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Hitting the target with antithrombotic therapy.

Overview: antithrombotics and their indications

Anticoagulants or antithrombotics, known to the public as "blood thinners" have been used successfully since the 1940s to reduce secondary thrombus formation. (1) Although they do not "thin" blood or dissolve clots, antithrombotics limit or prevent clotting in atrial fibrillation, percutaneous cardiac intervention (PCI), venous thromboembolism, coronary and peripheral artery disease, ischemic stroke, surgery, trauma, or other acute medical conditions.

The only oral antithrombotic is warfarin, synonym Coumadin, a high-volume drug that requires vigilant monitoring as overdose results in severe, sometimes fatal hemorrhage. (2) The most commonly used prophylactic antithrombotic is low molecular weight heparin (LMWH), enoxaparin, or Lovenox, conveniently packaged in syringes and requiring little monitoring. (3) Standard unfractionated heparin (UFH) has been used for decades to support coronary artery bypass graft (CABG) surgery and PCI because it is effective, inexpensive, and reversible, although it has been replaced by LMWH in therapeutic circumstances where rapid reversal is not a consideration. UFH triggers dangerous heparin-induced thrombocytopenia with thrombosis (HIT) in 1% to 5% of patients; LMWH does not. (4) A successful alternative to heparin is the direct thrombin inhibitor (DTI) class, including argatroban, lepirudin, and bivalirudin. (5) These are particularly useful in HIT. Oral antiplatelet drugs, aspirin and clopidogrel (Plavix), are prescribed in combination with warfarin and enoxaparin to prevent secondary thrombosis, (6) while the intravenous platelet inhibitors eptifibatide (Integrelin), abciximab (Rheopro), and tirofiban (Aggrastat) are used during PCI to maintain patency. (7)

The American College of Cardiac Physicians Conference on Antithrombotic and Thrombolytic Therapy meets every three years to review and update evidence-based anticoagulant guidelines. The last guidelines were published in a September 2004 Chest supplement, Vol. 126. A new series is due late in 2007. This is the U.S. standard for anticoagulant therapy.

Oral antithrombotic therapy: warfarin

Warfarin action

Warfarin (see Table 1) is a vitamin K antagonist. (8) Vitamin K, available from green vegetables and produced by intestinal bacteria, catalyzes [gamma]-carboxylation of glutamic acid in coagulation factors II (prothrombin), VII, IX, and X. Warfarin intercepts this process, inducing the liver to produce inactive copies, slowing fibrin production. Warfarin is metabolized by the liver cytochrome P450 pathway. (9)

Warfarin indications

Long-term warfarin prevents ischemic strokes in atrial fibrillation and prosthetic heart valves. Warfarin is prescribed for three to six months following deep vein thrombosis (DVT), pulmonary embolism (PE), and myocardial infarction with cardiac insufficiency. (10)

Warfarin dose management: PT

The starting dose is 5 mg/day to 10 mg/day; less than 5 mg/day for patients over 70 or with bleeding risks. A prothrombin time (PT) with international normalized ratio (INR) is required after the second or third dose and then daily until consecutive INRs match within the therapeutic range, 2.0 to 3.0. Monitoring and dose adjustment continues weekly until the INR is stable, typically four weeks. Subsequently, the PT with INR is required monthly throughout the therapeutic interval. The INR provides for normalization among laboratories, and an INR above 5.0 signals imminent risk of hemorrhage.

Variations in diet and concurrent drugs or dietary supplements affect warfarin efficacy. At least 80 commonly used drugs are metabolized through the cytochrome pathway, and are known to raise or lower the INR despite stable dosage and patient compliance. Patients are counseled to be consistent in their consumption of salads and green vegetables and to report changes in drugs or diet. (11)

Managing warfarin overdose

When the INR exceeds the therapeutic range, the dosage is reduced or the patient may be instructed to skip one dose, and weekly or biweekly PTs are ordered until the INR stabilizes. For bleeding, vitamin K is administered orally, by injection, or intravenously. If bleeding is severe, the patient is provided normal coagulation factors in frozen plasma, prothrombin complex concentrates such as Proplex, or activated factor VII, NovoSeven. Warfarin-induced hemorrhage is a medical emergency, and the PT is run daily until the dosage stabilizes.

