HEPARININDUCEDTHROMBOCYTOPENIAUniversityofheparininduced血小板減少大學(xué)課件

1、HEPARIN INDUCED THROMBOCYTOPENIA (HIT)第1頁，共51頁。HEPARIN-INDUCED THROMBOCYTOPENIAUnfractionated heparin (UFH) (beef pork)Continuous iv infusionCardiopulmonary bypassLow dose sqHeparin flushesHeparin-bonded cathetersLow molecular weight heparinMore likely to cause HIT if pt previously exposed to UFHCau

2、sative agents第2頁，共51頁。HEPARIN-INDUCED THROMBOCYTOPENIAIsolated thrombocytopenia (“Isolated HIT”)Arterial or venous thrombosis (HITT)DVT, PE, MI, stroke, peripheral arterial occlusionDIC, microangiopathic hemolytic anemiaSkin necrosis (at injection sites or distant)Venous limb gangrene (? Role of war

3、farin)Sudden deathARDSHemorrhagic adrenal infarctionClinical manifestations第3頁，共51頁。HEPARIN-INDUCED THROMBOCYTOPENIAUFH LMWH FondaparinuxDuration of heparin treatment 6 daysRarely occurs in patients medical obstetric patientsIncidence in trauma patients proportional to severity of traumaRelated to d

4、egree of platelet activation?EpidemiologyBlood 2012; 119: 2209第4頁，共51頁。HEPARIN-INDUCED THROMBOCYTOPENIAPresenting 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 Cardiovascular109

5、19 Oncology7613 General628 Neurosurgery314MEDICAL PTS142943 (33.9%) Cardiac61016 DVT or PE4711 Other41216Incidence and presenting featuresWarkentin and Kelton, Am J Med 1996;101:502第5頁，共51頁。THROMBOTIC COMPLICATIONS IN HITType of thrombosisPts presenting with thrombosis (n=65)Pts presenting with only

6、 thrombocytopenia (n=62)VENOUS (n=78)5424 DVT (n=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)NA30Am J Med 1996;101:502第6頁，共51頁。ISOLATE

7、D HIT IS ASSOCIATED WITH A HIGH RISK OF SUBSEQUENT THROMBOSISAm J Med 1996;101:502Over 50% of patients presenting with “isolated HIT” had a subsequent thrombotic episode within 30 daysSubstitution of warfarin for heparin after the onset of thrombocytopenia did not prevent thrombosis 第7頁，共51頁。UNFRACT

8、IONATED HEPARIN IS MORE LIKELY TO CAUSE HIT THAN LMWHRandomized trial in pts having hip surgeryWarkentin et al, NEJM 1995;332:1330第8頁，共51頁。Warkentin et al, NEJM 1995;332:1330THE FREQUENCY OF THROMBOSIS AFTER HIP SURGERY IS MUCH HIGHER IN PATIENTS WITH HIT THAN IN THOSE WITHOUT HITOdds ratio for thro

9、mbosis 37 times higher in HIT pts第9頁，共51頁。All cases in patients receiving UFH as prophylaxisHIT associated with 40-fold increase in risk of thrombosisTHE HIT INCIDENCE IN MEDICAL PATIENTS TREATED WITH LOW DOSE SQ UFH IS ABOUT 2%Girolami et al, Blood 2003;101:2955第10頁，共51頁。LMWH IS MORE LIKELY TO CAUS

10、E HIT IN PATIENTS WITH PRIOR UFH EXPOSUREPrandoni et al, Blood 2005;106:3049Prospective cohort study, 1754 medical pts0.8% overall incidence of HIT 0.3% incidence if no prior UFH exposure1.7% incidence if prior UFH exposureAll cases in first 2 weeksPrevalence of thromboembolism 16.6x higher in patie

11、nts with HIT (29% vs 2.4%)第11頁，共51頁。Development of HIT antibodies is more common in major surgery than minor surgery, and more common with UFH than LMWHResults of a prospective trialLubenow, N. et al. Blood 2010;115:1797-1803第12頁，共51頁。Warkentin et al, NEJM 1995;332:1330THROMBOSIS IN HIT MAY OCCUR WI

12、TH NORMAL PLATELET COUNT第13頁，共51頁。*Warkentin et al, NEJM 1995;332:1330THE PLATELET COUNT DROPS PRIOR TO THROMBOSIS IN HIT *Thrombotic episode第14頁，共51頁。Recent heparin exposure may cause “rapid onset” HITWarkentin and Kelton, NEJM 2001;344:1286第15頁，共51頁。Rapid-onset HIT is associated with re-exposure t

