Heparin-Induced Thrombocytopenia: An Update

US Pharm. 2008;33:10(Oncology suppl):24-26.

ABSTRACT: Heparin-induced thrombocytopenia (HIT) is a transient, prothrombotic state. Patients with HIT are at increased risk of thrombosis with demonstrated risk even after resolution of acute-phase HIT. Anticoagulation during acute-phase HIT continuing for some time thereafter is generally accepted as the standard of care. Anticoagulation with a direct thrombin inhibitor during acute phase HIT with transition to an agent that can be used in an outpatient setting is typically recommended. This article reviews the pathophysiology and provides updates presented in the recently revised American College of Chest Physicians practice guidelines with regard to management of HIT with and without thrombosis.

Heparin-induced thrombocytopenia (HIT) is a transient, immune-mediated, life-threatening prothrombotic syndrome that develops subsequent to the administration of a heparinoid product. It has been estimated that 0.3% to 5% of patients treated with unfractionated heparin (UFH) will develop HIT.¹ Less commonly, HIT occurs in association with the administration of low-molecular-weight heparin (LMWH) products. The majority of patients who develop HIT are 60 years or older.² Patients treated with UFH who undergo orthopedic surgery are associated with the highest frequency of developing HIT.³ Data have suggested that females treated with UFH are at twice the risk of developing HIT than males. Further, it has been demonstrated that a higher percentage of surgical patients will be diagnosed with HIT secondary to a thrombotic event when compared with medical patients.⁴

The primary adverse outcome of concern with regard to HIT is thrombosis. Among patients with confirmed HIT, 38% to 76% will develop thromboembolic complications.⁵ HIT-associated thrombosis can be fatal and may lead to severe morbidity such as limb amputations and tissue infarction.⁶ Although HIT has been associated with both arterial and venous thrombosis, venous thrombosis is most common; however, a higher incidence of venous thrombosis is likely attributable to the patient population rather than the condition of HIT.⁷ Patients with confirmed HIT at highest risk for thrombosis include those who undergo orthopedic surgery; those who experience a more pronounced thrombocytopenia; and those with a greater immune response. Further, patients treated with UFH have a higher likelihood of experiencing HIT with thrombosis when compared to patients treated with LMWH.⁶

The syndrome known as HIT became recognized as an immunologic phenomenon when researchers determined that it was caused by a noncomplement-fixing, heparin-dependent antibody.⁸ In a patient with HIT, partial platelet activation leads to release from and rebinding to of platelet-factor 4 (PF4) from the platelet. Subsequently, PF4 is bundled by the heparin glycosaminoglycan, inducing a conformational change. The conformational change allows the binding of HIT-immunoglobulin-G (IgG) to the PF4 bundle (HPF4-A), which subsequently binds the Fc receptor on adjacent platelets, initiating platelet activation. Activation of platelets enhances generation of thrombin resulting in a prothrombotic state.

HIT-IgG antibodies typically develop on day 5 to day 7 postinitiation of heparinoid therapy.⁹ Patients who have been treated with a heparinoid in the preceding 100 days, however, may develop antibodies more quickly. The median time to a negative antibody test is up to 85 days. It is recognized that formation of HIT-IgG antibodies is associated with morbidities such as heparin-induced skin lesions, acute systemic anaphylactoid reactions following an IV bolus of UFH, and warfarin-associated necrosis syndromes.¹⁰

Patients with HIT generally present with thrombocytopenia.¹¹ Onset of HIT will vary according to the patient's history of heparinoid exposure. In patients who are heparinoid naïve or who have had no exposure to heparin-based products in the 100 days prior to use, symptoms develop on average five to 10 days after initial exposure to a heparinoid product.⁹

