Haley M. Phillippe, PharmD, BCPS

CASE Anthony D, a 61-year-old patient of yours with hypertension and diabetes, is admitted to the hospital with atrial fibrillation and chest pain that radiates to his left arm and hand. On Day 1, he receives aspirin 325 mg and enoxaparin 1 mg/kg; the following day, the patient receives a 600-mg loading dose of clopidogrel prior to catheterization. He undergoes percutaneous coronary intervention and a bare metal stent is placed in his circumflex artery.

The following day, Anthony is ready for discharge and you consider which maintenance drugs to put him on, given that he already takes multiple medications. Is he a candidate for triple therapy?

Triple therapy—the concurrent use of aspirin, a thienopyridine antiplatelet agent, and warfarin—is often prescribed for patients with atrial fibrillation who experience acute coronary syndrome (ACS) or require percutaneous coronary intervention with the placement of a stent (PCI-S). The danger associated with concomitantly treating a patient with 3 agents, each of which has a distinct mechanism that increases bleeding risk, is high, but for carefully selected patients, the benefit may outweigh the risk.

Several studies have evaluated triple therapy and compared it with single or dual therapy (TABLE).^1-5 Due to a lack of robust outcome studies, however, the benefits and risks of triple therapy cannot be directly quantified, nor are they generalizable to all potential candidates for triple therapy. Thus, finding the optimal treatment for secondary prevention of ACS or prevention of stent thrombosis in a patient with atrial fibrillation requires an understanding of the potential consequences of triple therapy—and a thorough assessment of the patient’s risk of reinfarction, stroke, and bleeding complications.^6-9 To make the best treatment decisions and provide adequate support to patients who were started on triple therapy during a recent hospitalization, here’s what you need to know.

TABLE
Triple therapy: What the studies show

First, a review of the components

Aspirin, a key component of triple therapy, is the only nonsteroidal anti-inflammatory drug (NSAID) indicated for primary or secondary prevention of cardiovascular events.^10,11 The reason: Aspirin is more selective for cyclooxygenase-1 (COX-1) than other NSAIDs and irreversibly inhibits COX enzymes.¹¹ The aspirin-induced decrease in thromboxane production leads to a decline in platelet activation and aggregation, which accounts both for aspirin’s beneficial cardiovascular effects and the associated risk of bleeding—aspirin’s most common adverse effect.¹²

Most major bleeds linked to aspirin use involve the gastrointestinal (GI) tract, primarily because of the drug’s direct and indirect effects on the GI mucosa.^11-14 Aspirin’s toxicities are dose related, but its antiplatelet properties do not appear to be.¹⁴

Adding a thienopyridine
Thienopyridine antiplatelet drugs indicated for the secondary prevention of cardiovascular events after ACS or PCI-S include ticlopidine, clopidogrel, and prasugrel.¹⁵ Ticlopidine, the first such agent approved in the United States, is rarely used because of potential neutropenia and thrombotic thrombocytopenia purpura.¹⁶

Clopidogrel, the most commonly used agent for the purpose of secondary prevention, is the only thienopyridine with trial data for triple therapy.¹⁷ Clopidogrel’s antiplatelet effect, however, is highly dependent on specific cytochrome P-450 (CYP) enzymes for conversion to its active metabolite, and can be impaired by genetic variations in CYP 2C19, as well as by medication interactions. This has led to concern about the drug’s efficacy for secondary prevention of ACS.^6,17,18 In 2010, the US Food and Drug Administration (FDA) added a black-box warning for clopidogrel, emphasizing the risk of myocardial infarction (MI), stroke, and cardiovascular death in patients with defective CYP 2C19 activity.¹⁹

Prasugrel, approved by the FDA in 2009,²⁰ is useful for patients who respond poorly to clopidogrel. In fact, inadequate platelet inhibition with clopidogrel has prompted some physicians to choose prasugrel as a component of triple therapy.

While prasugrel may have greater efficacy compared with clopidogrel in preventing reinfarction, it appears to have a higher bleeding rate.^15,17 Because of its bleeding profile, prasugrel is not recommended for patients >75 years unless they are at high risk for MI (prior MI or diabetes), and it is contraindicated for patients with a history of stroke. Caution is needed when prasugrel is prescribed for patients who weigh <132 lb (consider a maintenance dose of 5 mg/d rather than the usual 10 mg/d) or have an increased propensity to bleed.¹⁵

Warfarin provides the anticoagulant component of triple therapy
Until late last year, when dabigatran received FDA approval for use in stroke prevention,²¹ warfarin was the only oral anticoagulant available in the United States. (To learn more about dabigatran, which is not included in this review because of the lack of evidence regarding its use in triple therapy, see “Time to try this warfarin alternative?”.)

Because multiple drug, food, and disease state interactions can interfere with warfarin therapy, frequent monitoring to maintain a target international normalized ratio (INR) is required.^22,23 (See Patient on warfarin? Steer clear of these drugs, in “Avoiding drug interactions: Here’s help,” J Fam Pract. 2010;59: 322-329).

Bridge therapy. Warfarin requires several days to reach its full effect, so anticoagulation with a more immediate-acting medication, such as a low-molecular-weight heparin or fondaparinux, is often used until the INR goal is reached.^22,23 Thus, there are instances in which patients requiring triple therapy are actually receiving 4 drugs that increase bleeding risk.

When (or whether) to consider triple therapy

While triple therapy may be an option for patients with atrial fibrillation and ACS or PCI-S, there is no validated scoring system to aid in treatment decisions.²⁴ As already noted, selecting the optimal therapy requires an individual assessment of the patient’s risk of reinfarction, stent thrombosis, stroke, and bleeding complications.

Risk factors for reinfarction and stent thrombosis are the same ones that increase the risk of ACS initially, and include diabetes mellitus, heart failure, smoking, hyperlipidemia, and hypertension.^10,16 Advanced age; uncontrolled hypertension; chronic conditions such as peripheral vascular disease, anemia, and peptic ulcer disease; and a history of major bleeds are associated with an increased risk of bleeding. ^24,25

In a retrospective trial evaluating independent predictors of major bleeding in patients with atrial fibrillation who underwent PCI-S,¹ the researchers identified several factors that increased the risk of early major bleeding (within 48 hours of stent placement): the use of a glycoprotein IIb/IIIa inhibitor, stenting of ≥3 vessels, or left main artery disease. Factors that significantly increased the risk of major bleeding more than 48 hours after the procedure included triple therapy, an early major bleed, and baseline anemia.¹

Drug combinations: What to consider
In addition to determining whether a patient is a good candidate for triple therapy, it is crucial to consider the choice of drugs. Benefits of prasugrel, compared with clopidogrel, include fewer drug interactions, less resistance to platelet inhibition, more rapid platelet inhibition after an oral loading dose, and higher levels of platelet inhibition during maintenance dosing.^15,17

Improved outcomes are another potential benefit, according to TRITON-Thrombolysis in Myocardial Infarction (TIMI) 38,¹⁷ a large randomized prospective trial comparing the use of prasugrel with clopidogrel in triple therapy. Among study participants, the primary outcome rate—the combined incidence of death from cardiovascular causes, nonfatal MI, and nonfatal stroke—was 9.9% for those on prasugrel vs 12.1% for the clopidogrel group (hazard ratio [HR]=0.81; 95% confidence interval [CI], 0.73-0.90, P<.001).¹⁷ The rate of TIMI major bleeding, however, was higher among those on prasugrel (HR=1.32; 95% CI, 1.03-1.68, P=.03). The evidence suggests that for every 1000 patients treated with prasugrel vs clopidogrel, 24 primary outcomes would be prevented but there would be 10 additional bleeding events.^17,26

CASE Anthony D’s risk for stroke, infarction, and stent thrombosis—based on his history of diabetes and hypertension, atrial fibrillation, and PCI-S—and absence of independent bleeding risk factors make him a good candidate for triple therapy. Because the patient is at high risk, the physician starts him on 2 anticoagulants—warfarin (5 mg at bedtime) and enoxaparin (125 mg every 12 hours)—on the evening of his second day in the hospital. On Day 3, clinicians test Anthony’s prothrombin time/international normalized ratio (PT/INR) and P₂Y₁₂ function assay, which measure 14.9/1.1 and 8% platelet inhibition, respectively.

The patient is discharged on the following medication schedule: enoxaparin 125 mg every 12 hours, to be discontinued after 3 days; warfarin 5 mg daily, prasugrel 10 mg daily, and aspirin 81 mg daily; metoprolol succinate 100 mg daily; lisinopril 10 mg daily; rosuvastatin 10 mg daily; glyburide-metformin 5 mg/500 mg, 2 tablets twice daily; and insulin glargine 20 units at bedtime.

Safety and efficacy: Do the benefits outweigh the risk?
Safety is central to the continuing controversy surrounding the use of triple therapy.^6,9 To date, however, no randomized prospective studies have evaluated its benefits and risks.

Numerous retrospective studies and case series have assessed the risk of bleeding associated with triple therapy.⁶ Several studies compared triple therapy with dual antiplatelet therapy without anticoagulation, and found a several-fold increase in both major and minor bleeding events in the triple therapy group.⁶

Few trials have assessed both the safety and the efficacy of triple therapy, however. One exception is a large retrospective trial, published in 2008.² The researchers found that triple therapy significantly reduced the incidence of major cardiac events (death, acute MI, and target lesion revascularization); all-cause mortality; and major adverse effects (ie, any major cardiovascular event, major bleeding complication, and/or stroke), with no statistically significant increase in major bleeding events compared with patients on antiplatelet therapy without anticoagulation.²

The results of this trial, like those of other studies evaluating triple therapy, were weakened by variance in both the duration of antithrombotic therapy and the drug therapies studied. This limitation was off set, however, by multivariant analysis and well-documented follow-up.² Despite the researchers’ findings, however, the results of other trials (and our knowledge of the mechanisms of action of the drug components) suggest that triple therapy significantly increases bleeding risk. For patients who would likely benefit from it but face an increased bleeding risk, there are ways to mitigate risk.

Prescribing triple therapy, while mitigating the risks
If bleeding is a serious concern in a patient who would benefit from triple therapy, the drug regimen may be adjusted. Options include:

• targeting a lower INR (2.0-2.5 vs the standard 2.0-3.0).⁶ While various trials have found a 2.0 to 3.0 range to reduce the risk of stroke, none has compared it with a lower range to evaluate reduction in bleeding risk.²⁷ One potential benefit of trying to maintain a lower INR is the decrease in deviations into the 3.0 to 4.0 range, which is associated with an increased bleeding risk.²⁸ However, lowering the INR target is not supported by any literature.^1,18
• using low-dose aspirin therapy after PCI-S
• limiting the thienopyridine component of triple therapy to one month after ACS or PCI-S.⁶

When the risks of triple therapy outweigh the benefits because of an exceedingly high bleeding risk, single antiplatelet therapy with warfarin is another option to consider.

CASE [H17012] Anthony D’s discharge instructions called for an 81 mg daily dose of aspirin, as opposed to the 325-mg dose for the first 3 months of triple therapy after stent placement recommended by the American College of Cardiology/American Heart Association (ACC/AHA) guidelines for unstable angina/ non-ST segment elevated MI.¹ Although the patient had no independent bleeding risk, his physician selected the lower dose of aspirin to mitigate the increased bleeding risk posed by the use of prasugrel as a component of triple therapy.⁶

Lower aspirin dose. Pharmacodynamic studies support the use of a lower dose of aspirin, finding that serum thromboxane is completely inhibited by a maintenance dose as low as 30 mg/d in healthy individuals and 50 mg/d for those with chronic stable angina.¹⁴ Using low-dose aspirin for the secondary prevention of ACS when triple therapy is indicated is likely to reduce GI toxicities as well as bleeding risk.

