DisordersofHemostasisandThrombosisFromWashingtonManualofMedicalTherapeutics2012.12.31ZhangXiaohongHematologyDepartmentCanapatientwithabnormalhemostasisreceiveanoperation?Whatisthecauseofhemorrhageinapatientwithabnormalhemostasis?Shouldapost-operativepatientbegivenanti-coagulativetherapyandhow?Challengesprimaryhemostasis----plateletaggregationsecondaryhemostasis----activationofcoagulationfactorsDefinitionAdetailedhistorycanassessbleedingseverity,congenitaloracquiredstatus,andprimaryorsecondaryhemostaticdefectsProlongedbleedingFamilyhistoryDIAGNOSISplateletcountreviewofbloodsmearbleedingtime(BT)plateletaggregationstudiesvonWillebrandfactor(vWF:Ag;vWF:Rco;Collagenbindingassay;Functionalimmunoassay)PrimaryhemostasistestsProthrombintime(PT)&internationalnormalizedratio(INR)Activatedpartialthromboplastintimes(APTT)Thrombintime(TT)theleveloffibrinogenD-dimersSecondaryhemostasistestsAbnormalAssaySuspectedFactorDeficienciesaPTTXII,XI,IX,orVIIIPTVIIPTandaPTTII,V,X,orfibrinogenFactorDeficienciesCauseProlongedPTand/orAPTTTCorrectedwith50:50MixMarrowfailuresyndromesCongenitalAcquired:aplasticanemia,paroxysmalnocturnalhemoglobinuriaHematologicmalignancies

Marrowinfiltration:cancer,granuloma

Fibrosis:primaryorsecondary

Nutritional:vitaminB12andfolatedeficiencies

Physicaldamage:radiation,alcohol,chemotherapyDecreasedplateletproductionImmune-mediatedmechanisms

Immunethrombocytopenicpurpura

Thromboticthrombocytopenicpurpura

Posttransfusionpurpura

Heparin-inducedthrombocytopeniaNonimmune-mediatedmechanisms

DIC

Localconsumption(aorticaneurysm)

