HEPARIN-INDUCEDTHROMBOCYTOPENIA：heparin-induced血小板减少症.ppt

HEPARIN-INDUCED THROMBOCYTOPENIA,Jeffrey M. Miller, MD Assistant Clinical Professor of Medicine Olive View - UCLA Medical Center,Heparin-Induced Thrombocytopenia,Heparin-induced thrombocytopenia (HIT) is a transient prothrombotic disorder initiated by heparin Main features: Thrombocytopenia resulting from IgGmediated platelet activation In vivo thrombin generation and increased risk of venous and arterial thrombosis,Warkentin TE. Hematology. 2003;503-509.,HIT: Clinical Findings,Thrombocytopenia with or without new thrombosis1,2 Skin lesions at heparin injection sites1,2 Acute systemic reactions (chills, cardio-respiratory distress) after IV heparin bolus administration2 Strong association with venous and arterial thrombosis2 Absolute thrombosis risk2: 30% 75% Depends on the patient population,1. Warkentin TE, Greinacher A. Chest. 2004;126:311S-337S. 2. Warkentin TE. Hematology. 2003;503-509.,HIT: Serologic Findings,Positive test for HIT antibodies Diagnostic specificity can be increased by use of a sensitive washed platelet activation assay More specific than a positive antigen assay,Warkentin TE, Greinacher A. Chest. 2004;126:311S-337S.,Frequency of HIT,Risk of HIT with respect to type of heparin Bovine lung unfractionated heparin (UFH) Porcine mucosal UFH Lowmolecular weight heparin (LMWH) Risk of HIT increases each day that heparin continues beyond day 4 Immunization risk declines after day 10,Warkentin TE. Hematology. 2003;503-509.,Frequency of HIT (cont),Risk of HIT with respect to patient population Surgical Medical Obstetrical Highest frequency of HIT, 5%, has been reported in post-orthopedic surgery patients receiving up to 2 weeks of UFH HIT occurred in about 0.5% of post-orthopedic surgery patients receiving LMWH for up to 2 weeks,Warkentin TE. Hematology. 2003;503-509.,Pathophysiology of HIT,PF4 is a platelet-specific C-X-C chemokine Released in high concentrations at sites of platelet activation Heparin binds to PF4 to form heparin-PF4 complexes Binding of PF4 to heparin appears to expose new antigenic epitopes on the surface of complex that lead to antibody formation Antibodies are mainly IgG IgG/heparin-PF4 complexes activate platelets through the platelet Fc receptor, resulting in further PF4 release and amplification of this process,Warkentin TE. Hematology. 2003;503-509.,PF4 = platelet factor 4.,Pathophysiology of HIT (cont),Platelet activation and PF4 release result in thrombin activation, eventually resulting in a systemic hypercoagulable state Increased risk of venous and arterial thrombosis Up to 50% of patients with HIT present with new thrombosis Patients who are not recognized and treated promptly and appropriately are at high risk for catastrophic outcomes Amputations (10 20%) Stroke / myocardial infarction / pulmonary embolism / death,Warkentin TE, Greinacher A. Chest. 2004;126:311S-337S.,Thrombosis in HIT,Warkentin TE. Hematology. 2003;503-509.,DVT = deep venous thrombosis.,Suspicion of HIT?,Pre-test probability (the “4 Ts”) Thrombocytopenia1 Timing of onset of platelet fall1,2 Typical-onset Rapid-onset Delayed-onset Thrombosis or other sequelae1 OTher cause of platelet fall1,Warkentin TE. Hematology. 2003;503-509. Warkentin TE, Greinacher A. Chest. 2004;126:311S-337S.,Warkentin TE. Hematology. 2003;503-509. 2003 American Society of Hematology. Reprinted with permission.,HIT Diagnosis & Treatment Algorithm,Laboratory Testing,PF4-dependent “antigen” assays PF4-dependent enzyme immunoassay (EIA) Very sensitive for HIT Clinically insignificant HIT antibodies are also often detected among patients who have received heparin 5 to 100 days earlier Antibodies against non-PF4/heparin antigens (eg, interleukin-8) are not detected by PF4-dependent EIA,Warkentin TE. Hematology. 2003;503-509.,Laboratory Testing (cont),Platelet activation (“functional”) assays Washed platelet activation assay Advantage: more sensitive and specific for HIT antibodies Disadvantage: technically demanding,Warkentin TE. Hematology. 2003;503-509.,Treatment of HIT,Stop all heparin No catheter “flushes” No heparin-coated catheters Give alternative non-heparin anticoagulant, even when thrombosis is not clinically apparent Direct thrombin inhibitors (eg, lepirudin, argatroban) Factor Xa inhibitors (fondaparinux),Warkentin TE. Hematology. 2003;503-509.,Treatment of HIT (cont),Start warfarin while patient receives alternative non-heparin anticoagulant1,2 Start when the platelet count has recovered to at least 100K (100 x 109/L) preferably, 150K (150 x 109/L)2 Start at a low daily dose (5 mg or lower) and ensure at least 4-5 days of overlap2 The alternative anticoagulant may be stopped only when the INR has been within the target range for 2 consecutive days and the platelet count has recovered to a stable plateau2,1. Warkentin TE. Hematology. 2003;503-509. 2. Warkentin TE, Greinacher A. Chest. 2004;126:311S-337S.,INR = International normalized ratio.,Treatment (cont.),Anticoagulation is recommended for at least 2 to 3 months1 Note: Initiation of warfarin alone has been associated with venous limb gangrene1-3 Mechanism may be due to the transient initial decrease in protein C caused by warfarin, combined with the ongoing thrombotic process1 Prophylactic platelet transfusions are generally considered to be relatively contraindicated3,Alving BM. Blood. 2003;101(1):31-37. Warkentin TE. Hematology. 2003;503-509. Warkentin TE, Greinacher A. Chest. 2004;126:311S-337S.,HIT Screening,Screening for subclinical HIT antibody seroconversion Performing HIT antibody testing in the absence of a clinical indication of HIT is not useful Unexpected fall in the platelet count Unexpected clinical event Routine platelet count monitoring is most useful (and most practical),Warkentin TE, Greinacher A. Chest. 2004;126:311S-337S.,Direct Thrombin Inhibitors (DTIs),Mechanism of action Bind directly to thrombin and blocks its interactions Univalent DTIs bind only to the active site Bivalent DTIs block thrombin at both the active site and exosite Biophysical properties Not bound to plasma proteins More predictable response than UFH Inhibit fibrin-bound thrombin Should be more effective than UFH or LMWH FDA-approved DTIs for HIT Lepirudin and argatroban,Di Nisio M, et al. N Engl J Med. 2005;353:1028-1040.,Di Nisio M, et al. N Engl J Med. 2005;353:1028-1040. 2005 Massachusetts Medical Society. Reprinted with permission.,Mechanism of Action: DTIs vs Heparin,Laboratory Monitoring of DTIs,aPTT Preferred test for monitoring the anticoagulant activity of DTIs Lepirudin: aPTT goal of 1.5 - 2.5 times Argatroban: aPTT goal of 1.5 - 3 times the aPTT is not to exceed 100 sec Quantitative Thrombin Time Measures the clotting time of purified fibrinogen in the presence of a standard concentration of thrombin and diluted patient plasma Test is not commercially available,aPTT = activated partial thromboplastin time . Alving BM. Blood. 2003;101(1):31-37.,DTIs: Argatroban,DTI = direct thrombin inhibitor.; aPTT = activated partial thromboplastin time . Alving BM. Blood. 2003;101(1):31-37,DTIs: Lepirudin,DTI = d