Reduce the duration of dual antiplatelet therapy. According to the ACC/AHA guidelines, thienopyridine therapy can be limited to one month in patients who are medically managed or have had a bare metal stent placed if there is concern about the patient’s risk of bleeding.^6,10 Based on the findings of the one study that found triple therapy to be an independent predictor of major bleeds, this approach seems reasonable.¹ It is called into question, however, by another recent trial, which found that patients on dual antiplatelet therapy for one year (vs one month) had a statistically significant improvement in cardiovascular outcomes.¹⁶

Before limiting a patient’s thienopyridine therapy to one month, consider his or her risk of reinfarction. If it is high, continuing the thienopyridine for at least one year is likely to provide the most benefit.

The largest triple therapy trial to date compared the efficacy of triple therapy vs dual therapy (a single antiplatelet agent plus warfarin) in patients with ACS and an indication for warfarin therapy.³ This trial found no statistically significant differences in the combined occurrence of death, stroke, unscheduled PCI, and MI between the 2 treatment groups. (Bleeding risk was not evaluated.) Stroke was significantly increased in the group that received therapy with warfarin and a single antiplatelet agent, with this caveat: The occurrence of stroke was so low overall that no conclusions could be reached from this difference.³

One problem with this trial, and with others evaluating triple therapy, has to do with the lack of consistency, as well as the duration. The warfarin and single antiplatelet group, for example, may have included patients who were receiving only warfarin, aspirin, or clopidogrel by 6 months after initiating treatment.³ Thus, although reinfarction or stent thrombosis after ACS or PCI-S typically occurs within the first few months, any triple therapy trial that lasts less than a year is likely to report skewed results. JFP

CORRESPONDENCE
Haley M. Phillippe, PharmD, BCPS, Auburn University Harrison School of Pharmacy, University of Alabama Birmingham School of Medicine?Huntsville, 301 Governors Drive, Huntsville, AL 35801; mccrahl@auburn.edu

CASE Anthony D, a 61-year-old patient of yours with hypertension and diabetes, is admitted to the hospital with atrial fibrillation and chest pain that radiates to his left arm and hand. On Day 1, he receives aspirin 325 mg and enoxaparin 1 mg/kg; the following day, the patient receives a 600-mg loading dose of clopidogrel prior to catheterization. He undergoes percutaneous coronary intervention and a bare metal stent is placed in his circumflex artery.

The following day, Anthony is ready for discharge and you consider which maintenance drugs to put him on, given that he already takes multiple medications. Is he a candidate for triple therapy?

Triple therapy—the concurrent use of aspirin, a thienopyridine antiplatelet agent, and warfarin—is often prescribed for patients with atrial fibrillation who experience acute coronary syndrome (ACS) or require percutaneous coronary intervention with the placement of a stent (PCI-S). The danger associated with concomitantly treating a patient with 3 agents, each of which has a distinct mechanism that increases bleeding risk, is high, but for carefully selected patients, the benefit may outweigh the risk.

Several studies have evaluated triple therapy and compared it with single or dual therapy (TABLE).^1-5 Due to a lack of robust outcome studies, however, the benefits and risks of triple therapy cannot be directly quantified, nor are they generalizable to all potential candidates for triple therapy. Thus, finding the optimal treatment for secondary prevention of ACS or prevention of stent thrombosis in a patient with atrial fibrillation requires an understanding of the potential consequences of triple therapy—and a thorough assessment of the patient’s risk of reinfarction, stroke, and bleeding complications.^6-9 To make the best treatment decisions and provide adequate support to patients who were started on triple therapy during a recent hospitalization, here’s what you need to know.

TABLE
Triple therapy: What the studies show

First, a review of the components

Aspirin, a key component of triple therapy, is the only nonsteroidal anti-inflammatory drug (NSAID) indicated for primary or secondary prevention of cardiovascular events.^10,11 The reason: Aspirin is more selective for cyclooxygenase-1 (COX-1) than other NSAIDs and irreversibly inhibits COX enzymes.¹¹ The aspirin-induced decrease in thromboxane production leads to a decline in platelet activation and aggregation, which accounts both for aspirin’s beneficial cardiovascular effects and the associated risk of bleeding—aspirin’s most common adverse effect.¹²

Most major bleeds linked to aspirin use involve the gastrointestinal (GI) tract, primarily because of the drug’s direct and indirect effects on the GI mucosa.^11-14 Aspirin’s toxicities are dose related, but its antiplatelet properties do not appear to be.¹⁴

Adding a thienopyridine
Thienopyridine antiplatelet drugs indicated for the secondary prevention of cardiovascular events after ACS or PCI-S include ticlopidine, clopidogrel, and prasugrel.¹⁵ Ticlopidine, the first such agent approved in the United States, is rarely used because of potential neutropenia and thrombotic thrombocytopenia purpura.¹⁶

Clopidogrel, the most commonly used agent for the purpose of secondary prevention, is the only thienopyridine with trial data for triple therapy.¹⁷ Clopidogrel’s antiplatelet effect, however, is highly dependent on specific cytochrome P-450 (CYP) enzymes for conversion to its active metabolite, and can be impaired by genetic variations in CYP 2C19, as well as by medication interactions. This has led to concern about the drug’s efficacy for secondary prevention of ACS.^6,17,18 In 2010, the US Food and Drug Administration (FDA) added a black-box warning for clopidogrel, emphasizing the risk of myocardial infarction (MI), stroke, and cardiovascular death in patients with defective CYP 2C19 activity.¹⁹

Prasugrel, approved by the FDA in 2009,²⁰ is useful for patients who respond poorly to clopidogrel. In fact, inadequate platelet inhibition with clopidogrel has prompted some physicians to choose prasugrel as a component of triple therapy.

While prasugrel may have greater efficacy compared with clopidogrel in preventing reinfarction, it appears to have a higher bleeding rate.^15,17 Because of its bleeding profile, prasugrel is not recommended for patients >75 years unless they are at high risk for MI (prior MI or diabetes), and it is contraindicated for patients with a history of stroke. Caution is needed when prasugrel is prescribed for patients who weigh <132 lb (consider a maintenance dose of 5 mg/d rather than the usual 10 mg/d) or have an increased propensity to bleed.¹⁵

Warfarin provides the anticoagulant component of triple therapy
Until late last year, when dabigatran received FDA approval for use in stroke prevention,²¹ warfarin was the only oral anticoagulant available in the United States. (To learn more about dabigatran, which is not included in this review because of the lack of evidence regarding its use in triple therapy, see “Time to try this warfarin alternative?”.)

Because multiple drug, food, and disease state interactions can interfere with warfarin therapy, frequent monitoring to maintain a target international normalized ratio (INR) is required.^22,23 (See Patient on warfarin? Steer clear of these drugs, in “Avoiding drug interactions: Here’s help,” J Fam Pract. 2010;59: 322-329).

Bridge therapy. Warfarin requires several days to reach its full effect, so anticoagulation with a more immediate-acting medication, such as a low-molecular-weight heparin or fondaparinux, is often used until the INR goal is reached.^22,23 Thus, there are instances in which patients requiring triple therapy are actually receiving 4 drugs that increase bleeding risk.

When (or whether) to consider triple therapy

While triple therapy may be an option for patients with atrial fibrillation and ACS or PCI-S, there is no validated scoring system to aid in treatment decisions.²⁴ As already noted, selecting the optimal therapy requires an individual assessment of the patient’s risk of reinfarction, stent thrombosis, stroke, and bleeding complications.

Risk factors for reinfarction and stent thrombosis are the same ones that increase the risk of ACS initially, and include diabetes mellitus, heart failure, smoking, hyperlipidemia, and hypertension.^10,16 Advanced age; uncontrolled hypertension; chronic conditions such as peripheral vascular disease, anemia, and peptic ulcer disease; and a history of major bleeds are associated with an increased risk of bleeding. ^24,25

In a retrospective trial evaluating independent predictors of major bleeding in patients with atrial fibrillation who underwent PCI-S,¹ the researchers identified several factors that increased the risk of early major bleeding (within 48 hours of stent placement): the use of a glycoprotein IIb/IIIa inhibitor, stenting of ≥3 vessels, or left main artery disease. Factors that significantly increased the risk of major bleeding more than 48 hours after the procedure included triple therapy, an early major bleed, and baseline anemia.¹

Drug combinations: What to consider
In addition to determining whether a patient is a good candidate for triple therapy, it is crucial to consider the choice of drugs. Benefits of prasugrel, compared with clopidogrel, include fewer drug interactions, less resistance to platelet inhibition, more rapid platelet inhibition after an oral loading dose, and higher levels of platelet inhibition during maintenance dosing.^15,17

Improved outcomes are another potential benefit, according to TRITON-Thrombolysis in Myocardial Infarction (TIMI) 38,¹⁷ a large randomized prospective trial comparing the use of prasugrel with clopidogrel in triple therapy. Among study participants, the primary outcome rate—the combined incidence of death from cardiovascular causes, nonfatal MI, and nonfatal stroke—was 9.9% for those on prasugrel vs 12.1% for the clopidogrel group (hazard ratio [HR]=0.81; 95% confidence interval [CI], 0.73-0.90, P<.001).¹⁷ The rate of TIMI major bleeding, however, was higher among those on prasugrel (HR=1.32; 95% CI, 1.03-1.68, P=.03). The evidence suggests that for every 1000 patients treated with prasugrel vs clopidogrel, 24 primary outcomes would be prevented but there would be 10 additional bleeding events.^17,26

CASE Anthony D’s risk for stroke, infarction, and stent thrombosis—based on his history of diabetes and hypertension, atrial fibrillation, and PCI-S—and absence of independent bleeding risk factors make him a good candidate for triple therapy. Because the patient is at high risk, the physician starts him on 2 anticoagulants—warfarin (5 mg at bedtime) and enoxaparin (125 mg every 12 hours)—on the evening of his second day in the hospital. On Day 3, clinicians test Anthony’s prothrombin time/international normalized ratio (PT/INR) and P₂Y₁₂ function assay, which measure 14.9/1.1 and 8% platelet inhibition, respectively.

The patient is discharged on the following medication schedule: enoxaparin 125 mg every 12 hours, to be discontinued after 3 days; warfarin 5 mg daily, prasugrel 10 mg daily, and aspirin 81 mg daily; metoprolol succinate 100 mg daily; lisinopril 10 mg daily; rosuvastatin 10 mg daily; glyburide-metformin 5 mg/500 mg, 2 tablets twice daily; and insulin glargine 20 units at bedtime.

Safety and efficacy: Do the benefits outweigh the risk?
Safety is central to the continuing controversy surrounding the use of triple therapy.^6,9 To date, however, no randomized prospective studies have evaluated its benefits and risks.

Numerous retrospective studies and case series have assessed the risk of bleeding associated with triple therapy.⁶ Several studies compared triple therapy with dual antiplatelet therapy without anticoagulation, and found a several-fold increase in both major and minor bleeding events in the triple therapy group.⁶

Few trials have assessed both the safety and the efficacy of triple therapy, however. One exception is a large retrospective trial, published in 2008.² The researchers found that triple therapy significantly reduced the incidence of major cardiac events (death, acute MI, and target lesion revascularization); all-cause mortality; and major adverse effects (ie, any major cardiovascular event, major bleeding complication, and/or stroke), with no statistically significant increase in major bleeding events compared with patients on antiplatelet therapy without anticoagulation.²

The results of this trial, like those of other studies evaluating triple therapy, were weakened by variance in both the duration of antithrombotic therapy and the drug therapies studied. This limitation was off set, however, by multivariant analysis and well-documented follow-up.² Despite the researchers’ findings, however, the results of other trials (and our knowledge of the mechanisms of action of the drug components) suggest that triple therapy significantly increases bleeding risk. For patients who would likely benefit from it but face an increased bleeding risk, there are ways to mitigate risk.

Prescribing triple therapy, while mitigating the risks
If bleeding is a serious concern in a patient who would benefit from triple therapy, the drug regimen may be adjusted. Options include:

• targeting a lower INR (2.0-2.5 vs the standard 2.0-3.0).⁶ While various trials have found a 2.0 to 3.0 range to reduce the risk of stroke, none has compared it with a lower range to evaluate reduction in bleeding risk.²⁷ One potential benefit of trying to maintain a lower INR is the decrease in deviations into the 3.0 to 4.0 range, which is associated with an increased bleeding risk.²⁸ However, lowering the INR target is not supported by any literature.^1,18
• using low-dose aspirin therapy after PCI-S
• limiting the thienopyridine component of triple therapy to one month after ACS or PCI-S.⁶

When the risks of triple therapy outweigh the benefits because of an exceedingly high bleeding risk, single antiplatelet therapy with warfarin is another option to consider.

