Transcript Thrombocytopenia

Thrombocytopenia
in the Intensive Care Unit
Ming S. He, M.D.
Platelet Counts
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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
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Produced in the bone
marrow by megakaryocytes
via cytoplasmic shedding
Circulate for 8-10 days then
removed by monocytemacrophage system
“Young platelets” are more
hemostatically active
1/3 of PLTs in normal
individual found in spleen
Mechanisms of Thrombocytopenia
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Decreased PLT production
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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
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Increased PLT destruction
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Immune mediated
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ITP
HIV
Antiphospholipid syndrome
Drugs
TTP-HUS (thrombotic thrombocytopenic purpurahemolytic uremic syndrome)
Physical destruction of PLT (cardiopulmonary
bypass, large aortic aneurysms, and/or intra-aortic
balloon pump)
Mechanisms of Thrombocytopenia
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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
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Blood sample inadequately anticoagulated
EDTA induced platelet clumping present in 0.1% of normal
population
Thrombocyopenia in the ICU
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Often multi-factorial
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DIC (disseminated intravascular coagulation)
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Post transfusion purpura
ARDS (adult respiratory distress syndrome)
Intra-aortic balloon pump
Drugs/Heparin
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Infection/sepsis
Shock
Cardiopulmonary bypass
Use of intravascular catheters
TTP
Evaluation of Thrombocytopenia
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History
Physical exam
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Abdominal exam
Rectal exam
Fundascopic exam
Skin exam
Peripheral Smear
Bone Marrow Aspiration
DIC
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Sepsis
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The likely culpurits
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Shock
Trauma/Extensive Surgery
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Meningococemia
Gram negative bacteremia (DIC in 30-50% of patients)
Gram postitive bacteremia (Staph aureus, Strep pneumoniae,
Clostridia perfringens)
Fungemia
Severe head injury
Malignancy
Obstetrical complications
DIC
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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
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Laboratory values
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Reduced PLT count
Prolonged PT, PTT
Reduced plasma fibrinogen
Elevated FDP
Elevated D-dimer
DIC
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Peripheral Smear reveals schistocytes, helmet cells
Drug Induced Thrombocytopenia
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Usually by accelerating PLT destruction via drugdependent anti-platelet antibodies
Drug binds to platelet surface glycoproteins (GPIbIX, 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
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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
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The mostly likely culpurits include
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Quinine
Quinidine
Valproic acid
Ranitidine
Rifampin
Trimethoprim-sulfamethoxazole
GPIIbIIIa inhibitors
Heparin
Some of the others…
GPIIb/IIIa Inhibitor Induced
Thrombocytopenia
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True thrombocytopenia
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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
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Analysis from the TARGET (tirofiban or
abciximab before PCI) trial showed patients
with thrombocytopenia
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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
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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
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Type I
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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
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Incidence of immune mediated HIT occurs in 0.3-3%
of patients exposed to heparin for more than 3 days
Pathophysiology
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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
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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
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Patients with HIT can develop venous and arterial
thrombosis
Events include
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DVT
Venous limb gangrene
PE
Stroke
MI
Organ infarction
Limb ischemia
Unusual complications of HIT
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Adrenal hemorrhage
Transient global amnesia
Heparin-Induced Thrombocytopenia
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Clinical diagnosis
Diagnostic tests
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14 C serotonin release assay
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Heparin-induced PLT aggregation assay
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100% sensitivity, 97% specificity
Very expensive and technically difficult
Less than 80% sensitivity, 90% specificity
Solid phase immunoassay (ELISA immunoassay to
detect presence of heparin dependent antibodies)
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91% sensitivity, very low specificity
Heparin-Induced Thrombocytopenia
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Treatment
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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
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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
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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
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Characteristics
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Thrombocytopenia
Microangiopathic hemolytic anemia
Neurologic signs and symptoms
Renal function abnormalities
Fever
Pathology
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Thrombi composed mainly of PLT
ADAMTS13 deficiency
Plasminogen activator inhibitor (inhibits fibrinolysis)
Lack of PLT inhibitor
TTP-HUS
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Etiology
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Idiopathic
Endothelial injury
Shiga like toxin (E. coli)
Drugs
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Most notably quinine
Cancer/Chemotherapy
Antiphospholipid antibody/SLE
Pregnancy/Post Partum
Immunosuppressive agents (cyclosporin)
Antiplatelet agents (ticlopidine, clopidegrol)
HIV/HAART
TTP
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Clinical diagnosis
Schistocytes on peripheral smear
Normal PT/PTT
Treatment
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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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www.uptodate.com
Thrombocytopenia in patients in the medical intensive care unit: bleeding prevalence, transfusion
requirements, and outcome. Strauss R - Crit Care Med - 01-AUG-2002; 30(8): 1765-71
From NIH/NLM MEDLINE
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Delayed-onset heparin-induced thrombocytopenia. Smythe MA - Ann Emerg Med - 01-APR-2005; 45(4):
417-9
From NIH/NLM MEDLINE
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Hoffman: Hematology: Basic Principles and Practice, 4th ed., Copyright © 2005 Elsevier
Disseminated Intravascular Coagulation: What's New? Critical Care Clinic Volume 21 • Number 3 • July
2005
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Disseminated intravascular coagulation current concepts of etiology, pathophysiology, diagnosis, and
treatment. Bick RL - Hematol Oncol Clin North Am - 01-FEB-2003; 17(1): 149-76
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Critical issues in hematology: anemia, thrombocytopenia, coagulopathy, and blood product transfusions in
critically ill patients. Drews RE - Clin Chest Med - 01-DEC-2003; 24(4): 607-22
From NIH/NLM MEDLINE
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Current concepts in the diagnosis and management of thrombotic thrombocytopenic purpura. Nabhan C Hematol Oncol Clin North Am - 01-FEB-2003; 17(1): 177-99
From NIH/NLM MEDLINE
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HIV: clinical manifestations. Moylett EH - J Allergy Clin Immunol - 01-JUL-2002; 110(1): 3-16
From NIH/NLM MEDLINE