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  Vol. IV, No. V
  September/October 2001

  Robert Barcelona,

 Return to
 Update Index


Type II Heparin-Induced Thrombocytopenia:
New Treatment Options

Introduction:Heparin-induced thrombocytopenia (HIT) may develop in two distinct forms, type I and type II (See Table 1). Type I HIT, also known as heparin-associated thrombocytopenia (HAT), is a non-immunologic response to heparin therapy, while type II HIT is an immunologic response to heparin therapy. Type I is more common than type II, occurring in 10 to 20% of patients given heparin, while type II occurs in 1 to 3% of patients receiving heparin.

The cause of type I HIT may be mediated by a direct interaction between heparin and circulating platelets causing platelet clumping or sequestration. This type of thrombocytopenia may exist in patients receiving heparin in the presence of other comorbid factors, such as other medications or sepsis, which may complicate the diagnosis. Type I HIT usually occurs within the first 48 to 72 hours after initiation of heparin therapy and the platelet count usually does not fall below 100 X 103/mm3, often returning to normal within 4 days despite continued heparin use. No laboratory tests are required to diagnose type I HIT, and it is not associated with an increased risk of thrombosis.

Type II HIT occurs in approximately 1 to 3% of patients receiving heparin and can occur at any dose or route of administration. Clinically, type II HIT displays thrombocytopenia after 5 to 10 days of heparin therapy, and the platelet count decreases approximately 30 to 50%, decreasing to less than 100 X 103/mm3, but usually not falling below 10 to 20 X 103/mm3. Type II HIT is more severe because of the increased risk of thrombotic events, occurring in 30 to 80% of patients. Thrombotic events may occur in both the arterial and venous systems. These events occur primarily in the venous system and may lead to deep venous thrombosis (DVT), pulmonary embolism (PE), acute myocardial infarction, skin necrosis, venous limb gangrene, and possibly death.

Type II HIT is caused by the formation of antibodies that activate platelets following heparin administration. This leads to an interaction with platelet factor 4 (PF4), which is normally found on endothelial cells and platelets, and formation of immunogenic heparin-PF4 complexes which cause an immunologic response. Antibodies are generated resulting in a complex forming between antibodies, heparin, and PF4 (mediated through the FcyIIa portion of the platelet). This complex leads to further platelet activation resulting in formation of microparticles and thrombin generation. Antibodies also recognize PF4 bound to heparin on the endothelial surface and this surface becomes activated leading to another route of thrombin production. These pathways of thrombin generation may ultimately lead to thrombus formation and possible thromboembolic sequelae. The antibodies that are formed may persist for weeks to months following heparin administration; therefore, if a patient develops type II HIT and is administered heparin at a later date when circulating antibodies are still present, platelet levels may decrease within hours.

Diagnosis: A number of diagnostic laboratory tests are available for type II HIT. The 14C-serotonin-release assay (SRA) combines serum from a suspected type II HIT patient with platelets of normal donors and adds them to therapeutic concentrations of heparin. A positive result detects if 14C-serotonin is released from the serum of suspected type II HIT patients. Another assay is the heparin-induced-platelet activation assay (HIPAA). This test assesses aggregation of platelets induced by the serum of patients in the presence of heparin. The platelet-rich plasma (PRP) aggregation assay is another diagnostic test. HIT-specific antibodies may also be assayed using the enzyme-linked immunosorbent assay (ELISA) test. Antibodies detected include IgG, IgM, and IgA. It is important to note that a patient may have type II HIT with negative laboratory results. Therefore, in patients with suspected type II HIT who have negative laboratory tests, the diagnosis is usually made clinically. This is due to the fact that adverse sequelae may occur with this condition and an alternative anticoagulation strategy may need to be initiated promptly.

Treatment: Treatment of type II HIT requires immediate discontinuation of all heparin products, including heparin infusions, heparin flushes, and heparin coated catheters used for hemodynamic monitoring. The use of an effective alternative anticoagulant also needs to be determined (See Table 2). Treatment options are focused on inhibiting thrombin formation or direct thrombin inhibition.

Lepirudin: Hirudin is an anticoagulant unrelated to heparin and is a direct thrombin inhibitor isolated from the salivary glands of the medicinal leech, Hirudo medicinalis. Hirudin binds with high affinity and specificity to the catalytic and substrate binding sites of thrombin, forming a noncovalent, irreversible complex that inhibits all proteolytic functions of thrombin. Hirudin binds to plasma thrombin as well as fibrin-bound thrombin. This is important because fibrin-bound thrombin is able to activate platelets and increase fibrin formation. Since it directly binds to thrombin, hirudin does not require a plasma cofactor such as antithrombin III for its anticoagulant properties, and it is not affected by PF4 or other substances that can cause heparin resistance. Lepirudin (Refludan®) is a recombinant form of hirudin and is FDA-approved for anticoagulation for patients with heparin-induced thrombocytopenia and heparin-induced thrombosis. The half-life of lepirudin is 40 to 120 minutes, and it undergoes renal elimination (i.e., its half-life may be increased in renal insufficiency).