CASE [H17012] Anthony D’s discharge instructions called for an 81 mg daily dose of aspirin, as opposed to the 325-mg dose for the first 3 months of triple therapy after stent placement recommended by the American College of Cardiology/American Heart Association (ACC/AHA) guidelines for unstable angina/ non-ST segment elevated MI.¹ Although the patient had no independent bleeding risk, his physician selected the lower dose of aspirin to mitigate the increased bleeding risk posed by the use of prasugrel as a component of triple therapy.⁶

Lower aspirin dose. Pharmacodynamic studies support the use of a lower dose of aspirin, finding that serum thromboxane is completely inhibited by a maintenance dose as low as 30 mg/d in healthy individuals and 50 mg/d for those with chronic stable angina.¹⁴ Using low-dose aspirin for the secondary prevention of ACS when triple therapy is indicated is likely to reduce GI toxicities as well as bleeding risk.

Reduce the duration of dual antiplatelet therapy. According to the ACC/AHA guidelines, thienopyridine therapy can be limited to one month in patients who are medically managed or have had a bare metal stent placed if there is concern about the patient’s risk of bleeding.^6,10 Based on the findings of the one study that found triple therapy to be an independent predictor of major bleeds, this approach seems reasonable.¹ It is called into question, however, by another recent trial, which found that patients on dual antiplatelet therapy for one year (vs one month) had a statistically significant improvement in cardiovascular outcomes.¹⁶

Before limiting a patient’s thienopyridine therapy to one month, consider his or her risk of reinfarction. If it is high, continuing the thienopyridine for at least one year is likely to provide the most benefit.

The largest triple therapy trial to date compared the efficacy of triple therapy vs dual therapy (a single antiplatelet agent plus warfarin) in patients with ACS and an indication for warfarin therapy.³ This trial found no statistically significant differences in the combined occurrence of death, stroke, unscheduled PCI, and MI between the 2 treatment groups. (Bleeding risk was not evaluated.) Stroke was significantly increased in the group that received therapy with warfarin and a single antiplatelet agent, with this caveat: The occurrence of stroke was so low overall that no conclusions could be reached from this difference.³

One problem with this trial, and with others evaluating triple therapy, has to do with the lack of consistency, as well as the duration. The warfarin and single antiplatelet group, for example, may have included patients who were receiving only warfarin, aspirin, or clopidogrel by 6 months after initiating treatment.³ Thus, although reinfarction or stent thrombosis after ACS or PCI-S typically occurs within the first few months, any triple therapy trial that lasts less than a year is likely to report skewed results. JFP

CORRESPONDENCE
Haley M. Phillippe, PharmD, BCPS, Auburn University Harrison School of Pharmacy, University of Alabama Birmingham School of Medicine?Huntsville, 301 Governors Drive, Huntsville, AL 35801; mccrahl@auburn.edu

CASE Anthony D, a 61-year-old patient of yours with hypertension and diabetes, is admitted to the hospital with atrial fibrillation and chest pain that radiates to his left arm and hand. On Day 1, he receives aspirin 325 mg and enoxaparin 1 mg/kg; the following day, the patient receives a 600-mg loading dose of clopidogrel prior to catheterization. He undergoes percutaneous coronary intervention and a bare metal stent is placed in his circumflex artery.

The following day, Anthony is ready for discharge and you consider which maintenance drugs to put him on, given that he already takes multiple medications. Is he a candidate for triple therapy?

Triple therapy—the concurrent use of aspirin, a thienopyridine antiplatelet agent, and warfarin—is often prescribed for patients with atrial fibrillation who experience acute coronary syndrome (ACS) or require percutaneous coronary intervention with the placement of a stent (PCI-S). The danger associated with concomitantly treating a patient with 3 agents, each of which has a distinct mechanism that increases bleeding risk, is high, but for carefully selected patients, the benefit may outweigh the risk.

Several studies have evaluated triple therapy and compared it with single or dual therapy (TABLE).^1-5 Due to a lack of robust outcome studies, however, the benefits and risks of triple therapy cannot be directly quantified, nor are they generalizable to all potential candidates for triple therapy. Thus, finding the optimal treatment for secondary prevention of ACS or prevention of stent thrombosis in a patient with atrial fibrillation requires an understanding of the potential consequences of triple therapy—and a thorough assessment of the patient’s risk of reinfarction, stroke, and bleeding complications.^6-9 To make the best treatment decisions and provide adequate support to patients who were started on triple therapy during a recent hospitalization, here’s what you need to know.

TABLE
Triple therapy: What the studies show

First, a review of the components

Aspirin, a key component of triple therapy, is the only nonsteroidal anti-inflammatory drug (NSAID) indicated for primary or secondary prevention of cardiovascular events.^10,11 The reason: Aspirin is more selective for cyclooxygenase-1 (COX-1) than other NSAIDs and irreversibly inhibits COX enzymes.¹¹ The aspirin-induced decrease in thromboxane production leads to a decline in platelet activation and aggregation, which accounts both for aspirin’s beneficial cardiovascular effects and the associated risk of bleeding—aspirin’s most common adverse effect.¹²

Most major bleeds linked to aspirin use involve the gastrointestinal (GI) tract, primarily because of the drug’s direct and indirect effects on the GI mucosa.^11-14 Aspirin’s toxicities are dose related, but its antiplatelet properties do not appear to be.¹⁴

Adding a thienopyridine
Thienopyridine antiplatelet drugs indicated for the secondary prevention of cardiovascular events after ACS or PCI-S include ticlopidine, clopidogrel, and prasugrel.¹⁵ Ticlopidine, the first such agent approved in the United States, is rarely used because of potential neutropenia and thrombotic thrombocytopenia purpura.¹⁶

Clopidogrel, the most commonly used agent for the purpose of secondary prevention, is the only thienopyridine with trial data for triple therapy.¹⁷ Clopidogrel’s antiplatelet effect, however, is highly dependent on specific cytochrome P-450 (CYP) enzymes for conversion to its active metabolite, and can be impaired by genetic variations in CYP 2C19, as well as by medication interactions. This has led to concern about the drug’s efficacy for secondary prevention of ACS.^6,17,18 In 2010, the US Food and Drug Administration (FDA) added a black-box warning for clopidogrel, emphasizing the risk of myocardial infarction (MI), stroke, and cardiovascular death in patients with defective CYP 2C19 activity.¹⁹

Prasugrel, approved by the FDA in 2009,²⁰ is useful for patients who respond poorly to clopidogrel. In fact, inadequate platelet inhibition with clopidogrel has prompted some physicians to choose prasugrel as a component of triple therapy.

While prasugrel may have greater efficacy compared with clopidogrel in preventing reinfarction, it appears to have a higher bleeding rate.^15,17 Because of its bleeding profile, prasugrel is not recommended for patients >75 years unless they are at high risk for MI (prior MI or diabetes), and it is contraindicated for patients with a history of stroke. Caution is needed when prasugrel is prescribed for patients who weigh <132 lb (consider a maintenance dose of 5 mg/d rather than the usual 10 mg/d) or have an increased propensity to bleed.¹⁵

Warfarin provides the anticoagulant component of triple therapy
Until late last year, when dabigatran received FDA approval for use in stroke prevention,²¹ warfarin was the only oral anticoagulant available in the United States. (To learn more about dabigatran, which is not included in this review because of the lack of evidence regarding its use in triple therapy, see “Time to try this warfarin alternative?”.)

Because multiple drug, food, and disease state interactions can interfere with warfarin therapy, frequent monitoring to maintain a target international normalized ratio (INR) is required.^22,23 (See Patient on warfarin? Steer clear of these drugs, in “Avoiding drug interactions: Here’s help,” J Fam Pract. 2010;59: 322-329).

Bridge therapy. Warfarin requires several days to reach its full effect, so anticoagulation with a more immediate-acting medication, such as a low-molecular-weight heparin or fondaparinux, is often used until the INR goal is reached.^22,23 Thus, there are instances in which patients requiring triple therapy are actually receiving 4 drugs that increase bleeding risk.

When (or whether) to consider triple therapy

While triple therapy may be an option for patients with atrial fibrillation and ACS or PCI-S, there is no validated scoring system to aid in treatment decisions.²⁴ As already noted, selecting the optimal therapy requires an individual assessment of the patient’s risk of reinfarction, stent thrombosis, stroke, and bleeding complications.

Risk factors for reinfarction and stent thrombosis are the same ones that increase the risk of ACS initially, and include diabetes mellitus, heart failure, smoking, hyperlipidemia, and hypertension.^10,16 Advanced age; uncontrolled hypertension; chronic conditions such as peripheral vascular disease, anemia, and peptic ulcer disease; and a history of major bleeds are associated with an increased risk of bleeding. ^24,25

In a retrospective trial evaluating independent predictors of major bleeding in patients with atrial fibrillation who underwent PCI-S,¹ the researchers identified several factors that increased the risk of early major bleeding (within 48 hours of stent placement): the use of a glycoprotein IIb/IIIa inhibitor, stenting of ≥3 vessels, or left main artery disease. Factors that significantly increased the risk of major bleeding more than 48 hours after the procedure included triple therapy, an early major bleed, and baseline anemia.¹

Drug combinations: What to consider
In addition to determining whether a patient is a good candidate for triple therapy, it is crucial to consider the choice of drugs. Benefits of prasugrel, compared with clopidogrel, include fewer drug interactions, less resistance to platelet inhibition, more rapid platelet inhibition after an oral loading dose, and higher levels of platelet inhibition during maintenance dosing.^15,17

Improved outcomes are another potential benefit, according to TRITON-Thrombolysis in Myocardial Infarction (TIMI) 38,¹⁷ a large randomized prospective trial comparing the use of prasugrel with clopidogrel in triple therapy. Among study participants, the primary outcome rate—the combined incidence of death from cardiovascular causes, nonfatal MI, and nonfatal stroke—was 9.9% for those on prasugrel vs 12.1% for the clopidogrel group (hazard ratio [HR]=0.81; 95% confidence interval [CI], 0.73-0.90, P<.001).¹⁷ The rate of TIMI major bleeding, however, was higher among those on prasugrel (HR=1.32; 95% CI, 1.03-1.68, P=.03). The evidence suggests that for every 1000 patients treated with prasugrel vs clopidogrel, 24 primary outcomes would be prevented but there would be 10 additional bleeding events.^17,26

CASE Anthony D’s risk for stroke, infarction, and stent thrombosis—based on his history of diabetes and hypertension, atrial fibrillation, and PCI-S—and absence of independent bleeding risk factors make him a good candidate for triple therapy. Because the patient is at high risk, the physician starts him on 2 anticoagulants—warfarin (5 mg at bedtime) and enoxaparin (125 mg every 12 hours)—on the evening of his second day in the hospital. On Day 3, clinicians test Anthony’s prothrombin time/international normalized ratio (PT/INR) and P₂Y₁₂ function assay, which measure 14.9/1.1 and 8% platelet inhibition, respectively.

The patient is discharged on the following medication schedule: enoxaparin 125 mg every 12 hours, to be discontinued after 3 days; warfarin 5 mg daily, prasugrel 10 mg daily, and aspirin 81 mg daily; metoprolol succinate 100 mg daily; lisinopril 10 mg daily; rosuvastatin 10 mg daily; glyburide-metformin 5 mg/500 mg, 2 tablets twice daily; and insulin glargine 20 units at bedtime.

Safety and efficacy: Do the benefits outweigh the risk?
Safety is central to the continuing controversy surrounding the use of triple therapy.^6,9 To date, however, no randomized prospective studies have evaluated its benefits and risks.

