Thomas G. DeLoughery, MD FACP
Professor of Medicine, Pathology, and Pediatrics
Oregon Health Sciences University
Portland, Oregon
delought@ohsu.edu
CRITICAL CARE CLOTTING CATASTROPHES
Coagulation Problems
Coagulation defects common in ICU patients
25-40% with counts under 100,000/ul
2-3% with counts under 10,000/ul
INITIAL EVALUATION
Key issues:
1) Is the patient bleeding or having thrombosis?
2) What are the underlying disorders that lead to the ICU admission?
3) What current and recent medications the patient was on
4) The past medical history.
Exposure to medicines is a common cause of thrombocytopenia and can augment certain coagulation
defects. (Tables One and Two).
Laboratory Testing
Common Causes of Abnormal Laboratory Tests
Elevated PT/INR, Normal aPTT
Factor VII deficiency
Vitamin K deficiency
Warfarin
Sepsis
Normal PT/INR, Elevated aPTT
Isolated factor deficiency (VIII, IX, XI, XII, Contact Pathway proteins)
Specific Factor Inhibitor
High Hematocrit (>60% - spurious)
Heparin
Lupus Inhibitor
Elevated PT/INR, Elevated aPTT
Multiple Coagulation Factor Deficiencies
Liver Disease
Disseminated Intravascular Coagulation
Isolated Factor X, V or II deficiency
Factor V inhibitors
High heparin levels
Warfarin excess
Low Fibrinogen (< 50 mg/dL)
Dysfibrinogemia
Dilutional
Thrombocytopenia
Differential Diagnosis of Thrombocytopenia
Disseminated Intravascular Coagulation
Drug induce thrombocytopenia
HELLP Syndrome
Hemophagocytic Syndrome
Heparin Induced thrombocytopenia
Immune Thrombocytopenia
Liver Disease
Post-Transfusion Purpura
Pseudothrombocytopenia
Thrombotic Thrombocytopenia Purpura
Typical Platelet Counts in Various Disease States
Moderate Thrombocytopenia (50,-100,000/ul)
Thrombotic Thrombocytopenic Purpura
Heparin induce thrombocytopenia
Disseminated Intravascular Coagulation
Hemophagocytic Syndrome
Severe Thrombocytopenia (<20,000/ul)
Drug induced Thrombocytopenia
Immune Thrombocytopenia
Post-Transfusion Purpura
Diagnostic Clues to Thrombocytopenia
CLINICAL SETTING
Cardiac Surgery
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
Diagnostic Clues to Coagulation Defects
CLINICAL SETTING
Cardiac Surgery
Sepsis Syndrome
Recent use of Quinine, Second or Third
generation cephalosporin
Post-surgery
Pregnancy
DIFFERENTIAL DIAGNOSES
Factor V inhibitor, heparin excess or rebound,
protamine excess, fibrinolysis
Isolated factor VII deficiency, DIC, vitamin K
deficiency,
Drug induced Hemolysis/DIC syndrome
Dilutional, DIC, thrombin inhibitors
HELLP syndrome, fatty liver of pregnancy, vitamin
K deficiency
Acute Liver failure
Consumption, DIC, fibrinolysis, vitamin K
deficiency (biliary obstruction)
DIC = disseminated intravascular coagulation, HELLP = Hemolysis
IMMEDIATE THERAPY - TRANSFUSION THERAPY
The Five Basic Coag Tests:
1. Hematocrit
2. Platelet count
3. Prothrombin time
4. Activated partial thromboplastin time
5. Fibrinogen level
Management of Coagulation Defects
A. Platelets <50-75,000/ul in a bleeding patient or <10,000/ul in a stable patient: Give Platelet
Concentrates or 6-8 Pack of Single Donor Platelets.
B. Fibrinogen <125mg/dl: Give 10 Units of Cryoprecipitate
C. Hematocrit below 30% in a bleeding patient: Give Red Cells
D. Protime >INR 2.0 and aPTT >1.3x control: Give 2-4 Units of FFP.
Massive Transfusions
Massively transfusion is defined as one who receives greater transfused blood than one blood volume in
24 hours or more practically defined as receiving one blood volume in two hours or less.
Coagulation defects are common in the massively transfused patients due to dilution or underlying
medical or surgical conditions.
Cannot predict the degree of coagulopathy from the amount of blood transfused - need lab testing!
Two common problems:
1) Isolated elevations of the PT/INR
* Factor VII labile
* If aPTT normal should not effect coagulation
2) Greatly prolonged INR
* Low fibrinogen
* heparin contamination
Correcting Coagulation Defects before Procedures
Risk correlated more with skill of operator than coag defects
Elective procedures:
Platelets 20-30,000/ul
aPTT < 1.5 times normal
Emergency: most skilled person to do procedures
When to use rVIIa in Massive Transfusion
 Determine that the patient has a survivable injury
 Attempt to correct coagulation defects with use of blood products as outlined in the transfusion
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
* Shorten euglobulin clot lysis time
Therapy: Use antifibrinolytic agents if no DIC or significant hematuria
* Epsilon-aminocaproic acid: bolus of 4-5 grams given over 1 hour followed by a continuous infusion 1
gram/hour for 8 hours. Oral dosing 4 grams every four hours.