13、o heparin within 90 daysWarkentin and Kelton, NEJM 2001;344:1286第16頁，共51頁。Heparin-dependent antibodies usually disappear within 90 days an episode of HITWarkentin et al, NEJM 1995;332:1330第17頁，共51頁。DELAYED ONSET HITDescribes 14 patients treated with heparin, discharged, and later re-hospitalized wit

14、h thromboembolism and positive tests for HIT antibodiesMost patients got heparin during cardiac surgery12/14 had mild thrombocytopenia (66-145K) at time of thrombotic episodeMedian time between discharge and readmission 14 days, maximum 40 days11 patients re-treated with heparin: all had clinical de

15、terioration and worsening thrombocytopenia3 patients diedAnn Intern Med 2002;136:210第18頁，共51頁。PATHOPHYSIOLOGY OF HIT第19頁，共51頁。HIT IS CAUSED BY ANTIBODIES AGAINST A HEPARIN-PLATELET FACTOR 4 COMPLEXPlatelet membraneFC receptorFabFCAntibody binding to platelet FC receptor activates platelet41PF4Activa

16、ted plateletsecretes PF42HeparinPF4 binds heparin3Antibody binds heparin-PF4 complex第20頁，共51頁。PATHOPHYSIOLOGY OF HITWarkentin, Brit J Haematol 2003;121:535Heparin-PF4 complexes stimulate antibody productionAg-Ab complex binds to and activates platelets, monocytesSize of immune complex is critical, v

17、aries with PF4 and heparin concentrationsInhibited by high heparin concentrationsActivated platelets release procoagulant microparticlesActivated monocytes produce tissue factorAntibodies may cross-react with PF4 bound to endothelial cell heparan sulfate vessel wall injurySome HIT antibodies can act

18、ivate platelets in the absence of heparin第21頁，共51頁。Heparin concentration affects the size and charge of heparin:PF4 complexes and their ability to activate plateletsBlood 2007;110:4253Low heparin:PF4 ratio small complexesHigh heparin:PF4 ratio small complexes1:1 heparin:PF4 large complexesCharge of

19、complexesHeparin conc第22頁，共51頁。Clinical factors may help determine the likelihood of developing HITHealthy volunteers given heparin or LMWH make IgM antibodies to heparin/PF4Pathologic HIT antibodies are usually IgGConcomitant immune stimulus necessary to promote IgG HIT antibody formation?Higher PF

20、4 levels after surgery or acute illness may promote formation of larger immune complexesBlood 2007;110:4253J Thromb Haemost 2012;10:1446第23頁，共51頁。HIT Antibodies can activate platelets in the absence of heparinJ Thromb Haemost 2005;3:2168第24頁，共51頁。DIAGNOSIS OF HIT第25頁，共51頁。DISTINGUISHING IMMUNE FROM

21、NON-IMMUNE HEPARIN INDUCED THROMBOCYTOPENIAMany patients have a transient decrease in platelets within 24 hours of receiving heparin. This is not an antibody-mediated effect and not associated with thrombosisHow can it be distinguished from HIT?By the time courseBy the clinical pictureBy serology an

22、d other lab tests第26頁，共51頁。Median platelet nadir 55K15% had nadir 150K (diagnosed because platelet count fell more than 50% or because of clinical events)The severity of thrombocytopenia did not predict thrombotic eventsSevere thrombocytopenia is rare in HITWarkentin, Brit J Haematol 2003;121:535第27

23、頁，共51頁。Clincal features that favor a diagnosis of HITBlood 2012;119:2209第28頁，共51頁。The 4 T score predicts a positive HIT antibody testJ Thrombos Haemost 2006;4:759Score% Testing positive534%第29頁，共51頁。LABORATORY DIAGNOSIS OF HITImmunoassay for heparin-PF4 antibodies (EIA)Very high sensitivity, rapid t

24、urnaround“High positive” results typical of HITTRapid “bedside” assayMany false positive results, not recommendedC14 Serotonin release assay (SRA)Measures heparin-dependent platelet activationBest predictor of thrombotic riskLimited availability (Blood Center of SE Wisconsin), slower turnaroundA pos