Venous blood specimens for the PT

For laboratory-based PTs, whole blood is collected in a blue-closure tube containing 3.2% sodium citrate and mixed by at least six gentle inversions. The tube must fill; clots and short draws falsely prolong the PT, resulting in inappropriate dosage reduction. Shaking causes hemolysis, falsely shortening the PT. The specimen may be stored sealed at room temperature for up to 24 hours.

Point-of-care warfarin management

Percent of time in therapeutic range is improved by anticoagulation clinics where testing and dosage adjustments are made on the spot. (12) Many anticoagulation clinics employ capillary whole-blood near-patient testing instruments such as the Coag-u-Chek. Patients may be trained to use home-testing coagulometers, although the clinic maintains control of dosage adjustment. (13) Home-testing percent of time in therapeutic range matches anticoagulation clinics and is supported by Medicare and many insurance carriers for mechanical heart valves and atrial fibrillation. When results are discrepant, a laboratory-based PT should be ordered.

Low molecular weight heparin therapy: enoxaparin

LMWH action

LMWH activates plasma antithrombin, which then binds coagulation factor Xa to reduce fibrin formation. (14) Acquired or congenital antithrombin deficiency may reduce LMWH therapeutic efficacy. LMWH is excreted by the kidney and must be monitored in renal insufficiency. Its peak antithrombin activity is three to five hours and its plasma half-life is three to six hours after subcutaneous (SC) injection.

LMWH indications

LMWH is recommended for prevention of thrombosis in major orthopedic surgery such as hip or knee replacement, and in acute medical conditions such as cancer, respiratory disease, and heart failure. (15) LMWH is also given for the first few days of oral anticoagulant therapy.

LMWH dose management

LMWH requires monitoring only in obesity >130 kg, children, or extremely small adults <40 kg; renal disease when the serum creatinine exceeds 2 mg/dL or the urine creatinine clearance is <25 mL/min; and in pregnancy, cancer, diabetes, or other chronic inflammatory disease. A blue-closure tube is collected four hours after injection. LMWH is monitored using the chromogenic anti-Xa heparin assay (see Table 2). The anti-Xa heparin assay is available in most laboratories. (16)

LMWH and HIT

LMWH does not cause HIT but may interact with HIT antibodies that arise in the prior use of UFH, thus is contraindicated in patients at risk for HIT.

Unfractionated (Standard) heparin

UFH action

UFH binds and activates plasma antithrombin, which then binds and inhibits thrombin, reducing fibrin formation. Acquired or congenital antithrombin deficiency may reduce UFH therapeutic efficacy. (17)

UFH indications

Intravenous UFH is therapeutic following acute thrombotic conditions such as myocardial infarction or venous thromboembolism and during PCI or CABG where immediate reversal is necessary. Because it is administered IV and requires vigilant laboratory management, UFH is largely confined to inpatient therapy.

UFH dose management and laboratory monitoring

UFH therapy is begun with a bolus of 5,000 to 10,000 units (U) and continues at 1,600 U/hour or a similar dosage keyed to patient weight. Therapy is discontinued at discharge or a maximum of five days to reduce the risk of HIT. UFH is continued as warfarin therapy is begun because warfarin requires four to seven days to stabilize. (18) UFH is managed using the partial thromboplastin time (PTT) test. (19) A baseline PTT is collected prior to therapy to establish its validity. The PTT is unusable in coagulation factor deficiency or when there are acquired inhibitors such as lupus anticoagulant. A second PTT is ordered four to six hours after initiation and compared to the laboratory target interval. The dosage is adjusted to the therapeutic target range and monitored at 24-hour intervals to discontinuation. Many texts indicate a target range that is 1.5 to 2.5 times the mean of the PTT reference interval. This historical error may lead to inadequate anticoagulation and the risk of a second thrombotic event. The therapeutic target range should be computed using the Brill-Edwards method, in which PTTs and chromogenic anti-Xa heparin assays are performed on 50 plasmas from patients on heparin therapy whose PTs are normal and 20 plasmas from normal subjects. A linear graph of the paired results is prepared. The PTT therapeutic range is the time in seconds corresponding to 0.3 U/mL to 0.7 U/mL. (20)

Venous blood specimens for the PTT

Venous blood specimens are collected and managed as for the PT. Blood for the PTT must be centrifuged within one hour of collection and the platelet-poor plasma separated from the red cells to prevent a falsely shortened result.

