Thrombocytopenia

in the Intensive Care Unit

Ming S. He, M.D.

 Platelet Counts
 Normal: 150,000 – 450,000 /μL
 Thrombocytopenia: Less than 150,000 /μL
 Beware of dramatic decline in platelet count
even if the count is still within normal range
 Surgical bleeding is a risk when PLT (platelet)
is less than 50,000 /μL
 Spontaneous bleeding is a risk when PLT is
less than 10,000 – 20,000 /μL
 Platelet Kinetics
 Produced in the bone
marrow by megakaryocytes
via cytoplasmic shedding
 Circulate for 8-10 days then
removed by monocyte-
macrophage system
 “Young platelets” are more
hemostatically active
 1/3 of PLTs in normal
individual found in spleen
 Mechanisms of Thrombocytopenia
 Decreased PLT production
 Viral Infections: HIV, hepatitis C, EBV,
parvovirus, rubella, mumps, and varicella
 Chemotherapy and radiation therapy
 Congenital and Acquired bone marrow aplasia /
hypoplasia
 Acute Leukemias
 Vitamin B12 and folic acid deficiency
 Mechanisms of Thrombocytopenia
 Increased PLT destruction
 Immune mediated
 ITP
 HIV
 Antiphospholipid syndrome
 Drugs
 TTP-HUS (thrombotic thrombocytopenic purpura-
hemolytic uremic syndrome)
 Physical destruction of PLT (cardiopulmonary
bypass, large aortic aneurysms, and/or intra-aortic
balloon pump)
 Mechanisms of Thrombocytopenia
 Dilutional thrombocytopenia occurs after large
volume transfusion after massive blood loss
 Splenomegaly can cause increase sequestration of
PLTs in the spleen by up to 90%. Clinical bleeding is
rare as total available PLT mass is normal
 Pseudothrombocytopenia
 Blood sample inadequately anticoagulated
 EDTA induced platelet clumping present in 0.1% of
normal population
 Thrombocyopenia in the ICU
 Often multi-factorial
 DIC (disseminated intravascular coagulation)
 Infection/sepsis
 Shock
 Post transfusion purpura
 ARDS (adult respiratory distress syndrome)
 Intra-aortic balloon pump
 Drugs/Heparin
 Cardiopulmonary bypass
 Use of intravascular catheters
 TTP
Evaluation of Thrombocytopenia
 History
 Physical exam
 Abdominal exam
 Rectal exam
 Fundascopic exam
 Skin exam
 Peripheral Smear
 Bone Marrow Aspiration
 DIC
 Sepsis
 The likely culpurits
 Meningococemia
 Gram negative bacteremia (DIC in 30-50% of patients)
 Gram postitive bacteremia (Staph aureus, Strep pneumoniae,
Clostridia perfringens)
 Fungemia
 Shock
 Trauma/Extensive Surgery
 Severe head injury
 Malignancy
 Obstetrical complications
 DIC
 Results from massive activation of clotting cascade
 Increase in thrombin formation causes widespread
aggregation of PLTs and fibrin deposition
 Compensatory generation of plasmin in the setting of
diffuse thrombosis causes thrombolysis and mass
release of fibrinogen degradation products (FDP).
 Plasmin also cause proteolytic degradation of other
clotting factors causing coagulopathy.
 FDP interferes with normal fibrin polymerization and
platelet aggregation
 DIC
 Laboratory values
 Reduced PLT count
 Prolonged PT, PTT
 Reduced plasma fibrinogen
 Elevated FDP
 Elevated D-dimer
 DIC

