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Antithrombotic Therapy: Laboratory Support of Dose Selection and Therapeutic Monitoring

Antithrombotic Therapy: Laboratory Support of Dose Selection and Therapeutic Monitoring

Clinical Focus

Antithrombotic Therapy

Laboratory Support of Dose Selection and Therapeutic Monitoring

  

Contents:

Clinical Background

Individuals Suitable for Testing

Test Availability - Table 1

Test Selection and Interpretation - Table 2 - Table 3

References

Appendix
 

Clinical Background [return to contents]

Antithrombotic therapies are widely used to treat coagulation disorders such as vascular ischemia, stroke, venous thromboembolism, coronary artery disease, and heart attack. Because antithrombotic therapies may produce highly variable responses among individuals, dosage selection and monitoring of drug effects are crucial. Dosage selection and therapeutic monitoring are particularly relevant for therapies with a narrow therapeutic window, such as warfarin, and for patients with conditions that are commonly associated with aberrant anticoagulation responses, including pregnancy and renal insufficiency.1,2 This Clinical Focus provides an overview of the use of laboratory testing to guide dosage selection, monitor therapeutic responses, and diagnose therapy-related adverse events for 7 common types of antithrombotic therapies.

Additional information about the mechanisms of action, clinical use, and adverse events associated with these antithrombotic therapies can be found in the Appendix.

Individuals Suitable for Testing [return to contents]

Dosage Selection

  • Individuals being considered for, or receiving, warfarin therapy

  • Individuals being considered for, or receiving, clopidogrel therapy

Therapeutic Response Monitoring

  • Individuals receiving warfarin therapy

  • Individuals who are receiving low-molecular-weight heparins (LMWHs) and

   are pregnant or obese,

   are symptomatic for heparin-induced thrombocytopenia (HIT), or

   have renal insufficiency

  • Individuals who are receiving fondaparinux and have renal insufficiency

  • Individuals who are receiving dabigatran and have at least 1 of the following:

   Excessive bleeding or thrombosis

   Suspicion of overdose

   Need for an invasive procedure

   Renal insufficiency

   Advanced age (≥75 years)

  • Individuals who are receiving rivaroxaban and

   have increased or decreased drug clearance,

   are not responding to treatment, or

   are suspected of overdose

  • Individuals who are receiving clopidogrel and are symptomatic for thrombotic thrombocytopenic purpura (TTP)

  • Individuals who have a recurrent thrombotic event despite aspirin therapy

Test Availability [return to contents]

Tests that can be used to optimize dose and monitor therapy are listed in Table 1. This table is provided for informational purposes only and is not intended as medical advice. A physician’s test selection and interpretation, diagnosis, and patient management decisions should be based on his/her education, clinical expertise, and assessment of the patient.

Table 1. Laboratory Tests Used to Guide Dosage, Monitor Therapeutic Responses, and Diagnose Adverse Events Related to Antithrombotic Therapies
Test Code Test Name Clinical Use

Warfarin (Coumadin®)

 
16160(X) AccuType® Warfarina,b Determine optimal warfarin dose during treatment initiation
8847 Prothrombin Time with INR Monitor response to warfarin therapy and determine optimal warfarin dose
10663(X) Factor X Activity, Chromogenic

Monitor response to warfarin therapy in patients who have strong lupus anticoagulants or those treated with direct thrombin inhibitors

Low-Molecular-Weight Heparins (LMWHs)  
30292 Heparin Anti-Xa (Low Molecular
Weight Heparin)
Monitor therapeutic drug levels in pregnant patients, obese patients, and patients with renal insufficiency
6399 CBC (Includes Differential and Platelets) Diagnose heparin-induced thrombocytopenia (HIT)
414 Heparin-Induced Platelet Antibody
15334(X) Heparin-Induced Platelet Antibody with Reflex to SRA, Unfractionated Heparinc,d
14874

Heparin-Induced Thrombocytopenia Panel

Includes heparin-induced platelet antibody and SRA

14627

Serotonin Release Assay (SRA), Unfractionated Heparind

16285 Serotonin Release Assay (SRA), Fondaparinuxd  
16284 Serotonin Release Assay (SRA), LMWHd  
Fondaparinux (Arixtra®)  
16103 Fondaparinux Sodium (Xa inhibition)d

Monitor therapeutic drug levels in patients with renal insufficiency

Dabigatran (Pradaxa®)  
15972

Dabigatran

Monitor drug levels in elderly patients and those with excessive bleeding or thrombosis; suspected overdose; planned invasive procedure; or renal insufficiency
Rivaroxaban (Xarelto®)  
90981