Numerous retrospective studies and case series have assessed the risk of bleeding associated with triple therapy.⁶ Several studies compared triple therapy with dual antiplatelet therapy without anticoagulation, and found a several-fold increase in both major and minor bleeding events in the triple therapy group.⁶

Few trials have assessed both the safety and the efficacy of triple therapy, however. One exception is a large retrospective trial, published in 2008.² The researchers found that triple therapy significantly reduced the incidence of major cardiac events (death, acute MI, and target lesion revascularization); all-cause mortality; and major adverse effects (ie, any major cardiovascular event, major bleeding complication, and/or stroke), with no statistically significant increase in major bleeding events compared with patients on antiplatelet therapy without anticoagulation.²

The results of this trial, like those of other studies evaluating triple therapy, were weakened by variance in both the duration of antithrombotic therapy and the drug therapies studied. This limitation was off set, however, by multivariant analysis and well-documented follow-up.² Despite the researchers’ findings, however, the results of other trials (and our knowledge of the mechanisms of action of the drug components) suggest that triple therapy significantly increases bleeding risk. For patients who would likely benefit from it but face an increased bleeding risk, there are ways to mitigate risk.

Prescribing triple therapy, while mitigating the risks
If bleeding is a serious concern in a patient who would benefit from triple therapy, the drug regimen may be adjusted. Options include:

• targeting a lower INR (2.0-2.5 vs the standard 2.0-3.0).⁶ While various trials have found a 2.0 to 3.0 range to reduce the risk of stroke, none has compared it with a lower range to evaluate reduction in bleeding risk.²⁷ One potential benefit of trying to maintain a lower INR is the decrease in deviations into the 3.0 to 4.0 range, which is associated with an increased bleeding risk.²⁸ However, lowering the INR target is not supported by any literature.^1,18
• using low-dose aspirin therapy after PCI-S
• limiting the thienopyridine component of triple therapy to one month after ACS or PCI-S.⁶

When the risks of triple therapy outweigh the benefits because of an exceedingly high bleeding risk, single antiplatelet therapy with warfarin is another option to consider.

CASE [H17012] Anthony D’s discharge instructions called for an 81 mg daily dose of aspirin, as opposed to the 325-mg dose for the first 3 months of triple therapy after stent placement recommended by the American College of Cardiology/American Heart Association (ACC/AHA) guidelines for unstable angina/ non-ST segment elevated MI.¹ Although the patient had no independent bleeding risk, his physician selected the lower dose of aspirin to mitigate the increased bleeding risk posed by the use of prasugrel as a component of triple therapy.⁶

Lower aspirin dose. Pharmacodynamic studies support the use of a lower dose of aspirin, finding that serum thromboxane is completely inhibited by a maintenance dose as low as 30 mg/d in healthy individuals and 50 mg/d for those with chronic stable angina.¹⁴ Using low-dose aspirin for the secondary prevention of ACS when triple therapy is indicated is likely to reduce GI toxicities as well as bleeding risk.

Reduce the duration of dual antiplatelet therapy. According to the ACC/AHA guidelines, thienopyridine therapy can be limited to one month in patients who are medically managed or have had a bare metal stent placed if there is concern about the patient’s risk of bleeding.^6,10 Based on the findings of the one study that found triple therapy to be an independent predictor of major bleeds, this approach seems reasonable.¹ It is called into question, however, by another recent trial, which found that patients on dual antiplatelet therapy for one year (vs one month) had a statistically significant improvement in cardiovascular outcomes.¹⁶

Before limiting a patient’s thienopyridine therapy to one month, consider his or her risk of reinfarction. If it is high, continuing the thienopyridine for at least one year is likely to provide the most benefit.

The largest triple therapy trial to date compared the efficacy of triple therapy vs dual therapy (a single antiplatelet agent plus warfarin) in patients with ACS and an indication for warfarin therapy.³ This trial found no statistically significant differences in the combined occurrence of death, stroke, unscheduled PCI, and MI between the 2 treatment groups. (Bleeding risk was not evaluated.) Stroke was significantly increased in the group that received therapy with warfarin and a single antiplatelet agent, with this caveat: The occurrence of stroke was so low overall that no conclusions could be reached from this difference.³

One problem with this trial, and with others evaluating triple therapy, has to do with the lack of consistency, as well as the duration. The warfarin and single antiplatelet group, for example, may have included patients who were receiving only warfarin, aspirin, or clopidogrel by 6 months after initiating treatment.³ Thus, although reinfarction or stent thrombosis after ACS or PCI-S typically occurs within the first few months, any triple therapy trial that lasts less than a year is likely to report skewed results. JFP

CORRESPONDENCE
Haley M. Phillippe, PharmD, BCPS, Auburn University Harrison School of Pharmacy, University of Alabama Birmingham School of Medicine?Huntsville, 301 Governors Drive, Huntsville, AL 35801; mccrahl@auburn.edu

Each year, venous thrombosis develops in approximately 1 in 1000 people.¹ The cause: An alteration in blood composition, venous stasis, or vascular damage—commonly known as Virchow’s triad. Changes in blood composition are associated with hereditary thrombophilias, such as factor V Leiden mutation or a deficiency in protein C or S or antithrombin III (AT). Changes in blood flow (stasis) and vessel damage stem from acquired conditions that commonly lead to hypercoagulability—pregnancy, malignancy, and estrogen use among them.

Regardless of the reason a patient is at elevated risk, however, the goal is the same: to prevent the development of thrombi, thereby reducing the increased morbidity and mortality associated with thromboembolism. Achieving that goal requires an understanding of both inherited and acquired risk factors, familiarity with diagnostic tools, and knowledge of appropriate treatment. This review, which begins with hereditary hypercoagulable states before turning to acquired conditions associated with hypercoagulability, will help toward that end.

Keep these thrombophilias on your radar screen

Factor V Leiden mutation is the most common inherited hypercoagulable disorder, and the most common form of activated protein C resistance. The mutation is found in an estimated 5% to 10% of the general population.² Among patients with thromboembolic disorders, however, the incidence is considerably higher, with estimates ranging from 21% to 60%.^3,4 Factor V Leiden mutation is more prevalent among Caucasian populations, and rarely found in people of Asian or African descent.²

Prothrombin G20210A mutation, an autosomal-dominant disorder, is the second most common inherited hypercoagulable state.⁴ This mutation is associated with an increase in prothrombin levels, causing an elevation in thrombin and, in turn, a heightened risk of thrombosis.

Although prothrombin G20210A mutation is found in only 1% to 2% of the general population, its prevalence among those with a history of thromboembolic events is estimated at 5% to 19%.⁴ This disorder, too, varies significantly by ethnicity: People from southern Europe are twice as likely to be affected as northern Europeans, and the mutation is rarely found in people of Asian or African descent.^2,5

Protein C deficiency. Protein C, a vitamin K-dependent anticoagulant produced in the liver, is activated when thrombomodulin binds with thrombin in the presence of protein S, which serves as the cofactor. Protein C is required to inactivate clotting factors V and VIII.² The deficiency is an autosomal-dominant disorder, and is more likely to result in venous than arterial thrombosis.²

Protein C deficiency affects 1 in every 200 to 500 people in the general population; among patients with a history of venous thrombosis, its prevalence is 2% to 9%.^2,3 Generally, people with a protein C deficiency begin developing thrombi in their late teens, and about 75% suffer from 1 or more thrombotic events during the course of their lives.²

There are 2 types of protein C deficiency: Patients with type I have a decreased production of protein C, while those with type II have normal levels of the protein, but in a form that is dysfunctional.⁶

AT deficiency. AT, a natural anticoagulant synthesized by the liver and endothelial cells, is responsible for inactivating several clotting factors, including thrombin and factors IXa, Xa, XIa, and XIIa. Like protein C deficiency, AT deficiency is an autosomal-dominant disorder with 2 subtypes. Individuals with type I deficiency have normal plasma levels of AT, but the anticoagulant has reduced biological activity or is dysfunctional; those with type II deficiency have decreased plasma levels of fully functional AT.² Both types are more likely to lead to venous than arterial thrombosis.

AT deficiency affects approximately 1 in 2000 to 5000 people, including 2.8% of patients who develop venous thrombosis.⁷ Nearly two-thirds of those with AT deficiency develop thrombi before the age of 35.²

Protein S deficiency. Endothelial cells are responsible for the synthesis of protein S, which, like protein C (for which it serves as a cofactor), is vitamin K-dependent. Protein S deficiency, also an autosomal-dominant disorder, has 3 subtypes: Type I, also known as classical deficiency, is characterized by reduced free and total levels of functional protein S; type II patients have a normal total level of protein S, but a decreased amount of free protein; and type III patients have normal levels of both free and total protein S, but the available proteins are dysfunctional.^2,6

The prevalence of this hypercoagulable state in the general population is unknown, and protein S deficiencies have been found in only 1% of patients with a history of deep vein thrombosis (DVT).^3,8 Although this hypercoagulable state is less common than other hereditary thrombophilias, 74% of people with this disorder develop DVT—half of them before the age of 25.²

Hyperhomocysteinemia. Elevations in homocysteine may occur as a result of a hereditary disorder (deficiencies in cystathionine beta-synthase or methylene-tetrahydrofolate reductase). Hyperhomocysteinemia may also be an acquired condition, associated with deficiencies in vitamins B6, B12, or folic acid; chronic kidney disease; hypothyroidism; and certain malignancies.

The prevalence of hyperhomocysteinemia varies, based on the underlying disorder. Only about 0.3% of the general population has a cystathionine beta-synthase deficiency. Methylene-tetrahydrofolate reductase deficiency, however, is common among Italian and Hispanic populations (occurring in about 20%), but rare (<1%) among African American people.³

When to test for thrombophilias
Idiopathic venous thrombosis is probably the most common reason for ordering testing for inherited hypercoagulable states, and an underlying thrombophilia is found in about 50% of cases.⁹ Other indications for testing include thrombus development in an unusual site (eg, splanchic, renal, retinal, or ovarian veins; cerebral venous sinuses; or upper limbs), recurrent venous thromboembolism (VTE), venous thrombosis at an early age (<45 years) or in a patient with a strong family history of VTE, and unexplained recurrent pregnancy loss.

Testing may also be considered for relatives of patients with known inherited hypercoagulability disorders, but this should be done only if the results could affect a treatment decision: Can a man safely undergo surgery with a high postoperative risk for thrombosis, for example? Should a woman take oral contraceptives (OCs), start hormone replacement therapy (HRT), or attempt another pregnancy?

Overall, testing for inherited hypercoagulable states should focus on the identification of individuals most likely to benefit from it; only tests yielding useful data should be performed. Testing of asymptomatic individuals for the sole purpose of initiating long-term prophylactic therapy is not recommended.

Which tests for which patients?
In some cases, selective assays may be more useful than test panels, for reasons associated with patient presentation as well as cost. Proper selection of specific tests should be individualized based on the patient’s age, thrombotic presentation, and family history, and on potential effects on patient management.

For patients with heparin resistance, cerebral vein thrombosis, intra-abdominal vein thrombosis, or recurrent superficial thrombophlebitis, AT testing may be in order. Patients with recurrent superficial thrombophlebitis may also benefit from testing for factor V Leiden mutation, and protein C and protein S testing may be beneficial for patients with warfarin skin necrosis, recurrent superficial thrombophlebitis, or neonatal purpura fulminans. Cerebral vein thrombosis in the general population and in women using OCs, in particular, is suggestive of a G20210A mutation,⁹ and is a possible indication for testing. Hyperhomocysteinemia testing may be considered for patients with premature arterial and venous thrombosis, as well as mental retardation, skeletal abnormalities, and vitamin B6 or B12 deficiency.

Many physicians prefer to order testing in stages, starting with tests for the most common thrombophilias. When ordering tests for the conditions detailed above and in the TABLE, be aware that test panels vary among facilities, so it may be necessary to check with the testing laboratory to ensure that it offers the tests that are indicated for a particular patient.