AcutehemorrhageIncreasedplateletclearancePortalhypertension

Felty'ssyndrome

Lysosomalstoragedisorders

Infiltrativehematologicmalignancies

ExtramedullaryhematopoiesisIncreasedsplenicsequestrationHIV,HHV-6,ehrlichiosis,rickettsia,malaria,hepatitisC,CMV,Epstein-Barr,Helicobacterpylori,E.coliO157InfectionsassociatedwiththrombocytopeniaThedecisiontotreatprimaryITPdependsupontheseverityofthrombocytopeniaandconcernsaboutbleeding.Initialtherapyconsistsofglucocorticoids(typicallyprednisone1mg/kg/d).NonrespondersorpatientswithactivebleedingtypicallyalsoreceiveIVIg(1g/kg×2days)TREATMENTrefractoryITP:nonrespondersand30%to40%ofpatientswhorelapseduringasteroidtaper.Thetherapeuticgoal:asafeplateletcount(30×109to50×109/L),minimizationoftreatment-relatedtoxicities.TreatmentofrefractoryITPThecompleteclinicalpentadofTTP,presentin<30%ofcases,includesconsumptivethrombocytopeniaMAHAFeverrenaldysfunctionfluctuatingneurologicdeficitsThromboticThrombocytopenicPurpura(TTP)Themainstayoftherapyconsistsofrapidtreatmentwithplasmaexchange(PEX)of1.0to1.5plasmavolumesdaily.PEXisusuallycontinuedforatleast5or2daysafternormalizationofplateletcountandlactatedehydrogenase.TREATMENTinfusefreshfrozenplasma(FFP)immediatelytoreplaceADAMTS13.glucocorticoids:prednisone,1mg/kgPOormethylprednisolone,1gIVdaily.Transfuseredcells.Platelettransfusionintheabsenceofseverebleedingisrelativelycontraindicatedduetopotentialriskofadditionalmicrovascularocclusions.TherapywithrituximabachievesdurableremissionsfollowingTTPrelapses.Immunosuppressionwithcyclophosphamide,azathioprine,orvincristineandsplenectomyTREATMENTtypical-onsetHITusuallydevelopsbetween5and14daysofheparinexposuredelayed-onsetHIToccursafterstoppingheparinearly-onsetHITstartswithinthefirst24hoursofheparinadministrationinpatientswithrecentexposuretoheparinHITrarelycausesseverethrombocytopeniaandbleeding.Thromboemboliccomplicationsin30%to75%ofHITpatients.Heparin-InducedThrombocytopeniaoccurin30%to75%ofHITpatients,venousmorethanarterial.HITcausingvenousthrombiatheparininjectionsitesproducesfull-thicknessskininfarctionssometimesintheabsenceofthrombocytopenia.HITcancausesystemicallergicresponsesfollowinganIVbolusofheparincharacterizedbyfever,hypotension,dyspnea,andcardiacarrest.ThromboemboliccomplicationsProphylacticplatelettransfusionseemsappropriateforasymptomaticoutpatientswithplateletcounts<20×109/Landasymptomaticinpatientswithplateletcounts<10×109/L.Patientsundergoingamajorinvasiveproceduretypicallyhaveaplatelettransfusionthresholdbelow50×109/L.High-risksurgerymaywarrantprophylactictransfusiontomaintaintheplateletcount>100×109/L.Platelettransfusionthreshold1.Inheriteddisordersofplateletfunction2.AcquiredplateletdefectsDrug-inducedplateletdysfunction:high-dosepenicillin,aspirin,andotherNSAIDs,andethanol.Withholdantiplateletagentsfor7to10daysbeforeelectiveinvasiveprocedures.QualitativePlateletDisordersanX-linkedrecessivecoagulationdisorderduetomutationsinthegeneencodingfactorVIII.affects~1in5,000livemalebirths.40%ofcaseswithnopriorfamilyhistory.FactorVIIIactivitydeterminesbleedingrisk:severe(<1%),moderate(1%to5%),andmild(>5%to40%).HemophiliaAlyophilizedfactorVIIIconcentratesandrecombinantfactorVIIIconcentratesPlasmafactorVIIIactivityincreasesapproximately2%forevery1IU/kgfactorVIIIconcentrateinfused.OnetothreedosesoffactorVIIIconcentratestargetingpeakplasmaactivitiesof30%to50%typicallystopmildhemorrhages.MajortraumasandsurgeryrequiremaintenanceoffactorVIIIlevels>80%forextendedperiods.treatmentDICoccursinsystemicillnessesincludingsepsis,trauma,burns,shock,obstetriccomplications,andmalignancies.Clinicalpresentationincludebleeding,organdysfunctionsecondarytomicrovascularthrombi,ischemiaandlargearterialandvenousthrombosis.DiagnosticTesting:PatientscommonlyhaveprolongedPTandaPTT,thrombocytopenia,lowfibrinogenlevels,elevatedfibrindegradationproducts,andapositived-dimer.DisseminatedIntravascularCoagulationsupportivecare.correctionoftheunderlyingdisorderifpossibleFFP,cryoprecipitate,andplateletsasneededforhypofibrinogenandthrombocytopenia.Heparintopreventthrombosis.Large-vesselthrombosisshouldbetreatedwithadjusted-doseheparin.RecombinantactivatedproteinCcanreducemortalityinpatientswithseveresepsisandDIC,butcanalsocausemajorhemorrhage.DICTreatmentVenousthromboembolism(VTE)referstothepresenceofdeepveinthrombosis(DVT)orpulmonaryembolism(PE).Superficialthrombophlebitismayoccurinanysuperficialveins.APAsyndrome.VENOUSTHROMBOEMBOLICDISORDERSatleastoneclinicalandonelaboratorycriterion.(a)theoccurrenceofarterialorvenousthrombosisinanytissueororgan.(b)pregnancymorbidities(unexplainedlatefetaldeath;prematurebirthcomplicatedbyeclampsia,preeclampsia,orplacentalinsufficiency;atleastthreeunexplainedconsecutivespontaneousabortions).persistent(atleast12weeksapart)detectionofautoantibodies(lupusanticoagulant,anticardiolipinantibody,andβ2-glycoprotein-1antibodies).APAsyndromeSymptomaticDVTsmostcommonlydevelopinthelowerlimbs.UntreatedcalfveinDVTsmaypropagateproximally.Wi