. A smaller study gave the frequency of azygos arch cannulation as 0.7%.¹⁰

All procedure-related complications of central line insertion in the neck can also occur with aberrant azygos vein cannulation. These include infection, bacteremia, pneumothorax, hemothorax, arterial puncture, and various other mechanical complications. It should be noted that aberrant cannulation of the azygos arch is particularly hazardous, and that complication rates are typically higher. These complications are mainly due to the smaller vascular lumen and to the direction of blood flow in the azygos venous system.

KNOWING THE ANATOMY IS CRUCIAL

Knowledge of venous anatomy and its variants is crucial both for insertion and for ascertaining the correct placement of central venous lines.

The azygos vein has a much smaller lumen than the superior vena cava. Although the lumen size may vary significantly, the maximum diameter of the anterior arch of the azygos vein is about 6 to 7 mm,¹¹ whereas the superior vena cava lumen is typically 1.5 to 2 cm in diameter.¹² In addition, when a catheter is inserted into the superior vena cava, the direction of blood flow and the direction of the infusion are the same, but when the catheter is inserted into the azygos system, the directions of blood flow and infusion are opposite, contributing to local turbulence.

Both these factors increase the chance of puncturing the vein when the azygos arch is aberrantly cannulated for central venous access.⁹ Venous perforation has been reported in as many as 19% of cases in which the azygos arch was inadvertently cannulated. Venous perforation can lead to hemopericardium, hemomediastinum, and hemorrhagic pleural effusions, which can lead to significant morbidity and even death. Perforation, thrombosis, stenosis, and complete occlusion have been reported subsequent to catheter malposition in the azygos vein.¹³

Patients in whom the azygos vein is inadvertently cannulated may tolerate infusions and blood draws, but this does not mean that inadvertent azygos vein cannulation is acceptable, especially given the late complications of vascular perforation that can occur.⁹

The cannulation of the azygos vein in our patient was completely unintentional; nevertheless, the line was kept in and used for a short period for the initial rehydration and pain control and was subsequently removed without any complications.

WHEN IS CANNULATION OF THE AZYGOS VEIN AN OPTION?

In patients with previous multiple central vein cannulations, the rates of thrombosis and of fibrotic changes in these veins are high. In patients with thrombosis of both the superior vena cava and the inferior vena cava, direct insertion of a catheter into the azygos vein has been suggested as an alternate route to obtain access for dialysis.⁸ This approach has also been used successfully to administer total parenteral nutrition for a prolonged time in pediatric patients.¹⁴ In short, the azygos vein is never preferred for central venous access, but it can occasionally serve as an alternate route.^5–9

TAKE-HOME POINTS

The radiographic assessment of an internal jugular or subclavian line may occasionally be deceptive if based solely on the anteroposterior view; confirmation may require a lateral view. We found no guidelines for using the azygos vein for central venous access. The options in cases of aberrant cannulation include leaving the line in, removing and reinserting it at the same or another site under fluoroscopy, and attempting to reposition it after changing the catheter over a guidewire.

The use of central lines found to be in an aberrant position should be driven by clinical judgment based on the urgency of the need of access, the availability or feasibility of other access options, and the intended use. The use of the azygos vein is fraught with procedural complications, as well as postprocedural complications related to vascular perforation. If the position of the catheter tip on the anteroposterior radiographic view is not satisfactory, obtaining a lateral view should be considered.

A 22-year-old African American man with sickle cell disease comes to the in his joints and chest—a presentation similar to those of his previous sickle cell crises. He is given intravenous fluids for dehydration and morphine sulfate for pain via a peripheral line, and he is admitted to the hospital.

Shortly afterward, the peripheral line becomes infiltrated. After failed attempts at peripheral cannulation, central venous cannulation via an internal jugular site is considered.

WHERE IS THE CATHETER TIP?

HAZARDS OF ABERRANT LINE PLACEMENT

Central venous catheters are commonly used to give various infusions (eg, parenteral nutrition), to draw blood, and to monitor the central venous pressure.¹ The internal jugular vein is one of the preferred veins for central venous access.^1,2 Normally, the anatomy of the jugular venous system and the design of the catheter facilitate proper insertion. Occasionally, however, despite proper technique, the tip of the catheter may not terminate at the desired level, resulting in aberrant placement in the internal thoracic vein, superior vena cava, azygos vein, accessory hemiazygos vein, or axillary vein.^1–8

The use of chest radiographs to establish the correct placement of internal jugular and subclavian lines has been advocated and is routinely practiced.^6,7 Obtaining a chest x-ray to confirm line placement is particularly important in patients with prior multiple and difficult catheterizations. The lateral view is seldom obtained when confirming central neck line placement, but when the anteroposterior view is not reassuring, it may be prudent to obtain this alternate view.