TABLE
Suspect a hereditary hypercoagulable disorder? Testing considerations to keep in mind^{2,3,8,9,11,12}

Timing of tests, and other specifics
Acute thrombosis, anticoagulation therapy, and some disease states—eg, liver disease, nephritic syndrome, disseminated intravascular coagulation, and acute illness—can affect levels of AT, protein C, and protein S. Within the first 48 hours of warfarin therapy, for example, a patient’s protein C and protein S levels decline about 50%; after 2 weeks, the levels rise to about 70% of their normal range. Because of warfarin’s effect on these proteins, evaluation for these deficiencies should be performed at least 1 week to 10 days after cessation of a 3- to 6-month course of anticoagulation therapy. Abnormal findings should be confirmed with a second test approximately 3 weeks later.^2,3,9

Several tests are used to detect factor V Leiden mutation, including the polymerase chain reaction-based test and the modified activated partial thromboplastin time (aPTT)-based test. The latter can be given to patients who are receiving anticoagulants. The results indicate the ratio of activated protein C (APC), and a finding of <2.0 is considered abnormal.⁸ The presence of lupus anticoagulant—autoantibodies that bind to phospholipids and proteins associated with the cell membrane—may yield a false-positive result on the modified aPTT test.

While the prothrombin G20210A mutation is linked to elevations in prothrombin, measuring prothrombin levels is not an accurate way to test for this hypercoagulable state. The prothrombin G20210A mutation generally is detected through DNA analysis instead.^2,8

Hyperhomocysteinemia is diagnosed by measuring fasting plasma levels of homocysteine. Although the results are not standardized, they generally correlate with the severity of disease (mild, 15-30 μmol/L; moderate, >30-100 μmol/L; severe, >100 μmol/L). However, plasma levels may be falsely elevated during an acute thrombotic episode and decreased by supplementation with folic acid, B6, and B12. The decrease, however, does not indicate a reduction in the risk of thrombosis.

Treatment, yes, but for how long?
Most thrombotic events are initially treated with a combination of a heparin product (low-molecular-weight heparin [LMWH] or unfractionated heparin [UFH]) and warfarin—commonly known as bridging therapy. The heparin is discontinued once the patient’s international normalized ratio (INR) has been maintained at a therapeutic level for more than 24 hours, which usually takes about 5 days. Warfarin therapy, however, should continue for at least 3 to 6 months, depending on the severity and cause of the thrombosis.

Individuals with an AT, protein C, or protein S deficiency may be at increased risk of recurrence, and long-term anticoagulant therapy may be warranted.⁵ Under current guidelines from the American College of Chest Physicians (ACCP), however, hereditary thrombophilias are not considered to be major determinants of recurrence or a major factor guiding the duration of anticoagulation therapy.¹⁰ Practitioners must use their judgment to determine the need for treatment; if anticoagulation therapy is initiated, the duration should be based on an individual assessment of benefit and risk.

Recognizing and responding to acquired risks

Several conditions associated with vessel wall changes and venous stasis—the hallmarks of acquired hypercoagulable states—put patients at increased risk of venous thrombosis. Following is a review of the most likely risk factors, including antiphospholipid antibody syndrome (APS), previously known as lupus anticoagulant syndrome; heparin-induced thrombocytopenia (HIT); pregnancy; trauma; estrogen; and malignancy.

When to test for—and treat—APS
APS, a systemic autoimmune disorder that can result in arterial or venous thrombosis or pregnancy loss and morbidity, is characterized by the presence of autoantibodies. Patients of all ages may be affected by APS, one of the most common acquired hypercoagulability disorders. APS affects an estimated 28% of the general population.² About 15% of recurrent pregnancy losses and 20% of recurrent thromboses in young adults are attributed to this autoimmune disorder.¹¹

A definitive diagnosis of APS requires a history of either vascular thrombosis or pregnancy morbidity—defined as miscarriage after the 10th gestational week, consecutive fetal losses before the 10th gestational week, or placental insufficiency and premature birth before 34 weeks.^11,12 APS testing may be useful in patients with cerebral vein thrombosis, intra-abdominal vein thrombosis, or unexplained recurrent fetal loss.⁹

In addition to clinical criteria, a diagnosis of APS is based on the presence of plasma antibodies on 2 or more occasions at least 12 weeks apart. APS encompasses 3 types of antiphospholipid antibodies—lupus anticoagulant antibodies, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies—which can be detected with 2 different tests. Coagulation assays are used to identify lupus anticoagulant antibodies because they prolong clotting time; however, immunoassays are used to measure immunologic reactivity to phospholipids to determine the presence of anticardiolipin antibodies and anti-beta 2-glycoprotein I antibodies.^11,12

Treatment for APS generally involves anticoagulant therapy for the prevention and treatment of acute thrombotic events, or as prophylaxis during pregnancy. ACCP guidelines call for initiating warfarin therapy with a target INR of 2.5 (range 2.0-3.0) in patients with no other risk factors. In patients who have had recurrent thromboembolic events or have additional risk factors, a target INR of 3.0 (range 2.5-3.5) is suggested.¹⁰ LMWH and UFH are also options for use in the event of recurrence or for prophylaxis during pregnancy.^11,13,14

HIT can be benign, or life threatening
HIT—defined by a decrease in platelet count to less than 150,000 (or a 50% drop from baseline) after initiation of heparin therapy—may or may not be benign. HIT type I (previously called heparin-associated thrombocytopenia), which affects approximately 10% of patients treated with heparin, is transient, asymptomatic, and not associated with an increased risk of thrombosis. Type I typically occurs within the first 2 days of heparin therapy.¹⁵

HIT type II is an immune-mediated response that does increase the risk of thrombosis. Patients usually develop type II 5 to 12 days after initiation of heparin, but in rare instances onset is delayed, occurring up to 40 days after heparin therapy. Approximately 5% of patients on heparin develop HIT type II, and the risk increases with frequent heparin use. Unlike other states of thrombocytopenia, HIT rarely causes bleeding. However, patients with HIT type II are at risk for a paradoxical thrombotic syndrome that may become life threatening.^13,15

To diagnose HIT, an enzyme-linked immunosorbent assay or other specific blood tests must be used to confirm the presence of circulating antibodies.¹³ The diagnosis is based on the following criteria: (1) thrombocytopenia, (2) exclusion of other possible causes of thrombocytopenia, and (3) resolution of thrombocytopenia after discontinuation of heparin.^13,15

When HIT is suspected, all heparin-containing products must be discontinued immediately and alternative anticoagulant therapy (typically, with danaparoid, lepirudin, or argatroban) should be initiated to reduce the risk of thrombosis. Warfarin alone should not be used for the treatment of HIT because of its association with worsening thrombosis and venous limb gangrene.¹³ However, warfarin should be initiated while the patient is receiving danaparoid or a thrombin-specific inhibitor—with at least 5 days of overlapping therapy recommended. Duration of therapy has not been well defined, but an overall course of at least 2 to 3 months is recommended to reduce the risk of recurrent thrombosis.^13,15

Pregnancy raises risk, but limits Tx options
By altering the body’s normal physiologic state in a way that may lead to hypercoagulability, pregnancy increases the risk of VTE 6-fold.¹⁶ The risk continues throughout pregnancy and peaks during puerperium, the 6-week period after delivery. Cesarean delivery, prolonged immobility, and obesity elevate the risk.^13,16

Treatment options for acute thrombotic events during pregnancy are limited because warfarin is contraindicated. Current ACCP guidelines recommend substituting UFH or LMWH for oral anticoagulant therapy when treatment for an acute thrombotic event is required.¹⁰ While no pharmacologic prophylaxis is currently recommended for pregnant patients with thrombophilias but no history of thrombotic events,^10,17 there are cases when it may be necessary. Patients with an AT deficiency, for example, may require prenatal and postpartum prophylaxis,¹⁰ and patients who deliver by cesarean and have 1 or more additional risk factors should receive prophylaxis for the duration of their hospitalization. Women with multiple risk factors, in addition to pregnancy and cesarean section, should receive pharmacologic prophylaxis for up to 4 to 6 weeks postpartum.

Choices for postpartum anticoagulation for the treatment of an acute thrombotic event should be based on guidelines developed for nonpregnant patients, with this caveat: For women who are breastfeeding, safety during lactation must be considered. Neither UFH nor warfarin enters breast milk, so both are safe for such patients.¹⁸ LMWH, although smaller in molecular weight than UFH, is considered moderately safe during breastfeeding, as well.¹⁸

Prophylaxis is vital for trauma patients
Trauma and major injuries increase the risk of thrombosis by approximately 50%. Patients who are hospitalized after a major trauma are at high risk for the development of a VTE. At the greatest risk are those with spinal cord injuries (62%), pelvic fractures (61%), and leg fractures (80%).¹⁶ Current ACCP guidelines recommend the use of LMWH as soon as it is safe for trauma patients, and continuing it until discharge in patients with no apparent contraindication. If a patient has an active bleed or other contraindication, mechanical thromboprophylaxis is indicated until the bleeding risk decreases.¹⁵

Estrogens increase platelet aggregation
Estrogens are considered a risk factor because of their effect on both natural anticoagulants and clotting factors. A reduction in AT activity and increasing concentrations of clotting factors VII, X, and XII result from the use of estrogens. Estrogen is also thought to be responsible for the increase in platelet count and aggregation associated with the use of combination OCs.¹⁹ In fact, OC use is associated with about a 3-fold overall risk of thrombosis, a risk reported to be highest during the first year of use.¹⁶ Among hormonal contraceptives, the transdermal formulation has the highest risk.^20-22 Hormone replacement therapy taken during menopause confers approximately a 2- to 4-fold increase in risk for VTE, and selective estrogen receptor modulators are associated with a 2-fold risk.¹⁶ Physicians should educate patients about the risks associated with these agents and signs and symptoms of thrombosis.

Cancer and hypercoagulability: Which patients need treatment?
Although the pathophysiologic process is not fully understood, a link between cancer and hypercoagulability has long been recognized. In fact, malignancy—the second most common cause of acquired hypercoagulability—is associated with 10% to 20% of spontaneous DVTs.²

One possible mechanism is the interaction of tumor cells with thrombin and plasmin-generating systems, directly influencing thrombus formation.⁷

Cancer patients also have an elevated risk for thrombosis related to immobilization, infection, treatment with antineoplastic agents, surgery, and the insertion of central venous catheters. Approximately 30% of patients with central venous catheters develop a DVT of the arm.¹⁶

Anticoagulant therapy in cancer patients varies, depending on the severity and circumstances of the patient. According to American Society of Clinical Oncology, National Comprehensive Cancer Center Network, and ACCP guidelines, LMWH is the preferred initial treatment for thromboses in patients with cancer— that is, in the first 3 to 6 months of therapy after a thrombotic event.^17,23,24 The guidelines also mention warfarin as an alternative for long-term (>6 months) anticoagulant therapy, if no contraindications exist.

Because cancer is usually a long-term illness, anticoagulant therapy should be continued indefinitely, or until the cancer has resolved.^10,23,24 Prophylaxis is recommended for cancer patients who are bedridden with an acute medical illness, but should not be routinely used in patients with indwelling venous catheters or those receiving chemotherapy or hormonal therapy.^13,15

CORRESPONDENCE Haley M. Phillippe, PharmD, BCPS, University of Alabama Birmingham School of Medicine-Huntsville Campus, Department of Family Medicine, 301 Governors Drive, Huntsville, AL 35801; mccrahl@auburn.edu

Each year, venous thrombosis develops in approximately 1 in 1000 people.¹ The cause: An alteration in blood composition, venous stasis, or vascular damage—commonly known as Virchow’s triad. Changes in blood composition are associated with hereditary thrombophilias, such as factor V Leiden mutation or a deficiency in protein C or S or antithrombin III (AT). Changes in blood flow (stasis) and vessel damage stem from acquired conditions that commonly lead to hypercoagulability—pregnancy, malignancy, and estrogen use among them.

Regardless of the reason a patient is at elevated risk, however, the goal is the same: to prevent the development of thrombi, thereby reducing the increased morbidity and mortality associated with thromboembolism. Achieving that goal requires an understanding of both inherited and acquired risk factors, familiarity with diagnostic tools, and knowledge of appropriate treatment. This review, which begins with hereditary hypercoagulable states before turning to acquired conditions associated with hypercoagulability, will help toward that end.

