Professional Documents
Culture Documents
DeLoughery, MD FACP
Professor of Medicine, Pathology, and Pediatrics
Oregon Health Sciences University
Portland, Oregon
delought@ohsu.edu
Thrombocytopenia
DIFFERENTIAL DIAGNOSES
Cardiopulmonary bypass, HIT, dilutional
thrombocytopenia
Interventional Cardiac Procedure
Glycoprotein IIb/IIIa blockers, HIT
Sepsis Syndrome
DIC, Ehrlichiosis, Sepsis hemophagocytosis
syndrome, drug-induced, misdiagnosed TTP,
mechanical ventilation, pulmonary artery
catheters
Pulmonary Failure
DIC, Hantavirus pulmonary syndrome,
mechanical ventilation, pulmonary artery
catheters
Mental Status Changes/Seizures
TTP, Ehrlichiosis
Renal Failure
TTP, Dengue, HIT, DIC
Cardiac Failure
HIT, drug induced, pulmonary artery catheter
Post-surgery
Dilutional, drug-induced, HIT
Pregnancy
HELLP syndrome, fatty liver of pregnancy,
TTP/HUS
Acute Liver failure
Splenic sequestration, HIT, drug induced, DIC
HIT = Heparin induced thrombocytopenia, DIC = disseminated intravascular coagulation, TTP =
thrombotic thrombocytopenic purpura, HELLP = Hemolysis, Elevated Liver function tests, and Low
Platelets
DIFFERENTIAL DIAGNOSES
Factor V inhibitor, heparin excess or rebound,
Sepsis Syndrome
Recent use of Quinine, Second or Third
generation cephalosporin
Post-surgery
Pregnancy
section
Attempt to repair large vessel bleeding
Attempt to raise the pH above 7.2
Use a dose of 90 ug/kg.
COAGULATION DEFECTS
Disseminated Intravascular Coagulation
DIC is the clinical manifestation of inappropriate thrombin activation
Patients with DIC can present in one of four ways:
1) Asymptomatic
2) Bleeding
3) Thrombosis
4) Purpura fulminans
Tests - routine coag tests may be normal. D-dimer has the highest predictive value for DIC.
Therapy
* Treat primary cause
* Replace coagulation factors guided by the 5 basic coag tests
* Heparin only if patient having thrombosis - will need to use heparin levels to guide therapy
* Recombinant activated protein C (rAPC) for patients with severe DIC and sepsis
Purpura Fulminans is DIC association with symmetrical limb ecchymosis and necrosis of the skin.
1) Primary purpura fulminans
* Often after viral infections
* Often with acquire protein S antibodies
* Therapy is with plasma to keep protein S > 25%, heparin, and IVIG
2) Secondary purpura fulminans
* Overwhelming infections esp meningealococcemia
* Therapy: transfusion therapy guided by 5 basic coag tests. Consider rAPC +/- CVVH
Drug Induced Hemolytic-DIC Syndromes
Patients with severe hemolytic anemia and thrombotic DIC
* One form seen with 2nd and 3rd generation cephalosporins (cefotetan most common). Starts 7-10 days
after getting ATB. Patient present with severe Coombs positive hemolytic anemia, hypotension and DIC.
* Second form seen with quinine. 24-96 hours after ingesting present with DIC, anemia, and renal
failure. Can also have immune neutropenia.
Therapy is uncertain and process has high mortality.
Liver Disease
Multiple coagulation defects:
1) Decrease synthesis of clotting factors
2) Increase consumption of factors
3) Thrombocytopenia
4) Platelet dysfunction
5) Fibrinolysis
However important to remember most bleeding in liver patients are due to mechanical defects (ulcers,
etc..) Increasing data that laboratory tests overstates coagulation defects
Therapy of bleeding is guided by the 5 basic coag tests. Can be very difficult to impossible to fully
correct INR and little utility in treating an elevated INR if the aPTT is normal.
Abnormal fibrinolysis is an often overlooked cause of bleeding in patients with liver disease.
* Diffuse bleeding from minor sites of trauma or IV sites
Factor V Inhibitors
* Occur in patients after the use of topical thrombin increasingly rarer
* Can present with either severe bleeding or abnormal laboratory screening.
* Lab findings: prolonged thrombin time, elevated INT/aPTT, low factor V levels.