Rivaroxaban

Monitor therapeutic drug levels in patients with increased or decreased drug clearance, poor treatment response, or suspected overdose.
Clopidogrel (Plavix®)  
16924

AccuType® CP, Clopidogrel
CYP2C19 Genotypea

Determine optimal clopidogrel dose
16605

CYP2C19 Genotyping

Includes detection of CYP2C19*1, *2, and
*3 genotypes; test also detects CYP2D6
(26 variants; not involved with clopidogrel
metabolism)

Determine optimal clopidogrel dose

6399

CBC (Includes Differential and Platelets)

Diagnose clopidogrel-induced TTP

Aspirin  
16174

Aspirin Resistance (11-dehydrothromboxane B2)

Diagnose aspirin resistance

TTP, thrombotic thrombocytopenic purpura.

a This test was developed and its performance characteristics have been determined by Quest Diagnostics Nichols Institute. Performance characteristics refer to the analytical performance of the test.

b A separate test for cytochrome P450 2C9 genotype is also available from Quest Diagnostics.

c Reflex tests are performed at additional charge and are associated with an additional CPT code(s).

d This test was developed and its performance characteristics have been determined by Quest Diagnostics Nichols Institute. It has not been cleared or approved by the U.S. Food and Drug Administration. The FDA has determined that such clearance or approval is not necessary. Performance characteristics refer to the analytical performance of the test.

Test Selection and Interpretation [return to contents]

Anticoagulants

Warfarin (Coumadin®)

Dose Selection

During the first weeks of warfarin therapy, dosage is usually adjusted to obtain a stable therapeutic response.3 Suboptimal dosing during this period leads to excessive bleeding in some patients.3 To reduce the bleeding risk, pharmacogenetic testing that predicts the patient’s response to warfarin and thus assists in determining the patient-specific optimal dose has been proposed.2-5 Pharmacogenetic testing has mainly focused on mutations in 2 genes: VKORC1, which codes for an enzyme inhibited by warfarin, and CYP2C9, which codes for the enzyme that metabolizes warfarin.2-5 Table 2 discusses the implications of VKORC1 and CYP2C9 genotypes for selecting initial warfarin doses.

Table 2. Use of Pharmacogenetic Test Results for Antithrombotic Therapy
Dosage Selection

VKORC1 and CYP2C9 genotypes, together with clinical factors, account for 50% to 60% of the variability in therapeutic warfarin dose.3-5 Clinical factors that influence dose requirements include race, age, height, weight, tobacco use, clinical indication, and concomitant medications.3,4,6 Several algorithms have been developed to determine initial warfarin dosage using pharmacogenetic and clinical factors.3,4,6

Some expert groups, including the International Warfarin Pharmacogenetics Consortium, recommend using pharmacogenetic testing and assessment of clinical factors to personalize warfarin dosage.2 Other groups, such as the American College of Chest Physicians (ACCP)7 and the American College of Medical Genetics,8 do not recommend routine pharmacogenetic testing to determine warfarin dose, citing insufficient evidence linking genotype to clinical outcomes such as warfarin efficacy and risk of severe bleeding.

Monitoring Therapeutic Response
After treatment initiation, warfarin responses are monitored with the international normalized ratio (INR), which is calculated using prothrombin times.2 Patients with an INR below the therapeutic range are at increased risk of recurrent thromboembolism, while those with an INR above the range have a greater risk of excessive bleeding.2 Thus, warfarin dose should be adjusted to maintain the INR within the therapeutic range for optimal efficacy and safety (Table 3). Patients with strong lupus anticoagulants and those transitioning from direct thrombin inhibitors to warfarin often have inaccurate INR results. The chromogenic factor X activity assay gives a more accurate representation of anticoagulation in these patients.9,10

  Table 3. Use of Laboratory Test Results for Monitoring Antithrombotic Therapy

LMWHs

Because of the relatively long half-life and predictable anticoagulant response associated with LMWHs, the ACCP does not recommend routine therapeutic drug monitoring (TDM) for most patients. Exceptions are pregnant women, obese patients, and patients with renal insufficiency, who should be monitored by measuring anti-Xa antithrombin activity (not to be confused with factor X activity).1 Target peak anti-Xa ranges (measured 3-5 h post dose) for patients treated with therapeutic doses are shown in Table 3.