Diagnosis of HIT is accomplished using both clinical and objective parameters.¹¹ In patients with observed thrombocytopenia, other potential etiologies must be ruled out. Thrombocytopenia is defined as a platelet count of less than 150,000 per cubic millimeter or a relative decrease of 50% or more from baseline. It should be noted that the definition of baseline is generally accepted as the platelet count prior to initiation of the heparinoid in medical patients or peak postoperative thrombocytosis in surgical patients.¹² When HIT is clinically suspected, laboratory testing for heparin-dependent antibodies is reasonable. In the setting of a clinical diagnosis of HIT, a positive lab result translates into a likely probability of HIT. The hypercoagulable nature of HIT gives rise to a high probability of thrombosis, which may not be clinically apparent. As such, surveillance ultrasonography is warranted upon, diagnosis as discovery of thromboembolic complications may the govern the duration of anticoagulation therapy.^13,14

Management of HIT
Upon diagnosis of HIT, the antigenic agent, a heparinoid, should be discontinued. No heparinoid products, including line flushes, should be used in patients with HIT to avoid augmenting the immunogenic response. Thrombotic complications that occur in the setting of HIT are associated with the excess production of thrombin as well as activation of platelets in the syndrome.¹¹ Approximately 5% to 10% of patients with HIT develop disseminated intravascular coagulation.¹⁴ Further, generation of thromboses increases the risk for tissue infarction, myocardial infarction, or stroke. Thus, despite a low platelet level, patients diagnosed with HIT require immediate initiation of anticoagulation therapy. Selection of a direct thrombin inhibitor (DTI) as an anticoagulant in the setting of HIT is logical. DTI agents provide anticoagulation through blockade of thrombin activity, thereby working to reduce the prothrombotic effects associated with excess production of thrombin in HIT.

Two agents, argatroban and lepirudin, are FDA approved for the treatment of HIT.¹⁵ Bivalirudin is FDA approved for use in patients with or at risk of HIT who are undergoing percutaneous coronary intervention (PCI).¹⁴ There are limited data that suggest fondaparinux may be an appropriate agent for use in HIT. Favorable results were observed in a recent open-label, prospective, single-center study conducted in Memphis, Tennessee.¹⁶ In this study, fondaparinux was given at higher doses when the patient was diagnosed as having HIT with thrombosis. Patients received either 5 mg, 7.5 mg, or 10 mg daily if they weighed less than 50 kg, between 50 and 100 kg, and more than 100 kg, respectively. If diagnosed as having HIT without thrombosis, the patient received the FDA-approved prophylactic fondaparinux dose of 2.5 mg daily. Seven patients met inclusion eligibility and were enrolled in the present study. Six of these patients were diagnosed with HIT with thrombosis. All subjects included in this study recovered their platelets with no new thrombotic event, major bleeding event, or death reported. These data represent an initial glimpse into the possibility that fondaparinux may be useful in HIT; however, further studies, which should include dose-finding trials, are warranted.

Evidence for the use of DTI agents in HIT in the form of randomized, controlled trials is limited due to the infrequency of serologically confirmed diagnoses and the variety of patient populations.¹⁴ The majority of clinical experience with regard to treatment of HIT has been with the use of argatroban and lepirudin. It is noteworthy that the American College of Chest Physicians (ACCP) recommends lower dosing than that which is FDA approved for lepirudin and, with selected comorbid conditions, for argatroban. Further analyses of lepirudin studies uncovered that higher doses were associated with increased bleeding events without any increase in efficacy. In addition, many studies used a mean dose comparable to the lower dosage recommended by the ACCP. Thus, the ACCP recommends that a bolus of lepirudin is not necessary except in cases where life- or limb-threatening thromboses occur. In this setting, the bolus should be 0.2 mg/kg for patients with normal organ function. Further, infusion rates should be initiated no higher than 0.1 mg/kg/h in patients with normal organ function.¹⁷ Patient monitoring includes obtaining activated partial thromboplastin time (aPTT) values every four hours upon infusion completion until steady state at 1.5 to 2 times the patient's baseline is achieved. Adjustment of lepirudin dosing is necessary in patients with renal dysfunction. The ACCP also recommends that argatroban dosing be initiated at 2 mcg/kg/min with no bolus dose except for patients with heart failure, multiple organ system failure, or severe anasarca. For these patients, a lower infusion rate of 0.5 to 1.2 mcg/kg/min is recommended. Patients with significant hepatic dysfunction who are receiving argatroban therapy require dose adjustment.