In a large retrospective analysis,⁹ cannulation of the azygos arch occurred in about 1.2% of insertions, and the rate was about seven times higher when the left jugular vein was used than when the right one was used. A smaller study gave the frequency of azygos arch cannulation as 0.7%.¹⁰

All procedure-related complications of central line insertion in the neck can also occur with aberrant azygos vein cannulation. These include infection, bacteremia, pneumothorax, hemothorax, arterial puncture, and various other mechanical complications. It should be noted that aberrant cannulation of the azygos arch is particularly hazardous, and that complication rates are typically higher. These complications are mainly due to the smaller vascular lumen and to the direction of blood flow in the azygos venous system.

KNOWING THE ANATOMY IS CRUCIAL

Knowledge of venous anatomy and its variants is crucial both for insertion and for ascertaining the correct placement of central venous lines.

The azygos vein has a much smaller lumen than the superior vena cava. Although the lumen size may vary significantly, the maximum diameter of the anterior arch of the azygos vein is about 6 to 7 mm,¹¹ whereas the superior vena cava lumen is typically 1.5 to 2 cm in diameter.¹² In addition, when a catheter is inserted into the superior vena cava, the direction of blood flow and the direction of the infusion are the same, but when the catheter is inserted into the azygos system, the directions of blood flow and infusion are opposite, contributing to local turbulence.

Both these factors increase the chance of puncturing the vein when the azygos arch is aberrantly cannulated for central venous access.⁹ Venous perforation has been reported in as many as 19% of cases in which the azygos arch was inadvertently cannulated. Venous perforation can lead to hemopericardium, hemomediastinum, and hemorrhagic pleural effusions, which can lead to significant morbidity and even death. Perforation, thrombosis, stenosis, and complete occlusion have been reported subsequent to catheter malposition in the azygos vein.¹³

Patients in whom the azygos vein is inadvertently cannulated may tolerate infusions and blood draws, but this does not mean that inadvertent azygos vein cannulation is acceptable, especially given the late complications of vascular perforation that can occur.⁹

The cannulation of the azygos vein in our patient was completely unintentional; nevertheless, the line was kept in and used for a short period for the initial rehydration and pain control and was subsequently removed without any complications.

WHEN IS CANNULATION OF THE AZYGOS VEIN AN OPTION?

In patients with previous multiple central vein cannulations, the rates of thrombosis and of fibrotic changes in these veins are high. In patients with thrombosis of both the superior vena cava and the inferior vena cava, direct insertion of a catheter into the azygos vein has been suggested as an alternate route to obtain access for dialysis.⁸ This approach has also been used successfully to administer total parenteral nutrition for a prolonged time in pediatric patients.¹⁴ In short, the azygos vein is never preferred for central venous access, but it can occasionally serve as an alternate route.^5–9

TAKE-HOME POINTS

The radiographic assessment of an internal jugular or subclavian line may occasionally be deceptive if based solely on the anteroposterior view; confirmation may require a lateral view. We found no guidelines for using the azygos vein for central venous access. The options in cases of aberrant cannulation include leaving the line in, removing and reinserting it at the same or another site under fluoroscopy, and attempting to reposition it after changing the catheter over a guidewire.

The use of central lines found to be in an aberrant position should be driven by clinical judgment based on the urgency of the need of access, the availability or feasibility of other access options, and the intended use. The use of the azygos vein is fraught with procedural complications, as well as postprocedural complications related to vascular perforation. If the position of the catheter tip on the anteroposterior radiographic view is not satisfactory, obtaining a lateral view should be considered.

A 22-year-old African American man with sickle cell disease comes to the in his joints and chest—a presentation similar to those of his previous sickle cell crises. He is given intravenous fluids for dehydration and morphine sulfate for pain via a peripheral line, and he is admitted to the hospital.

Shortly afterward, the peripheral line becomes infiltrated. After failed attempts at peripheral cannulation, central venous cannulation via an internal jugular site is considered.

WHERE IS THE CATHETER TIP?