Patients receiving LMWH therapy do not require HIT monitoring unless they: 1) have a history of HIT (>3 months before the latest course of LMWH) and require cardiac surgery; or 2) have no history of HIT but received heparin therapy ≤3 months before the latest course of LMWH.11 In the first group, the baseline platelet count is determined just before initiating the latest course of LMWH therapy. Followup counts are obtained every 2 or 3 days from day 4 to day 14, or until LMWH therapy is stopped. In the second group, the platelet count should be monitored at baseline and within 24 hours of LMWH initiation.11 A >50% drop in platelet count or a platelet count <150,000/μL indicates thrombocytopenia, and HIT should be suspected.12

Individuals treated with LMWHs who develop other clinical symptoms such as vascular thrombosis and skin lesions within 5 to 10 days of treatment initiation may also have HIT.13 Platelet count testing would be appropriate in these patients to help determine the need for additional laboratory tests.

Once HIT is suspected, additional laboratory tests including the heparin-induced platelet antibody test and the serotonin release assay (SRA) should be considered to support or rule out the diagnosis.12 The heparin-induced platelet antibody test is positive if antibodies against heparin-platelet factor 4 complex are detected. The SRA is positive if serotonin release is ≥20%. If both heparin-induced antibody and SRA tests are positive, HIT is probable; if both tests are negative, HIT is unlikely.12 While sensitivity of the 2 tests appears comparable, SRA is more specific for HIT.11,13 Thus, a patient who has a negative heparin-induced platelet antibody and a positive SRA is more likely to have HIT than one with a positive heparin-induced platelet antibody and a negative SRA. However, results of these 2 tests should always be interpreted in conjunction with the pretest probability of HIT.13

Fondaparinux (Arixtra®)

Because fondaparinux has almost 100% bioavailability and induces a consistent anticoagulant response, the ACCP does not recommend routine TDM.1 However, TDM may be beneficial for some patients, such as those with severe renal insufficiency and thus impaired elimination of fondaparinux.14 Target peak plasma fondaparinux levels, based on anti-Xa activity, are shown in Table 3.

Dabigatran (Pradaxa®)

Like warfarin, dabigatran is an oral anticoagulant. Unlike warfarin, it induces a predictable anticoagulant response and does not require routine TDM.15 However, TDM may be useful in patients treated with dabigatran who experience excessive bleeding or thrombosis, are suspected of overdose, or need an invasive procedure.16 Additionally, elderly patients (aged ≥75 years) or those with renal insufficiency are at higher risk of bleeding when treated with dabigatran and may benefit from TDM for dosage adjustment.16,17 The diluted thrombin time (TT) test is a sensitive and precise assay for dabigatran TDM, and diluted TT values show a linear correlation with plasma dabigatran concentration.16,18 The target peak plasma dabigatran concentration, based on the diluted TT value, is 64-443 ng/mL (Table 3).19 Currently, the Quest Diagnostics Dabigatran test (diluted TT test) is the only commercially available laboratory-developed test for monitoring dabigatran concentration.

Antiplatelet Drugs

Clopidogrel (Plavix®)

Dose Selection

Clinicians can use a combination of pharmacogenetic testing and assessment of nongenetic factors to predict clopidogrel responses and tailor therapy accordingly.20 Polymorphisms in the cytochrome P450 2C19 gene (CYP2C19) cause variation in clopidogrel prodrug metabolism and thus affect the dose required for an effective response (Table 2).21 Individuals carrying CYP2C19 alleles associated with reduced clopidogrel prodrug metabolism (*2, *3, *4, etc) have lower levels of active drug and a reduced antiplatelet response to clopidogrel.21,22 The results of several studies indicate that clopidogrel-treated patients with at least 1 reduced-function CYP2C19 allele had higher residual platelet aggregation, a 30% to 50% greater risk of cardiovascular events,21,23 a 50% greater risk of death from cardiovascular disease and stroke,22 and a 3-fold higher risk of stent thrombosis than non-carriers.22,23 However, 1 study of mostly non-stented patients did not show an increase in cardiovascular event rate.24 Strategies for combating clopidogrel resistance include increasing the clopidogrel dose and switching to prasugrel, a new antiplatelet drug whose activity is not affected by polymorphisms in cytochrome P450 2C19.25 Another CYP2C19 allele, CYP2C19*17, is associated with an enhanced antiplatelet response to clopidogrel. Individuals with 1 or 2 copies of this allele have a lower cardiovascular event rate and a higher bleeding risk relative to non-carriers.22,26-28

