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ThrombocytopeniaThrombocytopeniain the Intensive Care Unitin the Intensive Care Unit
Ming S. He, M.D.Ming S. He, M.D.
Platelet CountsPlatelet Counts
Normal: 150,000 – 450,000 /μLNormal: 150,000 – 450,000 /μL Thrombocytopenia: Less than 150,000 /μLThrombocytopenia: Less than 150,000 /μL Beware of dramatic decline in platelet count Beware of dramatic decline in platelet count
even if the count is still within normal rangeeven if the count is still within normal range Surgical bleeding is a risk when PLT (platelet) Surgical bleeding is a risk when PLT (platelet)
is less than 50,000 /μLis less than 50,000 /μL Spontaneous bleeding is a risk when PLT is Spontaneous bleeding is a risk when PLT is
less than 10,000 – 20,000 /μLless than 10,000 – 20,000 /μL
Platelet KineticsPlatelet Kinetics Produced in the bone Produced in the bone
marrow by megakaryocytes marrow by megakaryocytes via cytoplasmic shedding via cytoplasmic shedding
Circulate for 8-10 days then Circulate for 8-10 days then removed by monocyte-removed by monocyte-macrophage systemmacrophage system
““Young platelets” are more Young platelets” are more hemostatically activehemostatically active
1/3 of PLTs in normal 1/3 of PLTs in normal individual found in spleenindividual found in spleen
Mechanisms of ThrombocytopeniaMechanisms of Thrombocytopenia
Decreased PLT productionDecreased PLT production Viral Infections: HIV, hepatitis C, EBV, Viral Infections: HIV, hepatitis C, EBV,
parvovirus, rubella, mumps, and varicellaparvovirus, rubella, mumps, and varicella Chemotherapy and radiation therapyChemotherapy and radiation therapy Congenital and Acquired bone marrow aplasia / Congenital and Acquired bone marrow aplasia /
hypoplasiahypoplasia Acute LeukemiasAcute Leukemias Vitamin B12 and folic acid deficiencyVitamin B12 and folic acid deficiency
Mechanisms of ThrombocytopeniaMechanisms of Thrombocytopenia Increased PLT destructionIncreased PLT destruction
Immune mediatedImmune mediated ITPITP HIVHIV Antiphospholipid syndromeAntiphospholipid syndrome DrugsDrugs
TTP-HUS (thrombotic thrombocytopenic purpura-TTP-HUS (thrombotic thrombocytopenic purpura-hemolytic uremic syndrome)hemolytic uremic syndrome)
Physical destruction of PLT (cardiopulmonary Physical destruction of PLT (cardiopulmonary bypass, large aortic aneurysms, and/or intra-aortic bypass, large aortic aneurysms, and/or intra-aortic balloon pump)balloon pump)
Mechanisms of ThrombocytopeniaMechanisms of Thrombocytopenia
Dilutional thrombocytopenia occurs after large Dilutional thrombocytopenia occurs after large volume transfusion after massive blood lossvolume transfusion after massive blood loss
Splenomegaly can cause increase sequestration of Splenomegaly can cause increase sequestration of PLTs in the spleen by up to 90%. Clinical bleeding is PLTs in the spleen by up to 90%. Clinical bleeding is rare as total available PLT mass is normalrare as total available PLT mass is normal
PseudothrombocytopeniaPseudothrombocytopenia Blood sample inadequately anticoagulatedBlood sample inadequately anticoagulated EDTA induced platelet clumping present in 0.1% of EDTA induced platelet clumping present in 0.1% of
normal populationnormal population
Thrombocyopenia in the ICUThrombocyopenia in the ICU Often multi-factorialOften multi-factorial
DIC (disseminated intravascular coagulation)DIC (disseminated intravascular coagulation) Infection/sepsisInfection/sepsis ShockShock
Post transfusion purpuraPost transfusion purpura ARDS (adult respiratory distress syndrome)ARDS (adult respiratory distress syndrome) Intra-aortic balloon pumpIntra-aortic balloon pump Drugs/HeparinDrugs/Heparin
Cardiopulmonary bypassCardiopulmonary bypass Use of intravascular cathetersUse of intravascular catheters
TTPTTP
Evaluation of ThrombocytopeniaEvaluation of Thrombocytopenia History History Physical exam Physical exam
Abdominal examAbdominal exam Rectal examRectal exam Fundascopic examFundascopic exam Skin examSkin exam
Peripheral SmearPeripheral Smear Bone Marrow AspirationBone Marrow Aspiration
DICDIC SepsisSepsis
The likely culpuritsThe likely culpurits MeningococemiaMeningococemia Gram negative bacteremia (DIC in 30-50% of patients)Gram negative bacteremia (DIC in 30-50% of patients) Gram postitive bacteremia (Staph aureus, Strep pneumoniae, Gram postitive bacteremia (Staph aureus, Strep pneumoniae,
Clostridia perfringens)Clostridia perfringens) FungemiaFungemia
ShockShock Trauma/Extensive SurgeryTrauma/Extensive Surgery
Severe head injurySevere head injury MalignancyMalignancy Obstetrical complicationsObstetrical complications
DICDIC
Results from massive activation of clotting cascadeResults from massive activation of clotting cascade Increase in thrombin formation causes widespread Increase in thrombin formation causes widespread
aggregation of PLTs and fibrin depositionaggregation of PLTs and fibrin deposition Compensatory generation of plasmin in the setting of Compensatory generation of plasmin in the setting of
diffuse thrombosis causes thrombolysis and mass diffuse thrombosis causes thrombolysis and mass release of fibrinogen degradation products (FDP). release of fibrinogen degradation products (FDP).