 Peripheral Smear reveals schistocytes, helmet cells

 Drug Induced
Thrombocytopenia
 Usually by accelerating PLT destruction via drug-
dependent anti-platelet antibodies
 Drug binds to platelet surface glycoproteins (GPIb-
IX, GPIIB-IIIa) causing conformational change and
exposing neoepitope that serves as target for
antibodies
 The drug is generally a part of the neoepitope
 Drug-dependent anti-platelet antibodies are very
specific and usually do not cross react with other
drugs of the same class
 Drug Induced
Thrombocytopenia
 Diagnosis is made when thrombocytopenia resolves
after the suspected drug is discontinued
 Median for PLT count recovery after discontinuation
of drug is 5-7 days
 Assays for drug-dependent antiplatelet antibodies not
readily available
 If PLT is less than 10,000 /μL or bleeding occurs,
treat with steroids as well as transfusion incase of ITP
Drug Induced Thrombocytopenis
 The mostly likely culpurits include
 Quinine
 Quinidine
 Valproic acid
 Ranitidine
 Rifampin
 Trimethoprim-sulfamethoxazole
 GPIIbIIIa inhibitors
 Heparin
 Some of the others…
 GPIIb/IIIa Inhibitor Induced
Thrombocytopenia
 True thrombocytopenia
 Most common with abciximab
 Less common with tirofiban and eptifibatide
 Occurs within 24 hours
 When GPIIbIIIa inhibitors bind PLT neoepitopes are
exposed and induce antibody formation
 Thrombocytopenia can occur within 30 minutes of
abciximab administration because of naturally
occurring preformed antibodies
 GPIIb/IIIa Inhibitor Induced
Thrombocytopenia
 Analysis from the TARGET (tirofiban or
abciximab before PCI) trial showed patients
with thrombocytopenia
 More frequent severe bleeding
 Higher incidence of death
 Higher incidence of MI
 Higher incidence of need from target vessel
revascularization at 30 days
GPIIb/IIIa Inhibitor Induced
Thrombocytopenia
 Pseudothrombocytopenia
 Pseudothrombocytopenia occurs in 2% of
patients exposed to abciximab
 Not associated with adverse outcome
 Results from a naturally occurring platelet
autoantibody against a normally concealed
epitope of GPIIbIIIa which become exposed
after exposure to EDTA
 PLT count should be normal when heparin or
sodium citrate is used
Pseudothrombocytopenia
Heparin-Induced Thrombocytopenia
 Type I
 A relatively mild fall in PLT count within first 2
days of heparin initiation; PLT count often remains
in the normal range
 PLT count often returns to normal with continued
heparin administration
 Non-immune mediated
 No clinical consequence
Heparin-Induced Thrombocytopenia
 Incidence of immune mediated HIT occurs in 0.3-3%
of patients exposed to heparin for more than 3 days
 Pathophysiology
 Heparin binds platelet factor 4 (PF4) and a conformational
change occurs which forms an epitope recognized by most
HIT antibodies (IgG and IgM)
 Heparin-PF4-antibody complex leads to platelet activation
which leads to further release of PF4
 Activated PLT aggregate and leads to thrombosis as well as
thrombocytopenia
Heparin-Induced Thrombocytopenia
 Thrombocytopenia is usually not severe with PLT
count between 20,000 – 60,000/μL
 Spontaneous bleeding is rare
 Delayed onset HIT is the development of thrombosis
and thrombocytopenia after heparin has been
withdrawn.
 Has been documented to occur between 9 to 40 days
after last exposure to heparin
 Mechanism is unclear
 Heparin-Induced Thrombocytopenia
 Patients with HIT can develop venous and arterial
thrombosis
 Events include
 DVT
 Venous limb gangrene
 PE
 Stroke
 MI
 Organ infarction
 Limb ischemia
 Unusual complications of HIT
 Adrenal hemorrhage
 Transient global amnesia
Heparin-Induced Thrombocytopenia
 Clinical diagnosis
 Diagnostic tests
 14 C serotonin release assay
 100% sensitivity, 97% specificity
 Very expensive and technically difficult
 Heparin-induced PLT aggregation assay
 Less than 80% sensitivity, 90% specificity
 Solid phase immunoassay (ELISA immunoassay
to detect presence of heparin dependent antibodies)
 91% sensitivity, very low specificity
Heparin-Induced Thrombocytopenia
 Treatment
 Cessation of all heparin exposure
 Use of lepirudin/bivalirudin or argatroban (direct thrombin
inhibitor) for anticoagulation until PLT count has recovered
 Initiate warfarin after a patient is stably anticoagulated
 Other agents
 Fondaparinux
 Danaparoid
 Patients with a history of HIT who require
cardiopulmonary bypass who are antibody negative at
the time of surgery do not generally develop
complications with the brief heparin exposure
 Post Transfusion Purpura
 Severe thrombocytpenia 5 to 10 days after transfusion
of PLT containing product and recovery occurs
between days 7 to 48.
 Occurs primarily in women who had prior
exposure/sensitization to foreign antigen
 Antigen most commonly implicated is HPA 1a
 Patients’ own PLTs are HPA 1a negative, but are also
destroyed in PTP via unclear mechanism
 Treatment is IVIG or plasma exchange
 PLT transfusion is NOT effective
 TTP-HUS
 Characteristics
 Thrombocytopenia
 Microangiopathic hemolytic anemia
 Neurologic signs and symptoms
 Renal function abnormalities
 Fever
 Pathology
 Thrombi composed mainly of PLT
 ADAMTS13 deficiency
 Plasminogen activator inhibitor (inhibits fibrinolysis)
 Lack of PLT inhibitor
 TTP-HUS
 Etiology
 Idiopathic
 Endothelial injury
 Shiga like toxin (E. coli)
 Drugs
 Most notably quinine
 Cancer/Chemotherapy
 Antiphospholipid antibody/SLE
 Pregnancy/Post Partum
 Immunosuppressive agents (cyclosporin)
 Antiplatelet agents (ticlopidine, clopidegrol)
 HIV/HAART
 TTP
 Clinical diagnosis
 Schistocytes on peripheral smear
 Normal PT/PTT
 Treatment
 Renal failure and death if untreated
 Remove precipitating factor if possible
 Plasma exchange until PLT returns to normal
 Add steroids if poor response
 Dialysis if necessary
 Follow patients for relapse
When all else fails?

Heme/Onc Consult
 References
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417-9
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