OBJECTIVE: To assist clinicians with the diagnosis and initial management of heparin-induced thrombocytopenia (HIT) and suspected HIT.

Transcription

1 HEPARIN-INDUCED THROMBOCYTOPENIA TARGET AUDIENCE: All Canadian health care professionals. OBJECTIVE: To assist clinicians with the diagnosis and initial management of heparin-induced thrombocytopenia (HIT) and suspected HIT. ABBREVIATIONS: aptt activated partial thromboplastin time DVT deep vein thrombosis ELISA enzyme-linked immunosorbent assay HIPA heparin-induced platelet aggregation HIT heparin-induced thrombocytopenia HITT heparin-induced thrombocytopenia and thrombosis INR international normalized ratio IV intravenous LMWH low-molecular-weight heparin PF4 platelet factor 4 PT prothombin time PVS polyvinyl sulfonate SC subcutaneous UFH unfractionated heparin BACKGROUND: Heparin-induced thrombocytopenia is the development of thrombocytopenia due to the administration of heparin. HIT predisposes to thrombosis and, when identified, the condition is then called heparin-induced thrombocytopenia and thrombosis (HITT). HIT occurs in up to 5% of patients receiving unfractionated heparin (UFH), and in < 1% who receive low-molecular-weight heparin (LMWH). MECHANISM OF ACTION: HIT is a drug-induced immune-mediated syndrome characterized by thrombocytopenia and thrombotic events that may be life- or limb-threatening. HIT antibodies recognize an antigen 2013 Thrombosis Canada. Page 1 of 6

2 complex of platelet factor 4 (PF4) and heparin, resulting in platelet activation with release of procoagulant platelet-derived microparticles, and activation of endothelial cells and monocytes. These diverse effects explain the clinical manifestations of HIT. DIAGNOSIS: The diagnosis of HIT is based on three criteria: 1) The patient is receiving or has had recent exposure to heparin. 2) At least one clinical feature of the syndrome is present. 3) There is laboratory evidence of HIT antibodies. The approach shown in Figure 1 and Table 1 has not been rigorously evaluated, but provides a rational strategy to minimize the under diagnosis and over diagnosis of HIT, and the associated risks. CLINICAL FEATURES: HIT typically presents with a fall in platelet count with or without thrombosis. Thrombocytopenia: A platelet count fall > 50% or an absolute thrombocytopenia beginning 5-10 days after heparin exposure, in the absence of other causes of thrombocytopenia, should be considered to be HIT, unless proven otherwise. A more rapid onset of platelet count fall can occur when there is a history of heparin exposure within the preceding 100 days. Bleeding is infrequent. Thrombosis: HIT is associated with a high risk (30-50%) of new or recurrent venous or arterial thromboembolism. Thrombosis may be the presenting clinical manifestation of HIT or can occur during or shortly after the period of thrombocytopenia. Other Clinical Manifestations of HIT: Less frequent manifestations include heparin-induced skin lesions, adrenal hemorrhagic infarction, and acute systemic reactions (e.g. chills, dyspnea, cardiac or respiratory arrest following IV heparin bolus). HIT ASSAYS: Therapeutic decisions, including the administration of alternative anticoagulation, should not be delayed pending the results of laboratory testing if the clinical suspicion of HIT is strong. Serum should be sent for HIT testing using either an immunologic (antigen) assay (e.g. PF4/heparin, PF4/polyvinyl sulfonate (PVS), or polyanion enzyme-linked immunosorbent assay (ELISA) or particle gel immunoassay), or a functional assay (e.g. serotonin release assay, heparin-induced platelet aggregation (HIPA)) Thrombosis Canada. Page 2 of 6

3 MANAGEMENT: Patients with HIT are best managed by, or in consultation with, a specialist experienced in managing HIT. Stop all heparin exposure, including LMWH, prophylactic heparin, heparin locks or flushes, and remove heparin-coated catheters. Start anticoagulation with a non-heparin anticoagulant such as lepirudin, argatroban or danaparoid (see Table 2). This applies to all HIT, with or without thrombosis. Use of bivalirudin and fondaparinux may also be reasonable, but experience with these agents for general use in HIT is limited. Lower limb ultrasonography should be performed to investigate for leg deep vein thrombosis (DVT) (see DVT diagnosis guide), due to the high prevalence of asymptomatic thrombosis in HIT. Avoid platelet transfusions, unless bleeding or prior to an invasive procedure with a high risk of bleeding. Warfarin should be avoided in acute HIT. If warfarin has already been started when HIT is diagnosed, it should be stopped and vitamin K should be administered (2.5-5 mg orally). Warfarin is appropriate for longer-term anticoagulation, after thrombocytopenia has resolved. When transitioning to warfarin from a non-heparin anticoagulant: 2013 Thrombosis Canada. Page 3 of 6