Keep these thrombophilias on your radar screen

Factor V Leiden mutation is the most common inherited hypercoagulable disorder, and the most common form of activated protein C resistance. The mutation is found in an estimated 5% to 10% of the general population.² Among patients with thromboembolic disorders, however, the incidence is considerably higher, with estimates ranging from 21% to 60%.^3,4 Factor V Leiden mutation is more prevalent among Caucasian populations, and rarely found in people of Asian or African descent.²

Prothrombin G20210A mutation, an autosomal-dominant disorder, is the second most common inherited hypercoagulable state.⁴ This mutation is associated with an increase in prothrombin levels, causing an elevation in thrombin and, in turn, a heightened risk of thrombosis.

Although prothrombin G20210A mutation is found in only 1% to 2% of the general population, its prevalence among those with a history of thromboembolic events is estimated at 5% to 19%.⁴ This disorder, too, varies significantly by ethnicity: People from southern Europe are twice as likely to be affected as northern Europeans, and the mutation is rarely found in people of Asian or African descent.^2,5

Protein C deficiency. Protein C, a vitamin K-dependent anticoagulant produced in the liver, is activated when thrombomodulin binds with thrombin in the presence of protein S, which serves as the cofactor. Protein C is required to inactivate clotting factors V and VIII.² The deficiency is an autosomal-dominant disorder, and is more likely to result in venous than arterial thrombosis.²

Protein C deficiency affects 1 in every 200 to 500 people in the general population; among patients with a history of venous thrombosis, its prevalence is 2% to 9%.^2,3 Generally, people with a protein C deficiency begin developing thrombi in their late teens, and about 75% suffer from 1 or more thrombotic events during the course of their lives.²

There are 2 types of protein C deficiency: Patients with type I have a decreased production of protein C, while those with type II have normal levels of the protein, but in a form that is dysfunctional.⁶

AT deficiency. AT, a natural anticoagulant synthesized by the liver and endothelial cells, is responsible for inactivating several clotting factors, including thrombin and factors IXa, Xa, XIa, and XIIa. Like protein C deficiency, AT deficiency is an autosomal-dominant disorder with 2 subtypes. Individuals with type I deficiency have normal plasma levels of AT, but the anticoagulant has reduced biological activity or is dysfunctional; those with type II deficiency have decreased plasma levels of fully functional AT.² Both types are more likely to lead to venous than arterial thrombosis.

AT deficiency affects approximately 1 in 2000 to 5000 people, including 2.8% of patients who develop venous thrombosis.⁷ Nearly two-thirds of those with AT deficiency develop thrombi before the age of 35.²

Protein S deficiency. Endothelial cells are responsible for the synthesis of protein S, which, like protein C (for which it serves as a cofactor), is vitamin K-dependent. Protein S deficiency, also an autosomal-dominant disorder, has 3 subtypes: Type I, also known as classical deficiency, is characterized by reduced free and total levels of functional protein S; type II patients have a normal total level of protein S, but a decreased amount of free protein; and type III patients have normal levels of both free and total protein S, but the available proteins are dysfunctional.^2,6

The prevalence of this hypercoagulable state in the general population is unknown, and protein S deficiencies have been found in only 1% of patients with a history of deep vein thrombosis (DVT).^3,8 Although this hypercoagulable state is less common than other hereditary thrombophilias, 74% of people with this disorder develop DVT—half of them before the age of 25.²

Hyperhomocysteinemia. Elevations in homocysteine may occur as a result of a hereditary disorder (deficiencies in cystathionine beta-synthase or methylene-tetrahydrofolate reductase). Hyperhomocysteinemia may also be an acquired condition, associated with deficiencies in vitamins B6, B12, or folic acid; chronic kidney disease; hypothyroidism; and certain malignancies.

The prevalence of hyperhomocysteinemia varies, based on the underlying disorder. Only about 0.3% of the general population has a cystathionine beta-synthase deficiency. Methylene-tetrahydrofolate reductase deficiency, however, is common among Italian and Hispanic populations (occurring in about 20%), but rare (<1%) among African American people.³

When to test for thrombophilias
Idiopathic venous thrombosis is probably the most common reason for ordering testing for inherited hypercoagulable states, and an underlying thrombophilia is found in about 50% of cases.⁹ Other indications for testing include thrombus development in an unusual site (eg, splanchic, renal, retinal, or ovarian veins; cerebral venous sinuses; or upper limbs), recurrent venous thromboembolism (VTE), venous thrombosis at an early age (<45 years) or in a patient with a strong family history of VTE, and unexplained recurrent pregnancy loss.

Testing may also be considered for relatives of patients with known inherited hypercoagulability disorders, but this should be done only if the results could affect a treatment decision: Can a man safely undergo surgery with a high postoperative risk for thrombosis, for example? Should a woman take oral contraceptives (OCs), start hormone replacement therapy (HRT), or attempt another pregnancy?

Overall, testing for inherited hypercoagulable states should focus on the identification of individuals most likely to benefit from it; only tests yielding useful data should be performed. Testing of asymptomatic individuals for the sole purpose of initiating long-term prophylactic therapy is not recommended.

Which tests for which patients?
In some cases, selective assays may be more useful than test panels, for reasons associated with patient presentation as well as cost. Proper selection of specific tests should be individualized based on the patient’s age, thrombotic presentation, and family history, and on potential effects on patient management.

For patients with heparin resistance, cerebral vein thrombosis, intra-abdominal vein thrombosis, or recurrent superficial thrombophlebitis, AT testing may be in order. Patients with recurrent superficial thrombophlebitis may also benefit from testing for factor V Leiden mutation, and protein C and protein S testing may be beneficial for patients with warfarin skin necrosis, recurrent superficial thrombophlebitis, or neonatal purpura fulminans. Cerebral vein thrombosis in the general population and in women using OCs, in particular, is suggestive of a G20210A mutation,⁹ and is a possible indication for testing. Hyperhomocysteinemia testing may be considered for patients with premature arterial and venous thrombosis, as well as mental retardation, skeletal abnormalities, and vitamin B6 or B12 deficiency.

Many physicians prefer to order testing in stages, starting with tests for the most common thrombophilias. When ordering tests for the conditions detailed above and in the TABLE, be aware that test panels vary among facilities, so it may be necessary to check with the testing laboratory to ensure that it offers the tests that are indicated for a particular patient.

TABLE
Suspect a hereditary hypercoagulable disorder? Testing considerations to keep in mind^{2,3,8,9,11,12}

Timing of tests, and other specifics
Acute thrombosis, anticoagulation therapy, and some disease states—eg, liver disease, nephritic syndrome, disseminated intravascular coagulation, and acute illness—can affect levels of AT, protein C, and protein S. Within the first 48 hours of warfarin therapy, for example, a patient’s protein C and protein S levels decline about 50%; after 2 weeks, the levels rise to about 70% of their normal range. Because of warfarin’s effect on these proteins, evaluation for these deficiencies should be performed at least 1 week to 10 days after cessation of a 3- to 6-month course of anticoagulation therapy. Abnormal findings should be confirmed with a second test approximately 3 weeks later.^2,3,9

Several tests are used to detect factor V Leiden mutation, including the polymerase chain reaction-based test and the modified activated partial thromboplastin time (aPTT)-based test. The latter can be given to patients who are receiving anticoagulants. The results indicate the ratio of activated protein C (APC), and a finding of <2.0 is considered abnormal.⁸ The presence of lupus anticoagulant—autoantibodies that bind to phospholipids and proteins associated with the cell membrane—may yield a false-positive result on the modified aPTT test.

While the prothrombin G20210A mutation is linked to elevations in prothrombin, measuring prothrombin levels is not an accurate way to test for this hypercoagulable state. The prothrombin G20210A mutation generally is detected through DNA analysis instead.^2,8

Hyperhomocysteinemia is diagnosed by measuring fasting plasma levels of homocysteine. Although the results are not standardized, they generally correlate with the severity of disease (mild, 15-30 μmol/L; moderate, >30-100 μmol/L; severe, >100 μmol/L). However, plasma levels may be falsely elevated during an acute thrombotic episode and decreased by supplementation with folic acid, B6, and B12. The decrease, however, does not indicate a reduction in the risk of thrombosis.

Treatment, yes, but for how long?
Most thrombotic events are initially treated with a combination of a heparin product (low-molecular-weight heparin [LMWH] or unfractionated heparin [UFH]) and warfarin—commonly known as bridging therapy. The heparin is discontinued once the patient’s international normalized ratio (INR) has been maintained at a therapeutic level for more than 24 hours, which usually takes about 5 days. Warfarin therapy, however, should continue for at least 3 to 6 months, depending on the severity and cause of the thrombosis.

Individuals with an AT, protein C, or protein S deficiency may be at increased risk of recurrence, and long-term anticoagulant therapy may be warranted.⁵ Under current guidelines from the American College of Chest Physicians (ACCP), however, hereditary thrombophilias are not considered to be major determinants of recurrence or a major factor guiding the duration of anticoagulation therapy.¹⁰ Practitioners must use their judgment to determine the need for treatment; if anticoagulation therapy is initiated, the duration should be based on an individual assessment of benefit and risk.

Recognizing and responding to acquired risks

Several conditions associated with vessel wall changes and venous stasis—the hallmarks of acquired hypercoagulable states—put patients at increased risk of venous thrombosis. Following is a review of the most likely risk factors, including antiphospholipid antibody syndrome (APS), previously known as lupus anticoagulant syndrome; heparin-induced thrombocytopenia (HIT); pregnancy; trauma; estrogen; and malignancy.

When to test for—and treat—APS
APS, a systemic autoimmune disorder that can result in arterial or venous thrombosis or pregnancy loss and morbidity, is characterized by the presence of autoantibodies. Patients of all ages may be affected by APS, one of the most common acquired hypercoagulability disorders. APS affects an estimated 28% of the general population.² About 15% of recurrent pregnancy losses and 20% of recurrent thromboses in young adults are attributed to this autoimmune disorder.¹¹

A definitive diagnosis of APS requires a history of either vascular thrombosis or pregnancy morbidity—defined as miscarriage after the 10th gestational week, consecutive fetal losses before the 10th gestational week, or placental insufficiency and premature birth before 34 weeks.^11,12 APS testing may be useful in patients with cerebral vein thrombosis, intra-abdominal vein thrombosis, or unexplained recurrent fetal loss.⁹

In addition to clinical criteria, a diagnosis of APS is based on the presence of plasma antibodies on 2 or more occasions at least 12 weeks apart. APS encompasses 3 types of antiphospholipid antibodies—lupus anticoagulant antibodies, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies—which can be detected with 2 different tests. Coagulation assays are used to identify lupus anticoagulant antibodies because they prolong clotting time; however, immunoassays are used to measure immunologic reactivity to phospholipids to determine the presence of anticardiolipin antibodies and anti-beta 2-glycoprotein I antibodies.^11,12

Treatment for APS generally involves anticoagulant therapy for the prevention and treatment of acute thrombotic events, or as prophylaxis during pregnancy. ACCP guidelines call for initiating warfarin therapy with a target INR of 2.5 (range 2.0-3.0) in patients with no other risk factors. In patients who have had recurrent thromboembolic events or have additional risk factors, a target INR of 3.0 (range 2.5-3.5) is suggested.¹⁰ LMWH and UFH are also options for use in the event of recurrence or for prophylaxis during pregnancy.^11,13,14

HIT can be benign, or life threatening
HIT—defined by a decrease in platelet count to less than 150,000 (or a 50% drop from baseline) after initiation of heparin therapy—may or may not be benign. HIT type I (previously called heparin-associated thrombocytopenia), which affects approximately 10% of patients treated with heparin, is transient, asymptomatic, and not associated with an increased risk of thrombosis. Type I typically occurs within the first 2 days of heparin therapy.¹⁵

HIT type II is an immune-mediated response that does increase the risk of thrombosis. Patients usually develop type II 5 to 12 days after initiation of heparin, but in rare instances onset is delayed, occurring up to 40 days after heparin therapy. Approximately 5% of patients on heparin develop HIT type II, and the risk increases with frequent heparin use. Unlike other states of thrombocytopenia, HIT rarely causes bleeding. However, patients with HIT type II are at risk for a paradoxical thrombotic syndrome that may become life threatening.^13,15