Monitoring Therapeutic Response

Diagnosis of thrombotic thrombocytopenic purpura (TTP), an adverse event occurring in some patients receiving clopidogrel therapy, requires clinical findings (eg, neurological changes and fever) as well as laboratory test results. The following laboratory results are consistent with a TTP diagnosis: platelet count <100,000/μL, a decreased hemoglobin level, increased serum creatinine level, and the presence of schistocytes in a peripheral blood smear.29

Aspirin

Patients suspected of being resistant to aspirin therapy may be tested for urinary 11-dehydro thromboxane B2 (11-dhTxB2) concentrations. In patients receiving low-dose aspirin therapy, 11-dhTxB2 levels ≤1500 pg/mg creatinine suggest a normal response to aspirin whereas elevated levels (>1500 pg/mg creatinine) suggest aspirin resistance (Table 3). Such 11-dhTxB2 elevations have been associated with an increased risk of stroke, heart attack, and cardiovascular death.30,31

False positive aspirin resistance results (ie, elevated 11-dhTxB2 in a patient without a recurrent thrombotic event) can occur when urinary thromboxane is produced from non-platelet sources such as monocytes, a COX-2–dependent process that is always poorly inhibited by aspirin.32,33 False-negative aspirin resistance results (ie, decreased 11-dhTxB2 in a patient experiencing recurrent thrombotic event[s]) may be caused by decreased inhibition of non-COX-1 platelet aggregation and thrombotic pathways.34

Appendix. Additional Clinical Background Information on Warfarin, LMWHs, Fondaparinux, Clopidogrel, and Aspirin [return to contents]

Anticoagulants

Warfarin (Coumadin®)

Warfarin is an oral anticoagulant used to prevent and treat venous thrombosis and pulmonary embolism (PE), as well as to reduce the risk of stroke and recurrent heart attack after myocardial infarction.35 It acts by inhibiting vitamin K epoxide reductase (VKOR), a key enzyme in vitamin K-dependent coagulation.3 Because warfarin response is highly variable among individuals, the required dose also varies widely.2 Inappropriate dosing can result in either continued thromboembolism or major bleeding.2,36 Major bleeding occurs in 3% of patients during the first month of warfarin therapy, in 0.3% of patients per month after the first year of therapy, and in as many as 10% to 16% of patients treated long term with warfarin.36,37

Warfarin-associated skin necrosis, although rare, can occur within several days of therapy initiation, usually in the presence of protein C and protein S deficiencies.35

Low-Molecular-Weight Heparins (LMWHs)

Derived from heparin by depolymerization, LMWHs enhance the activity of antithrombin, an endogenous anticoagulant that inhibits the coagulation factors thrombin and factor Xa.1 Examples of LMWHs are dalteparin, enoxaparin, and tinzaparin. LMWHs tend to have better benefit-to-risk ratios than heparin and are used to prevent and treat thromboembolic diseases such as venous thromboembolism and pulmonary embolism.1 LMWHs are also used to treat non-ST-elevation acute coronary syndromes14 and to prevent thromboemboli in catheters and coronary arteries during percutaneous coronary intervention (PCI).38

Patients receiving LMWH therapy may experience heparin-induced thrombocytopenia (HIT).12 The clinical characteristics of HIT include arterial and/or venous thromboembolism, necrotic or non-necrotic skin lesions (10% to 20% of HIT patients39), and a decreased platelet count. Disease onset occurs between 5 days and 10 days after treatment initiation in treatment-naïve patients.12 In patients treated with LMWH or unfractionated heparin therapy 3 months before the most recent dose, HIT can develop within 1 day of the latest dose.12

Fondaparinux (Arixtra®)

Fondaparinux is a pentasaccharide heparin fragment that binds to antithrombin with high affinity and enhances antithrombin-mediated inhibition of factor Xa (anti-Xa inhibition).1 It has a higher specific anti-Xa activity and longer half-life than LMWH.1 Fondaparinux is used for deep venous thrombosis (DVT) prophylaxis in patients undergoing orthopedic or abdominal surgery and to treat DVT and PE in combination with warfarin.40 It appears to carry a low risk of HIT relative to LMWHs.41

Dabigatran (Pradaxa®)

Dabigatran, a direct thrombin inhibitor, is the first oral anticoagulant to be approved in the United States since warfarin.15 The drug is used to reduce the risk of stroke and systemic embolism in individuals with atrial fibrillation not caused by heart valve problems.42 It has also been shown to prevent venous thromboembolism in patients undergoing total hip or knee replacement surgery.43,44

Antiplatelet Drugs

Clopidogrel (Plavix®)