Monitoring of lepirudin is done by measuring the aPTT, with a therapeutic range of 1.5 to 3.0 times the median of normal range. The recommended dose of lepirudin is 0.4 mg/kg as an intravenous bolus, followed by a continuous infusion based on the body weight and renal function of the patient. Since lepirudin undergoes renal function of the patient. Since lepirudin undergoes renal elimination, dose reductions are necessary when the creatinine clearance of the patient is <45 to 60 ml/minute, and the infusion should be avoided or stopped in patients with a creatinine clearance of <15 ml/minute (See Table 3). There is no antidote for lepirudin, it is contraindicated in patients with hypersensitivity to the agent, and it should be used with caution in patients with active bleeding disorders. As with all anticoagulants, the most common adverse reaction with lepirudin is bleeding, occurring in 3 to 12% of patients, but fever may also occur. Lepirudin prolongs the prothrombin time making transition to warfarin therapy difficult. Antibody formation to lepirudin develops in 40% patients on therapy for >6 days and may lead to decreased clearance of the drug, thereby increasing the risk of bleeding.

Bivalirudin: Bivalirudin (Angiomax®) is a direct thrombin inhibitor and an analogue of the peptide fragment hirugen, a compound derived from hirudin. Unlike lepirudin, the binding of bivalirudin to thrombin is reversible. Bivalirudin specifically binds to the catalytic site and substrate-binding site of thrombin. Bivalirudin is FDA-approved for use in patients undergoing coronary angioplasty with unstable angina and concomitant aspirin therapy. The recommended dose of bivalirudin is 1 mg/kg as an intravenous bolus, followed by a continuous infusion of 2.5 mg/kg/hour for 4 hours, and then 0.2 mg/kg/hour for 14 to 20 hours. Bivalirudin is metabolized in the kidneys and blood, eliminated in the urine with 20% representing the parent compound, and has a half-life of approximately 25 minutes. Since a portion of bivalirudin is renally eliminated, dose adjustments are required in patients with renal dysfunction. When the creatinine clearance of the patient is 30 to 59 ml/min, the dose should be reduced by 20%. If the creatinine clearance is 10 to 29 ml/min, the dose should be decreased by 60%. If the patient is on dialysis, the dose should be reduced by 90%. Bivalirudin is contra-indicated in patients with active bleeding. Adverse reactions of bivalirudin include bleeding, back pain, nausea, headache, and hypotension. Since bivalirudin has similar pharmacology to lepirudin, it may be useful for HIT. However, at this time, there are no data to support this indication. At CCF, bivalirudin is restricted to the cardiac catheterization lab for patients who have an allergy to heparin.

Argatroban: Argatroban (Argatroban®) is a direct and selective thrombin inhibitor unrelated to heparin and is synthetically derived from the amino acid arginine. Argatroban is a racemic mixture with the S-isomer having twice the antithrombotic activity. Argatroban reversibly binds to the active site of thrombin, as well as soluble and clot-bound thrombin, to inhibit thrombin-catalyzed or thrombin-induced reactions. Through these reactions, argatroban inhibits fibrin formation, protein C, activation of factors V, VIII, and XIII, as well as platelet aggregation. Vascular smooth-muscle and endothelial-cell thrombin are also inhibited through this pathway. Like other direct thrombin inhibitors, argatroban does not require antithrombin III as a cofactor, is not inactivated by PF4, and does not cross-react with heparin-induced antibodies.

Argatroban is FDA-approved for prevention or treatment of thrombosis in patients with type II HIT. The initial intravenous dose of argatroban for type II HIT is 2 mcg/kg/min to maintain an aPTT at 1.5 to 3.0 times the control, with the maximum recommended dose of 10 mcg/kg/min. The aPTT is monitored 2 hours after the start of infusion, 2 hours after each dose adjustment, and then daily.

Argatroban is metabolized hepatically via the cytochrome P450 enzyme 3A4/5 system. Approximately 65% of the agent is metabolized resulting in four metabolites. The main metabolite has about three- to five-fold less of an anticoagulant effect than the parent compound. Elimination occurs mainly in the feces via biliary secretion and the half-life of argatroban is approximately 24 to 50 minutes. Since argatroban is predominantly metabolized in the liver, it may be useful in patients with type II HIT who have renal impairment or are on renal replacement therapies. Patients with moderate hepatic impairment should receive an initial argatroban dose of 0.5 mcg/kg/min, since the clearance of the drug is decreased four-fold in this patient population. Although argatroban undergoes hepatic metabolism, no significant drug interactions have been discovered in studies involving healthy subjects receiving erythromycin, a potent inhibitor of CYP 3A4/5 enzyme. Even though there is no reversal agent for argatroban, one may not be necessary because the compound has a relatively short half-life and does not undergo renal elimination.

