HEPARININDUCEDTHROMBOCYTOPENIAUniversityofheparininduced血小板减少大学学习教案

1、会计学1HEPARININDUCEDTHROMBOCYTOPENIAUniversityofheparininduced血小板减少血小板减少大学大学第1页/共51页第2页/共51页Blood 2012; 119: 2209第3页/共51页Presenting with thrombosis (n=65)Presenting with no thrombosis (n=62)Total (n=127)Age67 10.766.7 12.367.0 11.4Male/Female27/3833/2960/67SURGICAL PTS513384 (66.1%) Orthopedic251540 C

2、ardiovascular10919 Oncology7613 General628 Neurosurgery314MEDICAL PTS142943 (33.9%) Cardiac61016 DVT or PE4711 Other41216Warkentin and Kelton, Am J Med 1996;101:502第4页/共51页Type of thrombosisPts presenting with thrombosis (n=65)Pts presenting with only thrombocytopenia (n=62)VENOUS (n=78)5424 DVT (n=

3、61)4021 New3521 Progression40 Recurrence10PE (n=32)266 New255 Recurrence11ARTERIAL (n=18)126 Limb72 Myocardial infarct31 Thrombotic stroke23Other (n=3)12 Sudden death01 Adrenal hemorrhage11 NO THROMBOSIS (n=30)NA30第5页/共51页Am J Med 1996;101:502Over 50% of patients presenting with “isolated HIT” had a

4、 subsequent thrombotic episode within 30 daysSubstitution of warfarin for heparin after the onset of thrombocytopenia did not prevent thrombosis 第6页/共51页Warkentin et al, NEJM 1995;332:1330第7页/共51页Warkentin et al, NEJM 1995;332:1330Odds ratio for thrombosis 37 times higher in HIT pts第8页/共51页All cases

5、 in patients receiving UFH as prophylaxisHIT associated with 40-fold increase in risk of thrombosisGirolami et al, Blood 2003;101:2955第9页/共51页Prandoni et al, Blood 2005;106:3049(29% vs 2.4%)第10页/共51页Lubenow, N. et al. Blood 2010;115:1797-1803第11页/共51页Warkentin et al, NEJM 1995;332:1330第12页/共51页*Wark

6、entin et al, NEJM 1995;332:1330*Thrombotic episode第13页/共51页Warkentin and Kelton, NEJM 2001;344:1286第14页/共51页Warkentin and Kelton, NEJM 2001;344:1286第15页/共51页Warkentin et al, NEJM 1995;332:1330第16页/共51页days11 patients re-treated with heparin: all had clinical deterioration and worsening thrombocytope

7、nia3 patients diedAnn Intern Med 2002;136:210第17页/共51页第18页/共51页Platelet membraneFC receptorFabFCAntibody binding to platelet FC receptor activates platelet41PF4Activated plateletsecretes PF42HeparinPF4 binds heparin3Antibody binds heparin-PF4 complex第19页/共51页Warkentin, Brit J Haematol 2003;121:5351.

8、Heparin-PF4 complexes stimulate antibody production2.Ag-Ab complex binds to and activates platelets, monocytesSize of immune complex is critical, varies with PF4 and heparin concentrationsInhibited by high heparin concentrations3.Activated platelets release procoagulant microparticles4.Activated mon

9、ocytes produce tissue factor5.Antibodies may cross-react with PF4 bound to endothelial cell heparan sulfate vessel wall injury6.Some HIT antibodies can activate platelets in the absence of heparin第20页/共51页Blood 2007;110:4253Low heparin:PF4 ratio small complexesHigh heparin:PF4 ratio small complexes1

10、:1 heparin:PF4 large complexesCharge of complexesHeparin conc第21页/共51页Blood 2007;110:4253J Thromb Haemost 2012;10:1446第22页/共51页J Thromb Haemost 2005;3:2168第23页/共51页第24页/共51页第25页/共51页1.Median platelet nadir 55K2.15% had nadir 150K (diagnosed because platelet count fell more than 50% or because of cli

11、nical events)3.The severity of thrombocytopenia did not predict thrombotic eventsWarkentin, Brit J Haematol 2003;121:535第26页/共51页Blood 2012;119:2209第27页/共51页Score% Testing positive534%第28页/共51页第29页/共51页SRA and EIA positiveSRA and EIA negativeEIA positive, SRA negativeAm J Hematol 2007;82:1037第30页/共5

12、1页Warkentin, Brit J Haematol 2003;121:535 第31页/共51页J Thrombos Haemost 2004;2:2133-7OD values in HIT vs HITT patientsThrombosis-free survival vs OD第32页/共51页第33页/共51页第34页/共51页 (Refludan)Recombinant form of leech anticoagulant Clearance mainly renal (avoid in renal failure); halflife normally 80 min An

13、tibody formation may cause drug accumulation or anaphylaxis (rare) (Novastan)Synthetic arginine derivativeClearance mainly hepatic (can use in renal failure); halflife 40-50 minBoth given by continuous iv infusion, monitoring aPTTCoagulopathic patients (long baseline aPTT) difficult to monitorNo ant

14、idote for either drug第35页/共51页% with:Lepirudin treated patientsControlspNew thrombosis4.414.9.02Limb amputation3.30.24Death14.321.3.094Combined end point19.829.8.028第36页/共51页Cumulative incidence of death, thromboembolism or limb amputationCumulative incidence of major bleedingJ Thromb Haemost 2005;

15、3:2428第37页/共51页J Thromb Haemost 2005; 3:2428第38页/共51页第39页/共51页Chest 2006;129:1407第40页/共51页第41页/共51页(Arixtra) Rare reports of fondaparinux-associated HIT (NEJM 2007; 356:2653)第42页/共51页ReferenceNNew thrombosisMajor BleedingKuo & KovacsThromb Haemost 200550/50/5Lobo et alThromb Haemost 200770/70/7Grouzi et alClin Appl Thromb Haemost 2009240/240/24Pooled Data360/360/36Warkentin, Hematol Oncol Clin N Am 2010; 24:755第43页/共51页第44页/共51页