Plasmin also cause proteolytic degradation of other Plasmin also cause proteolytic degradation of other clotting factors causing coagulopathy.clotting factors causing coagulopathy.
FDP interferes with normal fibrin polymerization and FDP interferes with normal fibrin polymerization and platelet aggregationplatelet aggregation
DICDIC Laboratory valuesLaboratory values
Reduced PLT countReduced PLT count Prolonged PT, PTTProlonged PT, PTT Reduced plasma fibrinogenReduced plasma fibrinogen Elevated FDPElevated FDP Elevated D-dimerElevated D-dimer
DICDIC
Peripheral Smear reveals schistocytes, helmet cellsPeripheral Smear reveals schistocytes, helmet cells
Drug Induced Drug Induced ThrombocytopeniaThrombocytopenia
Usually by accelerating PLT destruction via drug-Usually by accelerating PLT destruction via drug-dependent anti-platelet antibodiesdependent anti-platelet antibodies
Drug binds to platelet surface glycoproteins (GPIb-Drug binds to platelet surface glycoproteins (GPIb-IX, GPIIB-IIIa) causing conformational change and IX, GPIIB-IIIa) causing conformational change and exposing neoepitope that serves as target for exposing neoepitope that serves as target for antibodiesantibodies
The drug is generally a part of the neoepitopeThe drug is generally a part of the neoepitope Drug-dependent anti-platelet antibodies are very Drug-dependent anti-platelet antibodies are very
specific and usually do not cross react with other specific and usually do not cross react with other drugs of the same classdrugs of the same class
Drug Induced Drug Induced ThrombocytopeniaThrombocytopenia
Diagnosis is made when thrombocytopenia resolves Diagnosis is made when thrombocytopenia resolves after the suspected drug is discontinuedafter the suspected drug is discontinued
Median for PLT count recovery after discontinuation Median for PLT count recovery after discontinuation of drug is 5-7 daysof drug is 5-7 days
Assays for drug-dependent antiplatelet antibodies not Assays for drug-dependent antiplatelet antibodies not readily availablereadily available
If PLT is less than 10,000 /μL or bleeding occurs, If PLT is less than 10,000 /μL or bleeding occurs, treat with steroids as well as transfusion incase of ITPtreat with steroids as well as transfusion incase of ITP
Drug Induced ThrombocytopenisDrug Induced Thrombocytopenis
The mostly likely culpurits includeThe mostly likely culpurits include QuinineQuinine QuinidineQuinidine Valproic acidValproic acid RanitidineRanitidine RifampinRifampin Trimethoprim-sulfamethoxazoleTrimethoprim-sulfamethoxazole GPIIbIIIa inhibitorsGPIIbIIIa inhibitors HeparinHeparin
Some of the others…Some of the others…
GPIIb/IIIa Inhibitor Induced GPIIb/IIIa Inhibitor Induced ThrombocytopeniaThrombocytopenia
True thrombocytopeniaTrue thrombocytopenia Most common with abciximabMost common with abciximab Less common with tirofiban and eptifibatideLess common with tirofiban and eptifibatide
Occurs within 24 hours Occurs within 24 hours When GPIIbIIIa inhibitors bind PLT neoepitopes are When GPIIbIIIa inhibitors bind PLT neoepitopes are
exposed and induce antibody formationexposed and induce antibody formation Thrombocytopenia can occur within 30 minutes of Thrombocytopenia can occur within 30 minutes of
abciximab administration because of naturally abciximab administration because of naturally occurring preformed antibodiesoccurring preformed antibodies