To diagnose HIT, an enzyme-linked immunosorbent assay or other specific blood tests must be used to confirm the presence of circulating antibodies.¹³ The diagnosis is based on the following criteria: (1) thrombocytopenia, (2) exclusion of other possible causes of thrombocytopenia, and (3) resolution of thrombocytopenia after discontinuation of heparin.^13,15

When HIT is suspected, all heparin-containing products must be discontinued immediately and alternative anticoagulant therapy (typically, with danaparoid, lepirudin, or argatroban) should be initiated to reduce the risk of thrombosis. Warfarin alone should not be used for the treatment of HIT because of its association with worsening thrombosis and venous limb gangrene.¹³ However, warfarin should be initiated while the patient is receiving danaparoid or a thrombin-specific inhibitor—with at least 5 days of overlapping therapy recommended. Duration of therapy has not been well defined, but an overall course of at least 2 to 3 months is recommended to reduce the risk of recurrent thrombosis.^13,15

Pregnancy raises risk, but limits Tx options
By altering the body’s normal physiologic state in a way that may lead to hypercoagulability, pregnancy increases the risk of VTE 6-fold.¹⁶ The risk continues throughout pregnancy and peaks during puerperium, the 6-week period after delivery. Cesarean delivery, prolonged immobility, and obesity elevate the risk.^13,16

Treatment options for acute thrombotic events during pregnancy are limited because warfarin is contraindicated. Current ACCP guidelines recommend substituting UFH or LMWH for oral anticoagulant therapy when treatment for an acute thrombotic event is required.¹⁰ While no pharmacologic prophylaxis is currently recommended for pregnant patients with thrombophilias but no history of thrombotic events,^10,17 there are cases when it may be necessary. Patients with an AT deficiency, for example, may require prenatal and postpartum prophylaxis,¹⁰ and patients who deliver by cesarean and have 1 or more additional risk factors should receive prophylaxis for the duration of their hospitalization. Women with multiple risk factors, in addition to pregnancy and cesarean section, should receive pharmacologic prophylaxis for up to 4 to 6 weeks postpartum.

Choices for postpartum anticoagulation for the treatment of an acute thrombotic event should be based on guidelines developed for nonpregnant patients, with this caveat: For women who are breastfeeding, safety during lactation must be considered. Neither UFH nor warfarin enters breast milk, so both are safe for such patients.¹⁸ LMWH, although smaller in molecular weight than UFH, is considered moderately safe during breastfeeding, as well.¹⁸

Prophylaxis is vital for trauma patients
Trauma and major injuries increase the risk of thrombosis by approximately 50%. Patients who are hospitalized after a major trauma are at high risk for the development of a VTE. At the greatest risk are those with spinal cord injuries (62%), pelvic fractures (61%), and leg fractures (80%).¹⁶ Current ACCP guidelines recommend the use of LMWH as soon as it is safe for trauma patients, and continuing it until discharge in patients with no apparent contraindication. If a patient has an active bleed or other contraindication, mechanical thromboprophylaxis is indicated until the bleeding risk decreases.¹⁵

Estrogens increase platelet aggregation
Estrogens are considered a risk factor because of their effect on both natural anticoagulants and clotting factors. A reduction in AT activity and increasing concentrations of clotting factors VII, X, and XII result from the use of estrogens. Estrogen is also thought to be responsible for the increase in platelet count and aggregation associated with the use of combination OCs.¹⁹ In fact, OC use is associated with about a 3-fold overall risk of thrombosis, a risk reported to be highest during the first year of use.¹⁶ Among hormonal contraceptives, the transdermal formulation has the highest risk.^20-22 Hormone replacement therapy taken during menopause confers approximately a 2- to 4-fold increase in risk for VTE, and selective estrogen receptor modulators are associated with a 2-fold risk.¹⁶ Physicians should educate patients about the risks associated with these agents and signs and symptoms of thrombosis.

Cancer and hypercoagulability: Which patients need treatment?
Although the pathophysiologic process is not fully understood, a link between cancer and hypercoagulability has long been recognized. In fact, malignancy—the second most common cause of acquired hypercoagulability—is associated with 10% to 20% of spontaneous DVTs.²

One possible mechanism is the interaction of tumor cells with thrombin and plasmin-generating systems, directly influencing thrombus formation.⁷

Cancer patients also have an elevated risk for thrombosis related to immobilization, infection, treatment with antineoplastic agents, surgery, and the insertion of central venous catheters. Approximately 30% of patients with central venous catheters develop a DVT of the arm.¹⁶

Anticoagulant therapy in cancer patients varies, depending on the severity and circumstances of the patient. According to American Society of Clinical Oncology, National Comprehensive Cancer Center Network, and ACCP guidelines, LMWH is the preferred initial treatment for thromboses in patients with cancer— that is, in the first 3 to 6 months of therapy after a thrombotic event.^17,23,24 The guidelines also mention warfarin as an alternative for long-term (>6 months) anticoagulant therapy, if no contraindications exist.

Because cancer is usually a long-term illness, anticoagulant therapy should be continued indefinitely, or until the cancer has resolved.^10,23,24 Prophylaxis is recommended for cancer patients who are bedridden with an acute medical illness, but should not be routinely used in patients with indwelling venous catheters or those receiving chemotherapy or hormonal therapy.^13,15

CORRESPONDENCE Haley M. Phillippe, PharmD, BCPS, University of Alabama Birmingham School of Medicine-Huntsville Campus, Department of Family Medicine, 301 Governors Drive, Huntsville, AL 35801; mccrahl@auburn.edu

Each year, venous thrombosis develops in approximately 1 in 1000 people.¹ The cause: An alteration in blood composition, venous stasis, or vascular damage—commonly known as Virchow’s triad. Changes in blood composition are associated with hereditary thrombophilias, such as factor V Leiden mutation or a deficiency in protein C or S or antithrombin III (AT). Changes in blood flow (stasis) and vessel damage stem from acquired conditions that commonly lead to hypercoagulability—pregnancy, malignancy, and estrogen use among them.

Regardless of the reason a patient is at elevated risk, however, the goal is the same: to prevent the development of thrombi, thereby reducing the increased morbidity and mortality associated with thromboembolism. Achieving that goal requires an understanding of both inherited and acquired risk factors, familiarity with diagnostic tools, and knowledge of appropriate treatment. This review, which begins with hereditary hypercoagulable states before turning to acquired conditions associated with hypercoagulability, will help toward that end.

Keep these thrombophilias on your radar screen

Factor V Leiden mutation is the most common inherited hypercoagulable disorder, and the most common form of activated protein C resistance. The mutation is found in an estimated 5% to 10% of the general population.² Among patients with thromboembolic disorders, however, the incidence is considerably higher, with estimates ranging from 21% to 60%.^3,4 Factor V Leiden mutation is more prevalent among Caucasian populations, and rarely found in people of Asian or African descent.²

Prothrombin G20210A mutation, an autosomal-dominant disorder, is the second most common inherited hypercoagulable state.⁴ This mutation is associated with an increase in prothrombin levels, causing an elevation in thrombin and, in turn, a heightened risk of thrombosis.

Although prothrombin G20210A mutation is found in only 1% to 2% of the general population, its prevalence among those with a history of thromboembolic events is estimated at 5% to 19%.⁴ This disorder, too, varies significantly by ethnicity: People from southern Europe are twice as likely to be affected as northern Europeans, and the mutation is rarely found in people of Asian or African descent.^2,5

Protein C deficiency. Protein C, a vitamin K-dependent anticoagulant produced in the liver, is activated when thrombomodulin binds with thrombin in the presence of protein S, which serves as the cofactor. Protein C is required to inactivate clotting factors V and VIII.² The deficiency is an autosomal-dominant disorder, and is more likely to result in venous than arterial thrombosis.²

Protein C deficiency affects 1 in every 200 to 500 people in the general population; among patients with a history of venous thrombosis, its prevalence is 2% to 9%.^2,3 Generally, people with a protein C deficiency begin developing thrombi in their late teens, and about 75% suffer from 1 or more thrombotic events during the course of their lives.²

There are 2 types of protein C deficiency: Patients with type I have a decreased production of protein C, while those with type II have normal levels of the protein, but in a form that is dysfunctional.⁶

AT deficiency. AT, a natural anticoagulant synthesized by the liver and endothelial cells, is responsible for inactivating several clotting factors, including thrombin and factors IXa, Xa, XIa, and XIIa. Like protein C deficiency, AT deficiency is an autosomal-dominant disorder with 2 subtypes. Individuals with type I deficiency have normal plasma levels of AT, but the anticoagulant has reduced biological activity or is dysfunctional; those with type II deficiency have decreased plasma levels of fully functional AT.² Both types are more likely to lead to venous than arterial thrombosis.

AT deficiency affects approximately 1 in 2000 to 5000 people, including 2.8% of patients who develop venous thrombosis.⁷ Nearly two-thirds of those with AT deficiency develop thrombi before the age of 35.²

Protein S deficiency. Endothelial cells are responsible for the synthesis of protein S, which, like protein C (for which it serves as a cofactor), is vitamin K-dependent. Protein S deficiency, also an autosomal-dominant disorder, has 3 subtypes: Type I, also known as classical deficiency, is characterized by reduced free and total levels of functional protein S; type II patients have a normal total level of protein S, but a decreased amount of free protein; and type III patients have normal levels of both free and total protein S, but the available proteins are dysfunctional.^2,6

The prevalence of this hypercoagulable state in the general population is unknown, and protein S deficiencies have been found in only 1% of patients with a history of deep vein thrombosis (DVT).^3,8 Although this hypercoagulable state is less common than other hereditary thrombophilias, 74% of people with this disorder develop DVT—half of them before the age of 25.²

Hyperhomocysteinemia. Elevations in homocysteine may occur as a result of a hereditary disorder (deficiencies in cystathionine beta-synthase or methylene-tetrahydrofolate reductase). Hyperhomocysteinemia may also be an acquired condition, associated with deficiencies in vitamins B6, B12, or folic acid; chronic kidney disease; hypothyroidism; and certain malignancies.

The prevalence of hyperhomocysteinemia varies, based on the underlying disorder. Only about 0.3% of the general population has a cystathionine beta-synthase deficiency. Methylene-tetrahydrofolate reductase deficiency, however, is common among Italian and Hispanic populations (occurring in about 20%), but rare (<1%) among African American people.³

When to test for thrombophilias
Idiopathic venous thrombosis is probably the most common reason for ordering testing for inherited hypercoagulable states, and an underlying thrombophilia is found in about 50% of cases.⁹ Other indications for testing include thrombus development in an unusual site (eg, splanchic, renal, retinal, or ovarian veins; cerebral venous sinuses; or upper limbs), recurrent venous thromboembolism (VTE), venous thrombosis at an early age (<45 years) or in a patient with a strong family history of VTE, and unexplained recurrent pregnancy loss.

Testing may also be considered for relatives of patients with known inherited hypercoagulability disorders, but this should be done only if the results could affect a treatment decision: Can a man safely undergo surgery with a high postoperative risk for thrombosis, for example? Should a woman take oral contraceptives (OCs), start hormone replacement therapy (HRT), or attempt another pregnancy?

Overall, testing for inherited hypercoagulable states should focus on the identification of individuals most likely to benefit from it; only tests yielding useful data should be performed. Testing of asymptomatic individuals for the sole purpose of initiating long-term prophylactic therapy is not recommended.

Which tests for which patients?
In some cases, selective assays may be more useful than test panels, for reasons associated with patient presentation as well as cost. Proper selection of specific tests should be individualized based on the patient’s age, thrombotic presentation, and family history, and on potential effects on patient management.

For patients with heparin resistance, cerebral vein thrombosis, intra-abdominal vein thrombosis, or recurrent superficial thrombophlebitis, AT testing may be in order. Patients with recurrent superficial thrombophlebitis may also benefit from testing for factor V Leiden mutation, and protein C and protein S testing may be beneficial for patients with warfarin skin necrosis, recurrent superficial thrombophlebitis, or neonatal purpura fulminans. Cerebral vein thrombosis in the general population and in women using OCs, in particular, is suggestive of a G20210A mutation,⁹ and is a possible indication for testing. Hyperhomocysteinemia testing may be considered for patients with premature arterial and venous thrombosis, as well as mental retardation, skeletal abnormalities, and vitamin B6 or B12 deficiency.