Argatroban is contraindicated in patients with active bleeding or known hypersensitivity to the agent. It should be used with caution in patients on any other forms of anticoagulation or any conditions that may increase the risk of bleeding. Bleeding is the major adverse effect of argatroban occurring in 2.3 to 14.4% of patients in clinical trials with other adverse effects including dyspnea, hypotension, and fever.

Patients who require transition to warfarin therapy should also have their international normalized ratio (INR) monitored while they are receiving argatroban. After warfarin therapy is initiated, argatroban should be continued until the INR is greater than or equal to 4. If the patient is receiving argatroban at 2 mcg/kg/min, and the INR is greater than or equal to 4, the argatroban infusion should be discontinued, and the INR rechecked in 4 to 6 hours. If the INR is therapeutic, the argatroban infusion does not need to be restarted. If the INR is subtherapeutic, the argatroban infusion should be reinitiated at 2 mcg/kg/min. If the patient is requiring >2 mcg/kg/min of argatroban, the infusion should be titrated down to 2 mcg/kg/min, the INR checked while the patient is receiving this dose for 4 to 6 hours, and adjusted as described above.

Danaparoid: Danaparoid (Orgaran®) is a heparinoid composed of a heterogeneous mixture containing 84% heparan sulfate, 12% dermatan sulfate, and 4% chondroitin sulfate. However, danaparoid does not contain heparin fragments and differs from unfractionated heparin and low molecular weight heparins (LMWHs) in its glycosaminoglycan backbone. The main activity of danaparoid is against factor Xa with the anti-Xa to anti-IIa ratio of >22:1 resulting in inhibition of fibrin formation. Approximately 4% of the heparan sulfate portion of danaparoid contains a pentasaccharide sequence that is found in heparin. This binds to antithrombin and enhances its anti-factor Xa activity. The remainder of the heparan sulfate has other anticoagulant effects that are unknown. Other properties of danaparoid are its anti-IIa effects, which are due to the dermatan sulfate portion of the agent that enhances the activity of heparin cofactor II and inhibits factor IIa (and its ability to specifically inhibit platelet aggregation caused by the HIT antibody). Danaparoid has a half-life of 18 to 28 hours and mainly undergoes renal elimination. Therefore, dose adjustments are required in renal impairment.

Danaparoid is FDA-approved for prophylaxis of postoperative DVT after elective hip surgery although it is approved in some countries for the treatment of type II HIT. Approximately 10 to 20% of patients have demonstrated cross-reactivity in vitro but <5% of patients have shown in vivo cross-reactivity to danaparoid. Prior to initiating therapy with danaparoid, a negative in vitro aggregation or serotonin release test result in response to danaparoid should be obtained, but this is not always possible. Dosing for danaparoid varies with the indication (See Table 4). The recommended dose for type II HIT is a loading dose of 2,250 units as an intravenous bolus (which is adjusted for body weight of the patient), followed by 400 units/hr for 4 hours, then 300 units/hr for 4 hours, and then a maintenance infusion of 150 to 200 units/hr (dosages based on anti-Xa levels). Although not required, it is suggested that anti-Xa levels be monitored in selected patients such as those weighing <55 kg or >90 to 95 kg, or patients with severe renal impairment (on days 1 to 3 of danaparoid therapy followed by every other day).

Danaparoid is contraindicated in patients with any active bleeding, medical conditions that increase the risk of bleeding, or a positive in vitro test for cross reactivity to type II HIT antibodies. Bleeding may occur in all patients but is dependent on variables such as weight and renal function. Other adverse effects include fever, nausea, and constipation. This agent does not interfere with the prothrombin time so bridging the patient to warfarin therapy is not as complicated. When using danaparoid for alternative anticoagulation, the goal of therapy is to maintain anti-Xa levels between 0.5 and 0.8 units/ml (if these levels are measured).

Conclusion: A variety of treatment options have emerged in treating type II HIT. Before starting any agents, clinicians must decide which of these agents are safe and effective for the patient. Lepirudin is an irreversible direct thrombin inhibitor that has shown effectiveness in patients with type II HIT. It does not cross react with heparin and can be readily monitored using aPTT. Disadvantages of this agent include a prolonged half-life, prolongation of the prothrombin time, possible antibody formation, and dose adjustments in patients with renal impairment. Argatroban is the newest agent used for type II HIT. It reversibly binds to thrombin and is monitored by using the aPTT. Patients who require anticoagulation and have renal impairment may benefit from the use of argatroban because of its hepatic metabolism. A disadvantage of this agent is prolongation of the prothrombin time (requiring additional monitoring in patients who are transitioned to warfarin) and dose adjustment in patient with hepatic impairment. Since danaparoid does not prolong the prothrombin time, it may be useful in patients who will be transferred to warfarin therapy, but monitoring is necessary in patients with extremes of weight or those with renal dysfunction. However, this agent is not FDA-approved for the treatment of type II HIT and may require anti-Xa levels to be monitored. Bivalirudin may be useful in type II HIT, but there are no data to support its use at this time.

See related table: Formulary Status of Agents for Type II HIT