GPIIb/IIIa Inhibitor Induced GPIIb/IIIa Inhibitor Induced ThrombocytopeniaThrombocytopenia
Analysis from the TARGET (tirofiban or Analysis from the TARGET (tirofiban or abciximab before PCI) trial showed patients abciximab before PCI) trial showed patients with thrombocytopeniawith thrombocytopenia More frequent severe bleedingMore frequent severe bleeding Higher incidence of deathHigher incidence of death Higher incidence of MIHigher incidence of MI Higher incidence of need from target vessel Higher incidence of need from target vessel
revascularization at 30 daysrevascularization at 30 days
GPIIb/IIIa Inhibitor Induced GPIIb/IIIa Inhibitor Induced ThrombocytopeniaThrombocytopenia
PseudothrombocytopeniaPseudothrombocytopenia
Pseudothrombocytopenia occurs in 2% of Pseudothrombocytopenia occurs in 2% of patients exposed to abciximabpatients exposed to abciximab
Not associated with adverse outcomeNot associated with adverse outcome Results from a naturally occurring platelet Results from a naturally occurring platelet
autoantibody against a normally concealed autoantibody against a normally concealed epitope of GPIIbIIIa which become exposed epitope of GPIIbIIIa which become exposed after exposure to EDTAafter exposure to EDTA
PLT count should be normal when heparin or PLT count should be normal when heparin or sodium citrate is usedsodium citrate is used
PseudothrombocytopeniaPseudothrombocytopenia
Heparin-Induced ThrombocytopeniaHeparin-Induced Thrombocytopenia
Type IType I A relatively mild fall in PLT count within first 2 A relatively mild fall in PLT count within first 2
days of heparin initiation; PLT count often remains days of heparin initiation; PLT count often remains in the normal rangein the normal range
PLT count often returns to normal with continued PLT count often returns to normal with continued heparin administrationheparin administration
Non-immune mediated Non-immune mediated No clinical consequenceNo clinical consequence
Heparin-Induced ThrombocytopeniaHeparin-Induced Thrombocytopenia Incidence of immune mediated HIT occurs in 0.3-3% Incidence of immune mediated HIT occurs in 0.3-3%
of patients exposed to heparin for more than 3 daysof patients exposed to heparin for more than 3 days PathophysiologyPathophysiology
Heparin binds platelet factor 4 (PF4) and a conformational Heparin binds platelet factor 4 (PF4) and a conformational change occurs which forms an epitope recognized by most change occurs which forms an epitope recognized by most HIT antibodies (IgG and IgM)HIT antibodies (IgG and IgM)
Heparin-PF4-antibody complex leads to platelet activation Heparin-PF4-antibody complex leads to platelet activation which leads to further release of PF4which leads to further release of PF4
Activated PLT aggregate and leads to thrombosis as well as Activated PLT aggregate and leads to thrombosis as well as thrombocytopeniathrombocytopenia
Heparin-Induced ThrombocytopeniaHeparin-Induced Thrombocytopenia
Thrombocytopenia is usually not severe with PLT Thrombocytopenia is usually not severe with PLT count between 20,000 – 60,000/μLcount between 20,000 – 60,000/μL
Spontaneous bleeding is rareSpontaneous bleeding is rare Delayed onset HIT is the development of thrombosis Delayed onset HIT is the development of thrombosis
and thrombocytopenia after heparin has been and thrombocytopenia after heparin has been withdrawn. withdrawn.
