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1、HEPARIN INDUCED THROMBOCYTOPENIA (HIT),HEPARIN-INDUCED THROMBOCYTOPENIA,Unfractionated heparin (UFH) (beef pork) Continuous iv infusion Cardiopulmonary bypass Low dose sq Heparin flushes Heparin-bonded catheters Low molecular weight heparin More likely to cause HIT if pt previously exposed to UFH,Ca
2、usative agents,HEPARIN-INDUCED THROMBOCYTOPENIA,Isolated thrombocytopenia (“Isolated HIT”) Arterial or venous thrombosis (HITT) DVT, PE, MI, stroke, peripheral arterial occlusion DIC, microangiopathic hemolytic anemia Skin necrosis (at injection sites or distant) Venous limb gangrene (? Role of warf
3、arin) Sudden death ARDS Hemorrhagic adrenal infarction,Clinical manifestations,HEPARIN-INDUCED THROMBOCYTOPENIA,UFH LMWH Fondaparinux Duration of heparin treatment 6 days Rarely occurs in patients medical obstetric patients Incidence in trauma patients proportional to severity of trauma Related to d
4、egree of platelet activation?,Epidemiology,Blood 2012; 119: 2209,HEPARIN-INDUCED THROMBOCYTOPENIA,Incidence and presenting features,Warkentin and Kelton, Am J Med 1996;101:502,THROMBOTIC COMPLICATIONS IN HIT,Am J Med 1996;101:502,ISOLATED HIT IS ASSOCIATED WITH A HIGH RISK OF SUBSEQUENT THROMBOSIS,A
5、m J Med 1996;101:502,Over 50% of patients presenting with “isolated HIT” had a subsequent thrombotic episode within 30 days Substitution of warfarin for heparin after the onset of thrombocytopenia did not prevent thrombosis,UNFRACTIONATED HEPARIN IS MORE LIKELY TO CAUSE HIT THAN LMWH,Randomized tria
6、l in pts having hip surgery,Warkentin et al, NEJM 1995;332:1330,Warkentin et al, NEJM 1995;332:1330,THE FREQUENCY OF THROMBOSIS AFTER HIP SURGERY IS MUCH HIGHER IN PATIENTS WITH HIT THAN IN THOSE WITHOUT HIT,Odds ratio for thrombosis 37 times higher in HIT pts,All cases in patients receiving UFH as
7、prophylaxis,HIT associated with 40-fold increase in risk of thrombosis,THE HIT INCIDENCE IN MEDICAL PATIENTS TREATED WITH LOW DOSE SQ UFH IS ABOUT 2% Girolami et al, Blood 2003;101:2955,LMWH IS MORE LIKELY TO CAUSE HIT IN PATIENTS WITH PRIOR UFH EXPOSURE Prandoni et al, Blood 2005;106:3049,Prospecti
8、ve cohort study, 1754 medical pts 0.8% overall incidence of HIT 0.3% incidence if no prior UFH exposure 1.7% incidence if prior UFH exposure All cases in first 2 weeks Prevalence of thromboembolism 16.6x higher in patients with HIT (29% vs 2.4%),Development of HIT antibodies is more common in major
9、surgery than minor surgery, and more common with UFH than LMWH Results of a prospective trial,Lubenow, N. et al. Blood 2010;115:1797-1803,Warkentin et al, NEJM 1995;332:1330,THROMBOSIS IN HIT MAY OCCUR WITH NORMAL PLATELET COUNT,Warkentin et al, NEJM 1995;332:1330,THE PLATELET COUNT DROPS PRIOR TO T
10、HROMBOSIS IN HIT,*Thrombotic episode,Recent heparin exposure may cause “rapid onset” HIT,Warkentin and Kelton, NEJM 2001;344:1286,Rapid-onset HIT is associated with re-exposure to heparin within 90 days,Warkentin and Kelton, NEJM 2001;344:1286,Heparin-dependent antibodies usually disappear within 90
11、 days an episode of HIT,Warkentin et al, NEJM 1995;332:1330,DELAYED ONSET HIT,Describes 14 patients treated with heparin, discharged, and later re-hospitalized with thromboembolism and positive tests for HIT antibodies Most patients got heparin during cardiac surgery 12/14 had mild thrombocytopenia
12、(66-145K) at time of thrombotic episode Median time between discharge and readmission 14 days, maximum 40 days 11 patients re-treated with heparin: all had clinical deterioration and worsening thrombocytopenia 3 patients died,Ann Intern Med 2002;136:210,PATHOPHYSIOLOGY OF HIT,HIT IS CAUSED BY ANTIBO
13、DIES AGAINST A HEPARIN-PLATELET FACTOR 4 COMPLEX,Platelet membrane,FC receptor,PATHOPHYSIOLOGY OF HIT,Warkentin, Brit J Haematol 2003;121:535,Heparin-PF4 complexes stimulate antibody production Ag-Ab complex binds to and activates platelets, monocytes Size of immune complex is critical, varies with
14、PF4 and heparin concentrations Inhibited by high heparin concentrations Activated platelets release procoagulant microparticles Activated monocytes produce tissue factor Antibodies may cross-react with PF4 bound to endothelial cell heparan sulfate vessel wall injury Some HIT antibodies can activate
15、platelets in the absence of heparin,Heparin concentration affects the size and charge of heparin:PF4 complexes and their ability to activate platelets,Blood 2007;110:4253,Clinical factors may help determine the likelihood of developing HIT,Healthy volunteers given heparin or LMWH make IgM antibodies
16、 to heparin/PF4 Pathologic HIT antibodies are usually IgG Concomitant immune stimulus necessary to promote IgG HIT antibody formation? Higher PF4 levels after surgery or acute illness may promote formation of larger immune complexes,Blood 2007;110:4253 J Thromb Haemost 2012;10:1446,HIT Antibodies can activate platelets in the absence of heparin,J Thromb Haemost 2005;3:2168,DIAGNOSIS OF HIT,DISTINGUISHING IMMUNE FROM NON-IMMUNE HEPARIN INDUCED THROMBOCYTOPENIA,Many patients have a tran