* Many patients do not bleed (Platelet factor V?).
* Antibodies disappear in a few weeks. IVIG may speed antibody disappearance
Very Quick Guide to Reversing Antithrombotic Therapy
Agent
Half-life
Renal Disease
Reversal
Aspirin
15-30 minutes
No change
DDAVP, Platelet
Clopidogrel
8 hours
Metabolites renally
Transfusions
DDAVP(?), platelet
Prasugrel
7 hours
cleared
Metabolites renally
transfusions
DDAVP(?), platelet
Abciximab
Tirofiban
30 minutes
2 hours
cleared
No change
Decrease dose by 50%
transfusions
Platelet Transfusion
Platelet transfusions,
DDAVP,
cryoprecipitate, dialysis
Platelet transfusions,
DDAVP,
Eptifibatide
2-3 hours
Unfractionated Heparin
Low Molecular Weight
30-150 minutes
2-8 hours
45-225
4-16 hours
cryoprecipitate, dialysis
Protamine - se table
Protamine
Heparin
Fondaparinux
17-21 hours
Clearance decreased
rVIIa
72 hours
ml/min
Clearance decrease in
rVIIa
Argatroban
Bivalirudin
40 minutes
25 minutes
renal insufficiency
No change
60% dose reduction if
APCC
APCC
Dabigatran
8 hours
APCC
Lepirudin
40 minutes
ml/min
t1/2 in renal failure
APCC, dialysis
8 hours
25 minutes
C2P9
renally cleared
renally cleared
Hepatically cleared
rVIIa
rVIIa?
rVIIa?
Plasma, platelet,
tPA
3 minutes
Hepatically cleared
cryoprecipitate
Plasma, platelet,
Reteplase
13-16 minutes
Hepatically cleared
cryoprecipitate
Plasma, platelet,
Tenecteplase
15-20 minutes
Hepatically cleared
cryoprecipitate
Plasma, platelet,
Warfarin
36 hours
BAY 59-7939
Dx-9065a
Streptokinase
cryoprecipitate
APCC = active prothrombin complex concentrates, PCC = prothrombin complex concentrates, FFP =
Pregnancy Related Diseases -TTP/HUS, HELLP Syndrome, and Acute Fatty Liver of Pregnancy
(FLP)
HELLP
TTP/HUS
AFLP
Hypertension
Always present
Sometimes present
Sometimes present
Proteinuria
Always present
Sometimes present
Sometimes present
Thrombocytopenia
Always
Always
Always
LDH Elevation
Present
Marked
Present
Fibrinogen
Normal to Low
Normal
Normal to Very Low
Schistocytes
Present
Present
Absent
Liver Tests
Elevated
Normal
Elevated
Ammonia
Normal
Normal
Elevated
Glucose
Normal
Normal
Low
HELLP = Hemolysis, Elevated Liver tests, and Low Platelets
TTP/HUS = Thrombotic Thrombocytopenic Purpura/Hemolytic Uremia Syndrome
AFLP = Acute Fatty Liver of Pregnancy
THROMBOCYTOPENIA AND PLATELET DYSFUNCTION
Heparin Induced Thrombocytopenia (HIT)
Natural History: Occurs at least 4 days after starting heparin in any form. Thrombocytopenia is modest
- 60,000/ul is average - rare for counts to be under 20,000/ul. 20-50% of patients will have thrombosis.
Can occur rapidly if patient has had heparin in past 100 days (esp previous 30 days). Some patients can
present with HIT up to 2 weeks after heparin exposure.
Pathogenesis: Formation of antibodies directed against the complex of heparin that bind to platelet
factor 4 (PF4)
Frequency of HIT: Standard heparin 1-5% (bovine > porcine), LMWH <1%.
Diagnosis: Suspect if any of these occur:
* Platelet counts drops by 50% from previous baseline
* Platelet counts fall under 100,000/ul
* New thrombosis on heparin
Thrombocytopenia
Thrombosis
Progressive or
recurrent thrombosis
or suspected but not
proven thrombosis
None
No
Possible
Definite
falling platelet count, falling hematocrit, and rising serum LDH level. Often (but not always) resolves with
decreasing the cyclosporine dose or changing to another agent.