Heparin-induced thrombocytopenia with thrombosis

HIT results from activation of platelets in patients who produce an IgG antibody to heparin-bound platelet factor 4 (PF4). To monitor for HIT, daily platelet counts are required for the duration of therapy. A 24-hour reduction in platelets of 40% or greater is presumptive evidence of HIT. UFH therapy should be immediately discontinued and replaced by a direct thrombin inhibitor. HIT may be confirmed using an immunoassay for the anti-heparin-PF4 antibody, however, tests require a 24-hour turnaround time and are not used for emergency diagnosis.

Pentasaccharide

Fondaparinux (Arixtra) is a synthetic version of the active pentasaccharide sequence in heparin that binds to antithrombin. It has a longer half-life than UFH or LMWH and a predictable dose response. Like LMWH, it only needs laboratory monitoring in special circumstances. The anti-Xa heparin assay is used for monitoring, but the standard curve must be prepared with fondaparinux instead of heparin. Blood is collected four hours after injection.

Direct Thrombin Inhibitors (DTIs): Argatroban, Lepirudin, Bivalirudin

DTI action

DTIs (see Table 3) bind and neutralize thrombin, the most active of the coagulation factors. Their action extends to fibrin-bound thrombin, increasing their antithrombotic effectiveness.

DTI indications

Intravenous DTIs substitute for UFH in HIT and may be used postoperatively or intraoperatively. (21)

DTI dose management (argatroban)

Argatroban is administered at 2 ug/kg/hour and achieves immediate steady state. It is monitored using the PTT, collected two hours after therapy is begun. The therapeutic target range is 1.5 to 3 times the mean of the PTT reference interval. The half-life of argatroban is 40 minutes. Argatroban prolongs the PT so when warfarin therapy is begun during argatroban administration, the target INR is doubled during the changeover. Lepirudin and bivalirudin are monitored similarly; however lepirudin may trigger antibody formation, thus is used for only one course of therapy. (22)

Antiplatelet agents aspirin, clopidogrel (Plavix) eptifibatide (Integrelin), abciximab (Rheopro) and tirofiban (Aggrastat)

Anti-platelet agent action

Antiplatelet agents reduce platelet activation and function, by mechanisms shown in Table 4.

Anti-platelet agent indications

Long-term aspirin is prescribed for the prevention of secondary events subsequent to acute myocardial infarction, peripheral artery disease, DVT, PE, or in atrial fibrillation, prosthetic heart valve, or thrombophilia. (23) Many self-administer aspirin to reduce the risk of a primary thrombotic event. Aspirin is used therapeutically in conjunction with UFH, LMWH, clopidogrel, and warfarin, and during PCI and coronary artery bypass graft surgery. (24) Aspirin is used in an effort to reduce thrombosis in acute chest pain and in onset of ischemic stroke. Plavix may be used in many of the aspirin applications; however, most therapy is confined to a one-month period following a thrombotic event. Intravenous glycoprotein IIb/IIIa inhibitors maintain vascular patency and reduce thrombotic risk during PCI.

Anti-platelet agent monitoring

Aspirin is prescribed at 81 mg/day or 325 mg/day alone or in combination with Plavix at 75 mg/day. As anti-platelet agent resistance becomes recognized, a number of laboratory platforms may be used to test for aspirin and Plavix efficacy. (25) These include near-patient whole blood platelet aggregometry by the Chronolog WBA, Dade-Behring PFA-100, Helena PlateletWorks, and Accumetrics VerifyNow. Corgenix AspirinWorks is an immunoassay screen for a platelet thromboxane A2 metabolite performed on random urine.

Summary

Thrombus treatment and prevention can be regulated by a number of intravenous or subcutaneous drugs, as well as oral warfarin. Many therapies require laboratory monitoring for efficacy and for detection of dangerous sequelae, such as bleeding, thrombosis, or heparin induced thrombocytopenia.