Has been documented to occur between 9 to 40 days Has been documented to occur between 9 to 40 days after last exposure to heparinafter last exposure to heparin
Mechanism is unclearMechanism is unclear
Heparin-Induced ThrombocytopeniaHeparin-Induced Thrombocytopenia Patients with HIT can develop venous and arterial Patients with HIT can develop venous and arterial
thrombosisthrombosis Events includeEvents include
DVTDVT Venous limb gangreneVenous limb gangrene PEPE StrokeStroke MIMI Organ infarctionOrgan infarction Limb ischemiaLimb ischemia
Unusual complications of HITUnusual complications of HIT Adrenal hemorrhageAdrenal hemorrhage Transient global amnesiaTransient global amnesia
Heparin-Induced ThrombocytopeniaHeparin-Induced Thrombocytopenia Clinical diagnosisClinical diagnosis Diagnostic testsDiagnostic tests
14 C serotonin release assay14 C serotonin release assay 100% sensitivity, 97% specificity100% sensitivity, 97% specificity Very expensive and technically difficultVery expensive and technically difficult
Heparin-induced PLT aggregation assayHeparin-induced PLT aggregation assay Less than 80% sensitivity, 90% specificityLess than 80% sensitivity, 90% specificity
Solid phase immunoassay (ELISA immunoassay Solid phase immunoassay (ELISA immunoassay to detect presence of heparin dependent antibodies)to detect presence of heparin dependent antibodies)
91% sensitivity, very low specificity91% sensitivity, very low specificity
Heparin-Induced ThrombocytopeniaHeparin-Induced Thrombocytopenia
TreatmentTreatment Cessation of all heparin exposureCessation of all heparin exposure Use of lepirudin/bivalirudin or argatroban (direct thrombin Use of lepirudin/bivalirudin or argatroban (direct thrombin
inhibitor) for anticoagulation until PLT count has inhibitor) for anticoagulation until PLT count has recoveredrecovered
Initiate warfarin after a patient is stably anticoagulated Initiate warfarin after a patient is stably anticoagulated Other agentsOther agents
FondaparinuxFondaparinux DanaparoidDanaparoid
Patients with a history of HIT who require Patients with a history of HIT who require cardiopulmonary bypass who are antibody negative at cardiopulmonary bypass who are antibody negative at the time of surgery do not generally develop the time of surgery do not generally develop complications with the brief heparin exposurecomplications with the brief heparin exposure
Post Transfusion PurpuraPost Transfusion Purpura
Severe thrombocytpenia 5 to 10 days after transfusion Severe thrombocytpenia 5 to 10 days after transfusion of PLT containing product and recovery occurs of PLT containing product and recovery occurs between days 7 to 48.between days 7 to 48.
Occurs primarily in women who had prior Occurs primarily in women who had prior exposure/sensitization to foreign antigenexposure/sensitization to foreign antigen
Antigen most commonly implicated is HPA 1aAntigen most commonly implicated is HPA 1a Patients’ own PLTs are HPA 1a negative, but are also Patients’ own PLTs are HPA 1a negative, but are also
destroyed in PTP via unclear mechanismdestroyed in PTP via unclear mechanism Treatment is IVIG or plasma exchangeTreatment is IVIG or plasma exchange PLT transfusion is NOT effectivePLT transfusion is NOT effective
TTP-HUSTTP-HUS CharacteristicsCharacteristics
ThrombocytopeniaThrombocytopenia Microangiopathic hemolytic anemiaMicroangiopathic hemolytic anemia Neurologic signs and symptomsNeurologic signs and symptoms Renal function abnormalitiesRenal function abnormalities FeverFever
PathologyPathology Thrombi composed mainly of PLT Thrombi composed mainly of PLT ADAMTS13 deficiency ADAMTS13 deficiency Plasminogen activator inhibitor (inhibits fibrinolysis)Plasminogen activator inhibitor (inhibits fibrinolysis) Lack of PLT inhibitorLack of PLT inhibitor
TTP-HUSTTP-HUS EtiologyEtiology
IdiopathicIdiopathic Endothelial injuryEndothelial injury Shiga like toxin (E. coli)Shiga like toxin (E. coli) DrugsDrugs
Most notably quinineMost notably quinine Cancer/ChemotherapyCancer/Chemotherapy Antiphospholipid antibody/SLEAntiphospholipid antibody/SLE Pregnancy/Post PartumPregnancy/Post Partum Immunosuppressive agents (cyclosporin)Immunosuppressive agents (cyclosporin) Antiplatelet agents (ticlopidine, clopidegrol)Antiplatelet agents (ticlopidine, clopidegrol) HIV/HAARTHIV/HAART
TTPTTP
Clinical diagnosisClinical diagnosis Schistocytes on peripheral smearSchistocytes on peripheral smear Normal PT/PTTNormal PT/PTT TreatmentTreatment
Renal failure and death if untreatedRenal failure and death if untreated Remove precipitating factor if possibleRemove precipitating factor if possible Plasma exchange until PLT returns to normalPlasma exchange until PLT returns to normal Add steroids if poor responseAdd steroids if poor response Dialysis if necessaryDialysis if necessary Follow patients for relapseFollow patients for relapse
When all else fails?When all else fails?
Heme/Onc ConsultHeme/Onc Consult
ReferencesReferences www.uptodate.comwww.uptodate.com Thrombocytopenia in patients in the medical intensive care unit: bleeding prevalence, transfusion Thrombocytopenia in patients in the medical intensive care unit: bleeding prevalence, transfusion
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