Clopidogrel reduces the incidence of cardiovascular atherothrombotic disease, including heart attack, ischemic stroke, and acute coronary syndromes, by inhibiting adenosine diphosphate (ADP)-dependent platelet aggregation.45,46 Clopidogrel and aspirin comprise the dual antiplatelet therapy of choice for preventing stent thrombosis in patients undergoing PCI with stent placement.47 Responses to clopidogrel vary among individuals, with 5% to 44% of patients demonstrating residual platelet aggregation despite treatment, a phenomenon termed “clopidogrel resistance.”46 Clopidogrel resistance has been associated with increased incidence of cardiovascular death, non-fatal heart attack, and stent thrombosis in patients undergoing PCI with drug-eluting stents48 and, more rarely, with stent thrombosis in patients undergoing PCI with bare metal stents.49,50 Potential causes of resistance include comorbid conditions favoring prothrombotic states; poor drug absorption; variations in the gene coding for cytochrome P450 2C19, which converts the clopidogrel prodrug to its active metabolite; insufficient dosing; and treatment nonadherence.22,25,46

Clopidogrel therapy increases the risk of bleeding in some patients,34 especially when used in combination with aspirin.51 Another important adverse event associated with clopidogrel therapy is thrombotic thrombocytopenic purpura (TTP), which involves thrombocytopenia (platelet count <100,000/μL), microangiopathic hemolytic anemia, fever, neurological and renal dysfunction, end organ damage, and death. Disease onset usually occurs within 2 weeks of treatment initiation. In some cases, TTP relapses 1 year after clopidogrel discontinuation and resolution of the initial syndrome.29 

Aspirin

Aspirin reduces the risk of atherothrombotic events and mortality in a wide variety of individuals at high risk of vascular disease.52 Aspirin exerts its antiplatelet effects mainly by inhibiting platelet cyclo-oxygenase-1 (COX-1), thereby decreasing production of the platelet aggregation activator thromboxane A2 and its stable metabolite, 11-dehydro thromboxane B2.31 To a lesser extent, aspirin also affects platelet aggregation and thrombosis via other pathways that are unrelated to COX-1.32 Clinical responses to aspirin vary among individuals; approximately 10% to 20% of patients with atherothrombosis develop recurrent cardiovascular disease or stroke despite aspirin treatment.30 This lack of aspirin responsiveness has been called “aspirin resistance.” Aspirin resistance has also been defined in terms of laboratory features such as the inability of aspirin to increase bleeding time, suppress platelet thromboxane A2 production, or inhibit platelet function in vitro.32 Neither the clinical nor the laboratory definition of aspirin resistance is precise or universally accepted. Patients may experience a vascular event despite optimal aspirin dosing or in vitro evidence of platelet inhibition.

Many causes of aspirin resistance have been proposed, including decreased aspirin inhibition of the COX-1 and thromboxane pathway and decreased aspirin effect on other mechanisms not related to COX-1 and thromboxane.31,34 Causes of aspirin resistance that involve decreased COX-1 and thromboxane inhibition include inadequate adherence to aspirin therapy, suboptimal dosage, concomitant use of other nonsteroidal anti-inflammatory drugs such as ibuprofen, comorbid diseases such as peripheral arterial disease, genetic mutations in the COX-1 gene, and high platelet turnover.31,34,53 Causes not related to COX-1 and thromboxane inhibition include decreased aspirin effect on inflammatory pathways, shear-induced platelet aggregation, and enhancement of fibrinolysis.34

Aspirin adverse events include gastrointestinal toxicity and excessive bleeding in the presence of underlying hemostatic defects.30

References [return to contents]

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  49. Morton J, Nelluri S. Use of a thrombelastograph platelet mapping assay for diagnosis of clopidogrel resistance: a case report. J Extra Corpor Technol. 2009;41:32-36.

  50. Motovska Z, Widimsky P, Marinov I, et al. Clopidogrel resistance "Live" - the risk of stent thrombosis should be evaluated before procedures. Thromb J. 2009;7:6.

  51. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345:494-502.

  52. Aspirin [package insert]. Morristown, NJ: Bayer Corporation; 2006. http://www.fda.gov/ohrms/dockets/ac
    /03/briefing/4012B1_03_Appd%201-Professional%20Labeling.pdf. Updated 2006. Accessed February 20, 2013.

  53. Catella-Lawson F, Reilly MP, Kapoor SC, et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med. 2001;345:1809-1817.
     

Content reviewed 02/2013
 
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* The tests listed by specialist are a select group of tests offered. For a complete list of Quest Diagnostics tests, please refer to our Directory of Services.