4 1. Do not initiate warfarin until platelet count is 150 x 10 9 /L. 2. Initial warfarin dose should be 5 mg/day. 3. Overlap warfarin with therapeutic doses of the non-heparin parenteral anticoagulant for 5 days and until the international normalized ratio (INR) is therapeutic. Caution should be used when transitioning to warfarin from argatroban because it can increase the INR. Duration of anticoagulation for HIT with thrombosis: at least 3 months. Duration of anticoagulation for HIT without thrombosis: approximately 4 weeks. SPECIAL CONSIDERATIONS: Reintroduction of heparin in the future in a patient with known HIT should involve consultation with a specialist. PEDIATRICS: Incidence is less than in adults, occurring in 0-2.3% of heparinized children. If HIT is suspected, stop all heparin exposure, including LMWH, prophylactic heparin, heparin locks or flushes, and remove heparin-coated catheters. Start anticoagulation with a non-heparin anticoagulant such as danaparoid, lepirudin, or argatroban. This applies to all HIT, with or without thrombosis. Use of bivalirudin and fondaparinux may also be reasonable, but experience with these agents for general use in HIT is limited. Pediatricians with expertise in thromboembolism should manage, where possible, pediatric patients with HIT. When this is not possible, a combination of a neonatologist/pediatrician and an adult hematologist, supported by consultation with an experienced pediatric hematologist, is recommended. Table 2. Non-heparin anticoagulants for the treatment of acute HIT* Anticoagulant Pharmacology Initial Dosing Monitoring Lepirudin Mechanism: Direct thrombin inhibitor Clearance: Renal Half-life: 80 min Prolongs activated partial thromboplastin time (aptt), prothrombin time (PT/INR) Anaphylaxis can occur with re-exposure Bolus: None (0.2 mg/kg IV bolus only if limbor life-threatening thrombosis) Continuous Infusion: 0.1 mg/kg/h IV Reduce dose in renal failure: Serum Creatinine (µmol/l) Infusion Rate (mg/kg/h IV) < > aptt q 4h after initiation or dosage change, then at least daily once therapeutic. Target: x patient baseline (or the mean laboratory) aptt 2013 Thrombosis Canada. Page 4 of 6

5 Table 2. Non-heparin anticoagulants for the treatment of acute HIT* (continued) Anticoagulant Pharmacology Initial Dosing Monitoring Argatroban Danaparoid Bivalirudin (not approved for treatment of HIT) Fondaparinux (not approved for treatment of HIT) Mechanism: Direct thrombin inhibitor Clearance: Hepatic Half-life: min Prolongs aptt, PT/INR Mechanism: Xainhibitor (primarily) Clearance: Renal Half-life: 25 hours No effect on aptt, PT/INR Clinical cross-reactivity with HIT antibody in 3% Mechanism: Direct thrombin inhibitor Clearance: Plasma proteases and renal Half-life: 25 min Prolongs aptt, PT/INR Mechanism: Xainhibitor Clearance: Renal Half-life: hours No effect on aptt, PT/INR Bolus: None Continuous Infusion: 2.0 mcg/kg/min IV Reduce dose to mcg/kg/min IV in patients with: hepatic insufficiency heart failure multiple organ failure severe anasarca post-cardiac surgery Bolus: Weight (kg) IV Bolus (units) < 60 1, , ,000 > 90 3,750 Continuous Infusion: 400 units/h IV x 4h, then 300 units/h IV x 4h, then 200 units/h IV Bolus: None Continuous Infusion: mg/kg/h IV Reduce dose in renal failure: Bolus: None SC Injection: Creatinine Initial Clearance Infusion Rate (ml/min) (mg/kg/h IV) > < 30 or renal replacement therapy Weight (kg) Dosage < 50 5 mg SC daily mg SC daily > mg SC daily aptt q 2h after initiation or dosage change, then at least daily once therapeutic Target: x patient baseline (or mean laboratory) aptt, not to exceed 100 sec Anti-Xa levels Target: anti-xa U/mL (using danaparoid standards) aptt Target: x patient baseline (or mean laboratory) aptt Not routinely required * This table does not address special populations and circumstances such as children, pregnancy, percutaneous coronary interventions, cardiac surgery, vascular surgery, and renal replacement therapy Thrombosis Canada. Page 5 of 6

6 REFERENCES: Cuker A, Cines DB. How I treat heparin-induced thrombocytopenia. Blood 2012;119: Linkins LA, Dans AL, Moores LK, et al. Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 Suppl):e495S-530S. Monagle P, Chan AK, Goldenberg NA, et al. Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 Suppl):e737S-801S. Warkentin TE. How I diagnose and manage HIT. Hematology Am Soc Hematol Educ Program 2011;2011: Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein Thrombosis Canada. Page 6 of 6