Selecting a DTI Agent
DTI agent selection can be suited to the clinical situation at hand by taking certain pharmacokinetic parameters, in conjunction with clinical parameters, into account. All three DTI agents used in HIT are only available by the parenteral route of administration. Both lepirudin and bivalirudin are eliminated renally; however, bivalirudin is also cleared via enzymic metabolism.¹⁴ Argatroban is eliminated through the hepatobiliary system. If organ function is normal, bivalirudin demonstrates the shortest half-life (25 min) and lepirudin has the longest half-life (80 min). DTI agents have no available reversal agent for their anticoagulant effects. As such, these agents must be dosed and monitored with extreme vigilance.

Once the patient has been stabilized on a therapeutic dose of DTI and the platelet count has returned to baseline or 150,000 platelets/mm³, transition to warfarin can be initiated.^18-20 Warfarin should never be used as monotherapy prior to platelet recovery because of a concern for increased thrombin production in the setting of HIT, combined with an acute reduction of activated protein C by warfarin. This could cause a worsening of the condition for which the warfarin is used and may even lead to limb gangrene. Warfarin should be given in modest doses--recommended as no higher than 5 mg daily--to avoid overshooting the international normalized ratio (INR), and both the DTI and warfarin should be given concurrently for at least four or five days prior to discontinuation of the DTI.

Treatment with DTI agents may affect INR values, causing them to be artificially inflated. This phenomenon is addressed in the package insert for argatroban, in which the manufacturer recommends aiming for an INR greater than four to ensure a therapeutic dose of warfarin prior to discontinuation of the DTI.²¹ Upon discontinuation of argatroban, the INR should be reevaluated after four to six hours have elapsed. If this evaluation demonstrates an INR below therapeutic goal, the manufacturer recommends restarting anticoagulation with argatroban. This procedure should be repeated daily until therapeutic INR values with warfarin alone are seen.

Implementing Chromogenic Factor X Assays
Many clinicians elect to use the chromogenic factor X assay to assist with interpretation of an artificially inflated INR value often observed when a patient receives concomitant warfarin and DTI treatment. Accurate interpretation of artificially inflated INR values allows confidence in therapeutic anticoagulation of the patient upon discontinuation of the DTI and initiation of warfarin monotherapy. The chromogenic factor X assay measures the amount of clotting factor X, which is pharmacologically decreased with warfarin therapy. Chromogenic factor X levels of 11% to 42% inversely correspond to therapeutic INR values of 2 to 3.5.²² A study evaluating the ability of the chromogenic factor X assay to predict the INR for patients receiving both argatroban and warfarin found that a chromogenic factor X level of 45% or less predicted an INR of two or greater with a sensitivity of 93%, a specificity of 78%, and an accuracy of 89%. Thus, this assay may provide a useful tool for clinicians to interpret the therapeutic effects of warfarin in this setting.

Duration of Warfarin Therapy
Clinical data directly addressing the optimal duration of therapy with warfarin in patients diagnosed with HIT are  not currently available; however, it is known that risk of thrombosis remains high for weeks after diagnosis of HIT.⁹ The ACCP guidelines recommend three months of treatment with warfarin for patients with a first episode of deep venous thrombosis or pulmonary embolism secondary to a transient risk factor.¹⁴ Determination of a reasonable duration of warfarin therapy is not quite as straightforward in patients who have not developed thrombosis in the setting of HIT. Although no thrombotic complication has occurred, there is substantial risk for HIT-related thrombosis. For treatment of isolated HIT without thrombosis, many clinicians initiate therapy with warfarin and transition to monotherapy once platelet counts have recovered. Evidence suggests that risk of thrombosis remains high in this patient population for at least 30 days. Therefore, it is logical to treat patients with isolated HIT for at least 30 days. Prior to discontinuation of warfarin therapy, surveillance ultrasonography can provide data to assist with medical decision making. Further prospective, randomized studies are necessary to concretely determine the optimal duration of warfarin therapy post-HIT diagnosis for patients with and especially without thrombotic complications.