HAZARDS OF ABERRANT LINE PLACEMENT

Central venous catheters are commonly used to give various infusions (eg, parenteral nutrition), to draw blood, and to monitor the central venous pressure.¹ The internal jugular vein is one of the preferred veins for central venous access.^1,2 Normally, the anatomy of the jugular venous system and the design of the catheter facilitate proper insertion. Occasionally, however, despite proper technique, the tip of the catheter may not terminate at the desired level, resulting in aberrant placement in the internal thoracic vein, superior vena cava, azygos vein, accessory hemiazygos vein, or axillary vein.^1–8

The use of chest radiographs to establish the correct placement of internal jugular and subclavian lines has been advocated and is routinely practiced.^6,7 Obtaining a chest x-ray to confirm line placement is particularly important in patients with prior multiple and difficult catheterizations. The lateral view is seldom obtained when confirming central neck line placement, but when the anteroposterior view is not reassuring, it may be prudent to obtain this alternate view.

In a large retrospective analysis,⁹ cannulation of the azygos arch occurred in about 1.2% of insertions, and the rate was about seven times higher when the left jugular vein was used than when the right one was used. A smaller study gave the frequency of azygos arch cannulation as 0.7%.¹⁰

All procedure-related complications of central line insertion in the neck can also occur with aberrant azygos vein cannulation. These include infection, bacteremia, pneumothorax, hemothorax, arterial puncture, and various other mechanical complications. It should be noted that aberrant cannulation of the azygos arch is particularly hazardous, and that complication rates are typically higher. These complications are mainly due to the smaller vascular lumen and to the direction of blood flow in the azygos venous system.

KNOWING THE ANATOMY IS CRUCIAL

Knowledge of venous anatomy and its variants is crucial both for insertion and for ascertaining the correct placement of central venous lines.

The azygos vein has a much smaller lumen than the superior vena cava. Although the lumen size may vary significantly, the maximum diameter of the anterior arch of the azygos vein is about 6 to 7 mm,¹¹ whereas the superior vena cava lumen is typically 1.5 to 2 cm in diameter.¹² In addition, when a catheter is inserted into the superior vena cava, the direction of blood flow and the direction of the infusion are the same, but when the catheter is inserted into the azygos system, the directions of blood flow and infusion are opposite, contributing to local turbulence.

Both these factors increase the chance of puncturing the vein when the azygos arch is aberrantly cannulated for central venous access.⁹ Venous perforation has been reported in as many as 19% of cases in which the azygos arch was inadvertently cannulated. Venous perforation can lead to hemopericardium, hemomediastinum, and hemorrhagic pleural effusions, which can lead to significant morbidity and even death. Perforation, thrombosis, stenosis, and complete occlusion have been reported subsequent to catheter malposition in the azygos vein.¹³

Patients in whom the azygos vein is inadvertently cannulated may tolerate infusions and blood draws, but this does not mean that inadvertent azygos vein cannulation is acceptable, especially given the late complications of vascular perforation that can occur.⁹

The cannulation of the azygos vein in our patient was completely unintentional; nevertheless, the line was kept in and used for a short period for the initial rehydration and pain control and was subsequently removed without any complications.

WHEN IS CANNULATION OF THE AZYGOS VEIN AN OPTION?

In patients with previous multiple central vein cannulations, the rates of thrombosis and of fibrotic changes in these veins are high. In patients with thrombosis of both the superior vena cava and the inferior vena cava, direct insertion of a catheter into the azygos vein has been suggested as an alternate route to obtain access for dialysis.⁸ This approach has also been used successfully to administer total parenteral nutrition for a prolonged time in pediatric patients.¹⁴ In short, the azygos vein is never preferred for central venous access, but it can occasionally serve as an alternate route.^5–9

TAKE-HOME POINTS

The radiographic assessment of an internal jugular or subclavian line may occasionally be deceptive if based solely on the anteroposterior view; confirmation may require a lateral view. We found no guidelines for using the azygos vein for central venous access. The options in cases of aberrant cannulation include leaving the line in, removing and reinserting it at the same or another site under fluoroscopy, and attempting to reposition it after changing the catheter over a guidewire.

The use of central lines found to be in an aberrant position should be driven by clinical judgment based on the urgency of the need of access, the availability or feasibility of other access options, and the intended use. The use of the azygos vein is fraught with procedural complications, as well as postprocedural complications related to vascular perforation. If the position of the catheter tip on the anteroposterior radiographic view is not satisfactory, obtaining a lateral view should be considered.