* Mitomycin C with an incidence of 10% when a dose of more than 60 mg is used. Slow onset but
relentless course of renal failure and death. A characteristic feature is the occurrence of a non-cardiac
pulmonary edema with red cell transfusions. Anecdotal reports state that treatment with staphycoccal A
columns may be useful for this condition.
* Carboplatinum and gemcitabine - rare reports
* Ticlopidine TTP incidence may be a high as 1:1600. Patients seem to respond to plasma exchange but
mortality rates of up to 50% have been reported. TTP/HUS is also reported with clopidogrel but with a
considerable lesser incidence.
* BMT - 5-15% with several types described:
1)"Multi-organ fulminant" which occurs early (20-60 days), has multi-organ system involvement and is
often fatal.
2) Cyclosporin/FK 506 HUS.
3) "Conditioning" TTP/HUS which occurs six months or more after total body irradiation, and is
associated with primary renal involvement.
4) Systemic CMV infections will present with a TTP/HUS syndrome related to vascular infection.
Pregnancy related TTP/HUS
* Unique presentation that occurs in the second trimester at 20-22 weeks.
* The fetus is uninvolved with no evidence of infarction or thrombocytopenia if the mother survives.
* Resolves with delivery or pregnancy termination
* Up to 30% relapse with next pregnancy
HUS-type syndrome seen up to 28 weeks post-partum which is severe, and permanent renal failure often
results despite aggressive therapy.
Drug Induced Thrombocytopenia
* Drugs indicated in less than 1% of ICU thrombocytopenia
* Usually severe thrombocytopenia with onset 2 weeks after drug is started
* Steroids, IVIG not helpful
* List of most common drugs in back of handout but vancomycin now most common agent implicated
* Severe thrombocytopenia has been reported in 0.5-2% of patients receiving GP IIb/IIIa inhibitors with
onset within hours of receiving drugs. Rapidly resolves with stopping drug but should transfuse if
platelets < 20,000/ul.
Sepsis
* Thrombocytopenia common in septic patients
* Most cases due to sepsis induced hemophagocytic syndrome
* Thrombocytopenia can be clue to certain diseases:
1) Ehrlichia: mild thrombocytopenia and leucopenia. Buffy coat reveals the organisms bundled in a 2-5
um morula in the cytoplasm of the granulocytes or monocytes.
2) Hantavirus pulmonary syndrome (HPS): Thrombocytopenia is almost an universal finding with the
median platelet counts being 50,000/ul.{17739} The triad of thrombocytopenia, increased and left-shifted
white cell count and more than 10% circulating immunoblasts can identify all cases of HPS. Marked
hemoconcentration is also present due to capillary leak syndrome.
3) Dengue infections and rickettsial infections also present with prominent thrombocytopenia.
4) SARS: Thrombocytopenia is relatively rare but many patients will develop a reactive thrombocytosis
one week into the illness.
5) Travel history: the viral hemorrhagic syndromes such as yellow fever or rift valley fever must be
considered.
Catastrophic Antiphospholipid Antibody Syndrome (CAPS)
Rarely patients with antiphospholipid antibody syndrome can present with fulminant multiorgan system
failure due to widespread microthrombi in multiple vascular fields:
* Renal failure
* Encephalopathy
Drug
Acetaminophen
Allopurinol
Aminodarone* (May Last for Months after Drug
Is Stopped)
Anabolic Steroids*
Aspirin*
Cephlasporins (Nmtt Group)
Cimetidine*
Ciprofloxacin
Clofibrate*
Cyclophosphamide
Disulfiram
Erythromycin*
Fluconazole*
Furosemide
Gemfibrozil
Isoniazid
Itraconazole*
Ketoconazole*
Metronidazole*
Micronase*
Omeprazole
Propafenone
Propranolol
Quinidine*
Quinine*
Quinolones
Serotonin Uptake Inhibitors
Sulfinpyrazone*
Sulfonyureas*
Tamoxifen*
Tetracycline*
Thyroid Hormones*
Tricyclics
Vitamin E*
Alcohol
Barbiturates*
Carbamazepine
Corticosteroids
Phenytoin (May Potentiate Warfarin with
Initiation of Drug)
Cholestyramine
Dicloxacillin
Estrogens
Griseofulvin
Nafcillin
Rifampin
Sucralfate
Vitamin K