25、itive EIA test in a patient with a low pre-test probability of HIT according to 4T rule is likely to be a false positive第30頁，共51頁。The serotonin release assay predicts thrombosis in HITSRA and EIA positiveSRA and EIA negativeEIA positive, SRA negativeAm J Hematol 2007;82:1037第31頁，共51頁。Warkentin, Brit

26、 J Haematol 2003;121:535The incidence of HIT antibody formation and risk of HIT varies among different patient populationsThe “Iceberg” model 第32頁，共51頁。J Thrombos Haemost 2004;2:2133-7A STRONGLY POSITIVE EIA RESULT IS ASSOCIATED WITH HIGHER RISK OF SUBSEQUENT THROMBOSISOD values in HIT vs HITT patie

27、ntsThrombosis-free survival vs OD第33頁，共51頁。TREATMENT OF HIT第34頁，共51頁。TREATMENT OF HITDiscontinue all heparin, including flushesLMWH may cross-react with HIT antibodies, should not be usedIf thrombosis present: give alternative thrombin inhibitorConsider treating even if thrombosis absent (high risk

28、of thrombosis in patients with isolated HIT)Treatment alternatives:Direct inhibitorsLepirudinBivalirudin (little data, but approved for HIT patients having PCI)ArgatrobanDabigatran?Indirect inhibitorsFondaparinux Do not give warfarin (risk of venous gangrene)第35頁，共51頁。DIRECT THROMBIN INHIBITORSLepir

29、udin (Refludan)Recombinant form of leech anticoagulantClearance mainly renal (avoid in renal failure); halflife normally 80 minAntibody formation may cause drug accumulation or anaphylaxis (rare)Argatroban (Novastan)Synthetic arginine derivativeClearance mainly hepatic (can use in renal failure); ha

30、lflife 40-50 minBoth given by continuous iv infusion, monitoring aPTTCoagulopathic patients (long baseline aPTT) difficult to monitorNo antidote for either drug第36頁，共51頁。LEPIRUDIN PROPHYLAXIS IN HITBlood 2004;104:3072Patients: 91 patients with isolated HIT (no thrombosis) treated with lepirudin (thr

31、ee separate trials)Controls: 47 contemporaneously diagnosed HIT patients without thrombosis not treated with anticoagulants% with:Lepirudin treated patientsControlspNew thrombosis4.414.9.02Limb amputation3.30.24Death14.321.3.094Combined end point19.829.8.028第37頁，共51頁。LEPIRUDIN IN HITHAT-3 trial (HIT

32、 with or without concurrent thrombosis)Cumulative incidence of death, thromboembolism or limb amputationCumulative incidence of major bleedingJ Thromb Haemost 2005; 3:2428第38頁，共51頁。The risk of bleeding with lepirudin is higher with impaired renal functionHAT-3 trial dataJ Thromb Haemost 2005; 3:2428

33、第39頁，共51頁。LEPIRUDIN IN HITACCP RECOMMENDATIONSBolus 0.2 mg/kg only if life- or limb-threatening thrombosis presentContinuous infusion rate:Cr 4.5: 0.005 mg/kg/hrAdjust to aPTT 1.5-2.0 times baselineCheck aPTT q 4hThese doses are lower than recommended in the drug package insert第40頁，共51頁。Argatroban t

34、herapy in HITPooled data from 2 prospective non-randomized trialsHazard ratio with argatroban 0.3 vs historical controlsNo difference in major bleeding vs controlsChest 2006;129:1407第41頁，共51頁。ARGATROBAN IN HITACCP RECOMMENDATIONSBolus: NoneContinuous infusion:Normal organ function: 2 mcg/kg/monLiver

35、 dysfunction, post cardiac surgery, anasarca: 0.5-1.2 mcg/kg/monAdjust aPTT to 1.5-3.0 x baselineCheck aPTT q 4hArgatroban prolongs PT/INR, making transition to warfarin tricky第42頁，共51頁。FONDAPARINUX (Arixtra) Synthetic polysaccharide, inhibits factor Xa preferentiallyDoes not typically cross-react w

36、ith HIT antibodiesLong half-life (17-20 h), no antidoteSQ administrationMonitoring unnecessaryNot FDA-approved for HIT treatmentRare reports of fondaparinux-associated HIT (NEJM 2007; 356:2653)第43頁，共51頁。Fondaparinux appears to be effective and safe in patients with HITReferenceNNew 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; 24:7