Margaret G. Fritsma, MA, MT(ASCP) SBB, is an associate professor in clinical laboratory sciences and pathology at the School of Health Professions at the University of Alabama-Birmingham. Bernadette. F. Rodak, MS, CLSpH(NCA), is a professor in the clinical laboratory science program within the Department of Pathology and Laboratory Medicine at the Indiana University School of Medicine in Indianapolis.

References

1. Kresge N, Simoni RD, Hill RL. Hemorrhagic sweet clover disease, dicumarol, and warfarin: the work of Karl Paul Link. J Biol Chem. 2005;280:5-15.

2. Levine MN, Raskob G, Beyth RJ, et al. Hemorrhagic complications of anticoagulant treatment the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest. 2004;126:287S-310S.

3. Hirsch J, Raschke R. Heparin and low-molecular-weight heparin: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest. 2004;126:188S-203S.

4. Warkentin TE. Coumarin-induced skin necrosis and venous limb gangrene. In: Colman RW, Clowes AW, Goldhaber SZ, et al (eds). Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Philadelphia: Lippincott, 2006:1663-1671.

5. Weitz JI, Hirsh J, Samama MM. New anticoagulant drugs: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest.2004;126:265S-287S.

6. Antiplatelet Trialists' Collaboration: Collaborative overview of randomized trials of antiplatelet therapy: I. prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ. 1994;308:81-106.

7. Popma JJ, Berger P, Ohman EM, et al. Antithrombotic therapy during percutaneous coronary intervention: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest. 2004;126:576S-600S.

8. Poller L: Laboratory control of anticoagulant therapy. Semin Thromb Hemost. 1986;12:13-19.

9. Schalekamp T, Brasse BP, Roijers JF, et al. VKORC1 and CYP2C9 genotypes and acenocoumarol anticoagulation status: interaction between both genotypes affects over-anticoagulation. Clin Pharmacol Ther. 2006;80:13-22.

10. Ansell J, Hirsh J, Poller L, et al. The pharmacology and management of the vitamin K antagonists: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest. 2004;126:204S-233S.

11. Fritsma GA. Chapter 46, Monitoring Anticoagulant Therapy. In Rodak BF, Fritsma GA, Doig K. Hematology: Clinical Principles and Applications, 3rd ed. 2007. Elsevier, St. Louis.

12. Wittkowsky AK, Nutescu EA, Blackburn J, et al. Outcomes of oral anticoagulant therapy managed by telephone vs in-office visits in an anticoagulation clinic setting. Chest. 2006;130:1385-1389.

13. Hill J, Perreault S, Dorval M. Validity of CoaguChek S for home monitoring of anticoagulant therapy in pediatrics. Can J Cardiol. 2007;23:47-50.

14. Rubboli A, Ottani F, Capecchi A, et al. Low-molecular-weight heparins in conjunction with thrombolysis for ST-elevation acute myocardial infarction. A critical review of the literature. Cardiology. 2007;107:132-139.

15. Turpie AGG. Extended duration of thromboprophylaxis in acutely ill medical patients: optimizing therapy? J Thrombos Haemost. 2007;7:5-11.

16. McGlasson DL: Using a single calibration curve with the anti-Xa chromogenic assay for monitoring heparin anticoagulation. Lab Med. 2005;36:297-299.

17. Bharadwaj J, Jayaraman C, Shrivastava R: Heparin resistance. Lab Hematol. 2003;9:125-131.

18. Warkentin TE: Coumarin-induced skin necrosis and venous limb gangrene. In Colman RW, Clowes AW, Goldhaber SZ, et al (eds): Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Philadelphia: Lippincott, 2006:1663-1671.

19. Olson JD, Arkin CF, Brandt JT, et al (eds): College of American Pathologists conference XXXI on laboratory monitoring of anticoagulant therapy: laboratory monitoring of unfractionated heparin therapy. Arch Pathol Lab Med. 1998;122:782-798

20. Brill-Edwards P, Ginsberg JS, Johnston M, et al. Establishing a therapeutic range for heparin therapy. Ann Intern Med. 1993;119:104-109.

21. Lewis BE, Hursting MJ. Direct thrombin inhibition during percutaneous coronary intervention in patients with heparin-induced thrombocytopenia. Expert Rev Cardiovasc Ther. 2007;5:57-68.