REFERENCES
1. Lindhoff-Last E, Nakov R, Misselwitz F, et al. Incidence and clinical relevance of heparin-induced antibodies in patients with deep vein thrombosis treated with unfractionated or low-molecular-weight heparin. Br J Haematol. 2002;118:1137-1142.
2. Greinacher A, Farner B, Kroll H. Clinical features of heparin-induced thrombocytopenia including risk factors for thrombosis. Thromb Haemost. 2005;94:132-135.
3. Warkentin TE, Sheppard JA, Horsewood P, et al. Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood. 2000;96:1703-1708.
4. Warkentin TE, Sheppard JA, Sigouin CS, et al. Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia. Blood. 2006;108:2937-2941.
5. Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Med. 1996;101:502-507.
6. Levine RL, McCollum, D, Hursting MJ. How frequently is venous thromboembolism in heparin-treated patients associated with heparin-induced thrombocytopenia? Chest. 2006;130:681-687.
7. Fabris F, Luzzato G, Soini S, et al. Risk factors for thrombosis in patients with immune mediated heparin-induced thrombocytopenia. J Intern Med. 2002;252:149-154.
8. Kelton JG. The pathophysiology of heparin-induced thrombocytopenia. Chest. 2005;127:9S-20S.
9. Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med. 2001;344:1286-1292.
10. Warkentin TE, Roberts RS, Hirsh J, Kelton JG. Heparin-induced skin lesions and other unusual sequelae of the heparin-induced thrombocytopenia syndrome: a nested cohort study. Chest. 2005;127:1857-1861.
11. Gowthami AM, Ortel TL. Heparin-induced thrombocytopenia. N Engl J Med. 2006;355:809-817.
12. Warkentin TE, Roberts RS, Hirsh, J, Kelton JG. An improved definition of immune heparin-induced thrombocytopenia in postoperative orthopedic patients. Arch Intern Med. 2003;163:2518-2524.
13. Tardy B. Lower limb veins should be systematically explored in patients with isolated heparin-induced thrombocytopenia. Thromb Haemost. 1999;82:1199-1200.
14. Warkentin TE, Greinacher A, Koster A, Lincoff AM. American College of Chest Physicians. Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed). Chest. 2008;133:340S-380S.
15. Dang CH, Durkalski VL, Nappi JM. Evaluation of treatment with direct thrombin inhibitors in patients with heparin-induced thrombocytopenia. Pharmacotherapy. 2006;26:461-468.
16. Lobo B, Finch C, Howard A, Minhas S. Fondaparinux for the treatment of patients with acute heparin induced thrombocytopenia. Thromb Haemost. 2008;99:208-214.
17. Lubenow N, Eichler P, Lietz T, et al. Lepirudin for prophylaxis of thrombosis in patients with acute isolated heparin-induced thrombocytopenia: an analysis of 3 prospective studies. Blood. 2004;104:3072-3077.
18. Bartholomew JR, Hursting MJ. Transitioning from argatroban to warfarin in heparin-induced thrombocytopenia: an analysis of outcomes in patients with elevated international normalized ratio (INR). J Thromb Thrombolysis. 2005;19:183-188.
19. Bartholomew JR. Transition to an oral anticoagulant in patients with heparin-induced thrombocytopenia. Chest. 2005;127:27S-34S.
20. Hursting MJ, Lewis BE, Macfarlane DE. Transitioning from argatroban to warfarin therapy in patients with heparin-induced thrombocytopenia. Clin Appl Thromb Hemost. 2005;11:279-287.
21. Argatroban [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2008.
22. Arpino PA, Demirjian Z, Van Cott EM. Use of the chromogenic factor X assay to predict the international normalized ratio in patients transitioning from argatroban to warfarin. Pharmacotherapy. 2005;25:157-164.

To comment on on this article, contact rdavidson@jobson.com.