Thrombocytopenia in the Intensive Care Unit Ming S. He, M.D.

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Thrombocytopenia Thrombocytopenia in the Intensive in the Intensive Care Unit Care Unit Ming S. He, M.D. Ming S. He, M.D.

Transcript of Thrombocytopenia in the Intensive Care Unit Ming S. He, M.D.

Page 1: Thrombocytopenia in the Intensive Care Unit Ming S. He, M.D.

ThrombocytopeniaThrombocytopeniain the Intensive Care Unitin the Intensive Care Unit

Ming S. He, M.D.Ming S. He, M.D.

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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

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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

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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

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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)

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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

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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

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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

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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

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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

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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

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DICDIC

Peripheral Smear reveals schistocytes, helmet cellsPeripheral Smear reveals schistocytes, helmet cells

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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

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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

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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…

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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

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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

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GPIIb/IIIa Inhibitor Induced GPIIb/IIIa Inhibitor Induced ThrombocytopeniaThrombocytopenia

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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

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PseudothrombocytopeniaPseudothrombocytopenia

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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When all else fails?When all else fails?

Heme/Onc ConsultHeme/Onc Consult

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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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