22. Cardenas GA, Deitcher SR. Risk of anaphylaxis after reexposure to intravenous lepirudin in patients with current or past heparin-induced thrombocytopenia. Mayo Clin Proc. 2005;80:491-493.

23. Juul-Moller S, Edvardsson N, Jahnmatz B, et al. Double-blind trial of aspirin in primary prevention of myocardial infarction in patients with stable chronic angina pectoris. Lancet. 1992;340:1421-1425.

24. Hirsh J, Dalen JE, Fuster V, et al. Aspirin and other platelet-active drugs: the relationship among dose, effectiveness, and side effects. Chest. 1995;108:247S-257S.

25. Eikelboom JW, Hirsh J, Weitz JI, et al. Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events. Circulation. 2002;105:1650-1655.

By Margaret G. Fritsma, MA, MT(ASCP) SBB, and Bernadette F. Rodak, MS, CLSpH(NCA)
Table 1. Oral anticoagulant therapy

Agent Action Administration

Warfarin Inhibits vitamin K mediated Oral, 5 mg/d to 10 mg/d
(Coumadin) g-carboxylation of factors II, 4 to 7 days required to
 VII, IX, X, proteins C, S, and Z reach therapeutic level
 Careful monitoring require

 Therapeutic Prophylactic
Agent range range Laboratory monitoring

Warfarin INR 2-3 INR 2-3 PT/ INR
(Coumadin)
 Daily until therapeutic level
 achieved; twice/week for two
 weeks; once/every 3 to 4 weeks
 thereafter

Table 2. Heparin therapy

Agent Administration Half-life Therapeutic range

Unfractionated Intravenous, 1 to 2 0.3 to 0.7
 heparin (UFH) continuous hours anti-Xa heparin
 U/mL

Low molecular weight Subcutaneous, 3 to 6 0.4 to 1.0 anti-Xa
 heparin (LMWH) 1-two times/day hours heparin assay U/mL
 (enoxaparin, if dosed twice/day;
 Lovenox) 1.0 to 2.0 anti-Xa
 U/mL if once/day
Pentasaccharide Subcutaneous, 12 to 17 0.14 to 0.19 mg/L
 (fondaparinux, once/day hours
 Arixtra)

Agent Prophylactic range Laboratory monitoring

Unfractionated 0.1 to 0.4 Chromogenic anti-Xa heparin
 heparin (UFH) anti-Xa heparin U/mL assay or PTT in seconds
 corresponding to anti-Xa
 heparin assay
 Daily platelet count
Low molecular weight 0.2 to 0.4 anti-Xa Chromogenic anti-Xa heparin
 heparin (LMWH) heparin U/mL assay
 (enoxaparin,
 Lovenox)
Pentasaccharide Chromogenic anti-Xa assay
 (fondaparinux, using plasma w/ fondaparinux
 Arixtra) for standard curve

Table 3. Direct thrombin inhibitors (DTIs)

DTI Administration Indications Laboratory monitoring

Argatroban IV, 2 mg/kg/min Substitute for PTT 1.5-3.0 X mean of
Lepirudin IV, 0.4 mg/kg, UFH or LMWH in reference interval
 then 0.15 patients at Activated Clotting Time
 mg/kg/hr risk for HIT (ACT)--PCI patients
Bivalirudin IV, 0.75 mg/kg, Ecarin clotting time
 then 0.1.75 (ECT)
 mg/kg/hr.
 Use with aspirin
 325 mg/d

Table 4. Antiplatelet therapy

Agent Action LaboratorymMonitoring

Aspirin Irreversibly acetylates AspirinWorks
 cyclooxygenase to PlateletWorks
 reduce production of VerifyNow
 thromboxane A2 PFA-100
 Chronolog WBA
Clopidogrel (Plavix) Binds platelet membrane VerifyNow
Ticlopidine (Ticlid) ADP receptor P2Y12 PFA-100
Eptifibatide Binds GP IIb/IIIa Chronolog WBA
 (Integrelin)
Abciximab (Rheopro)
Tirofiban (Aggrastat)
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Title Annotation:CLINICAL ISSUES
Author:Fritsma, Margaret G.; Rodak, Bernadette F.
Publication:Medical Laboratory Observer
Geographic Code:1USA
Date:May 1, 2007
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