Many physicians prefer to order testing in stages, starting with tests for the most common thrombophilias. When ordering tests for the conditions detailed above and in the TABLE, be aware that test panels vary among facilities, so it may be necessary to check with the testing laboratory to ensure that it offers the tests that are indicated for a particular patient.

TABLE
Suspect a hereditary hypercoagulable disorder? Testing considerations to keep in mind^{2,3,8,9,11,12}

Timing of tests, and other specifics
Acute thrombosis, anticoagulation therapy, and some disease states—eg, liver disease, nephritic syndrome, disseminated intravascular coagulation, and acute illness—can affect levels of AT, protein C, and protein S. Within the first 48 hours of warfarin therapy, for example, a patient’s protein C and protein S levels decline about 50%; after 2 weeks, the levels rise to about 70% of their normal range. Because of warfarin’s effect on these proteins, evaluation for these deficiencies should be performed at least 1 week to 10 days after cessation of a 3- to 6-month course of anticoagulation therapy. Abnormal findings should be confirmed with a second test approximately 3 weeks later.^2,3,9

Several tests are used to detect factor V Leiden mutation, including the polymerase chain reaction-based test and the modified activated partial thromboplastin time (aPTT)-based test. The latter can be given to patients who are receiving anticoagulants. The results indicate the ratio of activated protein C (APC), and a finding of <2.0 is considered abnormal.⁸ The presence of lupus anticoagulant—autoantibodies that bind to phospholipids and proteins associated with the cell membrane—may yield a false-positive result on the modified aPTT test.

While the prothrombin G20210A mutation is linked to elevations in prothrombin, measuring prothrombin levels is not an accurate way to test for this hypercoagulable state. The prothrombin G20210A mutation generally is detected through DNA analysis instead.^2,8

Hyperhomocysteinemia is diagnosed by measuring fasting plasma levels of homocysteine. Although the results are not standardized, they generally correlate with the severity of disease (mild, 15-30 μmol/L; moderate, >30-100 μmol/L; severe, >100 μmol/L). However, plasma levels may be falsely elevated during an acute thrombotic episode and decreased by supplementation with folic acid, B6, and B12. The decrease, however, does not indicate a reduction in the risk of thrombosis.

Treatment, yes, but for how long?
Most thrombotic events are initially treated with a combination of a heparin product (low-molecular-weight heparin [LMWH] or unfractionated heparin [UFH]) and warfarin—commonly known as bridging therapy. The heparin is discontinued once the patient’s international normalized ratio (INR) has been maintained at a therapeutic level for more than 24 hours, which usually takes about 5 days. Warfarin therapy, however, should continue for at least 3 to 6 months, depending on the severity and cause of the thrombosis.

Individuals with an AT, protein C, or protein S deficiency may be at increased risk of recurrence, and long-term anticoagulant therapy may be warranted.⁵ Under current guidelines from the American College of Chest Physicians (ACCP), however, hereditary thrombophilias are not considered to be major determinants of recurrence or a major factor guiding the duration of anticoagulation therapy.¹⁰ Practitioners must use their judgment to determine the need for treatment; if anticoagulation therapy is initiated, the duration should be based on an individual assessment of benefit and risk.

Recognizing and responding to acquired risks

Several conditions associated with vessel wall changes and venous stasis—the hallmarks of acquired hypercoagulable states—put patients at increased risk of venous thrombosis. Following is a review of the most likely risk factors, including antiphospholipid antibody syndrome (APS), previously known as lupus anticoagulant syndrome; heparin-induced thrombocytopenia (HIT); pregnancy; trauma; estrogen; and malignancy.

When to test for—and treat—APS
APS, a systemic autoimmune disorder that can result in arterial or venous thrombosis or pregnancy loss and morbidity, is characterized by the presence of autoantibodies. Patients of all ages may be affected by APS, one of the most common acquired hypercoagulability disorders. APS affects an estimated 28% of the general population.² About 15% of recurrent pregnancy losses and 20% of recurrent thromboses in young adults are attributed to this autoimmune disorder.¹¹

A definitive diagnosis of APS requires a history of either vascular thrombosis or pregnancy morbidity—defined as miscarriage after the 10th gestational week, consecutive fetal losses before the 10th gestational week, or placental insufficiency and premature birth before 34 weeks.^11,12 APS testing may be useful in patients with cerebral vein thrombosis, intra-abdominal vein thrombosis, or unexplained recurrent fetal loss.⁹

In addition to clinical criteria, a diagnosis of APS is based on the presence of plasma antibodies on 2 or more occasions at least 12 weeks apart. APS encompasses 3 types of antiphospholipid antibodies—lupus anticoagulant antibodies, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies—which can be detected with 2 different tests. Coagulation assays are used to identify lupus anticoagulant antibodies because they prolong clotting time; however, immunoassays are used to measure immunologic reactivity to phospholipids to determine the presence of anticardiolipin antibodies and anti-beta 2-glycoprotein I antibodies.^11,12

Treatment for APS generally involves anticoagulant therapy for the prevention and treatment of acute thrombotic events, or as prophylaxis during pregnancy. ACCP guidelines call for initiating warfarin therapy with a target INR of 2.5 (range 2.0-3.0) in patients with no other risk factors. In patients who have had recurrent thromboembolic events or have additional risk factors, a target INR of 3.0 (range 2.5-3.5) is suggested.¹⁰ LMWH and UFH are also options for use in the event of recurrence or for prophylaxis during pregnancy.^11,13,14

HIT can be benign, or life threatening
HIT—defined by a decrease in platelet count to less than 150,000 (or a 50% drop from baseline) after initiation of heparin therapy—may or may not be benign. HIT type I (previously called heparin-associated thrombocytopenia), which affects approximately 10% of patients treated with heparin, is transient, asymptomatic, and not associated with an increased risk of thrombosis. Type I typically occurs within the first 2 days of heparin therapy.¹⁵

HIT type II is an immune-mediated response that does increase the risk of thrombosis. Patients usually develop type II 5 to 12 days after initiation of heparin, but in rare instances onset is delayed, occurring up to 40 days after heparin therapy. Approximately 5% of patients on heparin develop HIT type II, and the risk increases with frequent heparin use. Unlike other states of thrombocytopenia, HIT rarely causes bleeding. However, patients with HIT type II are at risk for a paradoxical thrombotic syndrome that may become life threatening.^13,15

To diagnose HIT, an enzyme-linked immunosorbent assay or other specific blood tests must be used to confirm the presence of circulating antibodies.¹³ The diagnosis is based on the following criteria: (1) thrombocytopenia, (2) exclusion of other possible causes of thrombocytopenia, and (3) resolution of thrombocytopenia after discontinuation of heparin.^13,15

When HIT is suspected, all heparin-containing products must be discontinued immediately and alternative anticoagulant therapy (typically, with danaparoid, lepirudin, or argatroban) should be initiated to reduce the risk of thrombosis. Warfarin alone should not be used for the treatment of HIT because of its association with worsening thrombosis and venous limb gangrene.¹³ However, warfarin should be initiated while the patient is receiving danaparoid or a thrombin-specific inhibitor—with at least 5 days of overlapping therapy recommended. Duration of therapy has not been well defined, but an overall course of at least 2 to 3 months is recommended to reduce the risk of recurrent thrombosis.^13,15

Pregnancy raises risk, but limits Tx options
By altering the body’s normal physiologic state in a way that may lead to hypercoagulability, pregnancy increases the risk of VTE 6-fold.¹⁶ The risk continues throughout pregnancy and peaks during puerperium, the 6-week period after delivery. Cesarean delivery, prolonged immobility, and obesity elevate the risk.^13,16

Treatment options for acute thrombotic events during pregnancy are limited because warfarin is contraindicated. Current ACCP guidelines recommend substituting UFH or LMWH for oral anticoagulant therapy when treatment for an acute thrombotic event is required.¹⁰ While no pharmacologic prophylaxis is currently recommended for pregnant patients with thrombophilias but no history of thrombotic events,^10,17 there are cases when it may be necessary. Patients with an AT deficiency, for example, may require prenatal and postpartum prophylaxis,¹⁰ and patients who deliver by cesarean and have 1 or more additional risk factors should receive prophylaxis for the duration of their hospitalization. Women with multiple risk factors, in addition to pregnancy and cesarean section, should receive pharmacologic prophylaxis for up to 4 to 6 weeks postpartum.

Choices for postpartum anticoagulation for the treatment of an acute thrombotic event should be based on guidelines developed for nonpregnant patients, with this caveat: For women who are breastfeeding, safety during lactation must be considered. Neither UFH nor warfarin enters breast milk, so both are safe for such patients.¹⁸ LMWH, although smaller in molecular weight than UFH, is considered moderately safe during breastfeeding, as well.¹⁸

Prophylaxis is vital for trauma patients
Trauma and major injuries increase the risk of thrombosis by approximately 50%. Patients who are hospitalized after a major trauma are at high risk for the development of a VTE. At the greatest risk are those with spinal cord injuries (62%), pelvic fractures (61%), and leg fractures (80%).¹⁶ Current ACCP guidelines recommend the use of LMWH as soon as it is safe for trauma patients, and continuing it until discharge in patients with no apparent contraindication. If a patient has an active bleed or other contraindication, mechanical thromboprophylaxis is indicated until the bleeding risk decreases.¹⁵

Estrogens increase platelet aggregation
Estrogens are considered a risk factor because of their effect on both natural anticoagulants and clotting factors. A reduction in AT activity and increasing concentrations of clotting factors VII, X, and XII result from the use of estrogens. Estrogen is also thought to be responsible for the increase in platelet count and aggregation associated with the use of combination OCs.¹⁹ In fact, OC use is associated with about a 3-fold overall risk of thrombosis, a risk reported to be highest during the first year of use.¹⁶ Among hormonal contraceptives, the transdermal formulation has the highest risk.^20-22 Hormone replacement therapy taken during menopause confers approximately a 2- to 4-fold increase in risk for VTE, and selective estrogen receptor modulators are associated with a 2-fold risk.¹⁶ Physicians should educate patients about the risks associated with these agents and signs and symptoms of thrombosis.

Cancer and hypercoagulability: Which patients need treatment?
Although the pathophysiologic process is not fully understood, a link between cancer and hypercoagulability has long been recognized. In fact, malignancy—the second most common cause of acquired hypercoagulability—is associated with 10% to 20% of spontaneous DVTs.²

One possible mechanism is the interaction of tumor cells with thrombin and plasmin-generating systems, directly influencing thrombus formation.⁷

Cancer patients also have an elevated risk for thrombosis related to immobilization, infection, treatment with antineoplastic agents, surgery, and the insertion of central venous catheters. Approximately 30% of patients with central venous catheters develop a DVT of the arm.¹⁶

Anticoagulant therapy in cancer patients varies, depending on the severity and circumstances of the patient. According to American Society of Clinical Oncology, National Comprehensive Cancer Center Network, and ACCP guidelines, LMWH is the preferred initial treatment for thromboses in patients with cancer— that is, in the first 3 to 6 months of therapy after a thrombotic event.^17,23,24 The guidelines also mention warfarin as an alternative for long-term (>6 months) anticoagulant therapy, if no contraindications exist.

Because cancer is usually a long-term illness, anticoagulant therapy should be continued indefinitely, or until the cancer has resolved.^10,23,24 Prophylaxis is recommended for cancer patients who are bedridden with an acute medical illness, but should not be routinely used in patients with indwelling venous catheters or those receiving chemotherapy or hormonal therapy.^13,15

CORRESPONDENCE Haley M. Phillippe, PharmD, BCPS, University of Alabama Birmingham School of Medicine-Huntsville Campus, Department of Family Medicine, 301 Governors Drive, Huntsville, AL 35801; mccrahl@auburn.edu