* Tranexamic acid 10mg/kg IV bolus followed either by 10mg/kg IV every 6 to 8 hours or 25mg/kg every 6
to 8 hours orally.
Vitamin K Deficiency
Vitamin K deficiency can present dramatically.
Antibiotics affect vitamin K metabolism by two mechanisms.
1) Sterilizing the gut
2) Certain cephalosporins that contain the N-methylthiotetrazole (NMTT) group can inhibit vitamin K
epoxide reductase (cefamandole, cefoperazone, cefotetan, cefmenoxime and cefmetazole)
* Use of prophylactic vitamin K, 10mg weekly, during chronic antibiotic administration.
Treatment (and a diagnostic test of vitamin K deficiency): replacement of vitamin K.
* 10 mg po
* 5-10 mg slow IV push for severe bleeding + plasma
Therapy of the Bleeding Patient on Warfarin
Key point about vitamin K
* sub-Q erratic and should NOT be used
* PO effective in most patients
* IV should be given slowly (over one hour)
* A little goes a long way - the RDA is 80 ug/day
Not Bleeding:
INR
3-3.45
4.5-10
> 10
Should see INR back in therapeutic range in 24 hours
Action
Hold dose until INR decreased
1 mg Vitamin K PO
2.5 -5 mg Vitamin K PO
Bleeding
INR
Action
2-4.5
4.5-10
>10
5Consider Intravenous route for Vitamin K if faster effect desired
Intracranial Hemorrhage:
Prothrombin Complex Concentrates:
● 3- factor concentrates – 4000 units plus 1mg rVIIa
● 4-factor concentrates - 4000 units or 50 units/kg
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
Transfusions
Clopidogrel
Prasugrel
8 hours
7 hours
Metabolites renally
DDAVP(?), platelet
cleared
transfusions
Metabolites renally
DDAVP(?), platelet
cleared
transfusions
Abciximab
30 minutes
No change
Platelet Transfusion
Tirofiban
2 hours
Decrease dose by 50%
Platelet transfusions,
if ClCr < 30 ml/min
DDAVP,
cryoprecipitate, dialysis
Eptifibatide
2-3 hours
Decrease dose by 50%
Platelet transfusions,
if ClCr < 30 ml/min
DDAVP,
cryoprecipitate, dialysis
Unfractionated Heparin
30-150 minutes
45-225
Protamine - se table
Low Molecular Weight
2-8 hours
4-16 hours
Protamine
17-21 hours
Clearance decreased
rVIIa
Heparin
Fondaparinux
by 50% if ClCr < 30
ml/min
Idraparinux
72 hours
Clearance decrease in
rVIIa
renal insufficiency
Argatroban
40 minutes
No change
APCC
Bivalirudin
25 minutes
60% dose reduction if
APCC
ClCr < 30 ml/min
Dabigatran
8 hours
Avoid if ClCr < 30
APCC
ml/min
Lepirudin
40 minutes
t1/2 in renal failure
APCC, dialysis
ranges from 18-300
hours
Warfarin
36 hours
50% reduction in CYP
vitamin K, FFP, PCC,
C2P9
rVIIa
BAY 59-7939
8 hours
renally cleared
rVIIa?
Dx-9065a
25 minutes
renally cleared
rVIIa?
Hepatically cleared
Plasma, platelet,
Streptokinase
cryoprecipitate
tPA
3 minutes
Hepatically cleared
Plasma, platelet,
cryoprecipitate
Reteplase
13-16 minutes
Hepatically cleared
Plasma, platelet,
cryoprecipitate
Tenecteplase
15-20 minutes
Hepatically cleared
Plasma, platelet,
cryoprecipitate
APCC = active prothrombin complex concentrates, PCC = prothrombin complex concentrates, FFP =
fresh frozen plasma, rVIIa = recombinant active factor VII
Critical Illness and Pregnancy
Three syndromes in the critically ill pregnant woman who presents with coagulation defects.
1) HELLP (Hemolysis, Elevated Liver tests, Low Platelets)
* Variant of pre-eclampsia
* High LDH, schistocytes, DIC
* Responds to delivery of child
* Severe cases may require plasma exchange
2) Fatty liver of pregnancy
* Severe coagulation defects and liver failure
* Responds to delivery of child
3) TTP
* Occurs most often in 2nd trimester
* Can support mother through pregnancy with plasma exchange
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
* Scoring system (below) may help pre-test probability for HIT
Laboratory testing:
* Platelet activation assays - sensitive and specific but technically difficult and not always available
* Anti-PF4 ELISA – new assay sensitive but not specific especially in cardiac and vascular surgery
patients.
Testing most useful for patients with multiple causes for their thrombocytopenia and low to moderate
pretest probability for HIT
Therapy
The first step in therapy of HIT consists of stopping all heparin. Given high rate of thrombosis all patients
with HIT should receive antithrombotic therapy. LMWH CANNOT be used due to cross-reactivity. Of
agents available best choice for ICU patients is argatroban.
Argatroban: Direct thrombin inhibitor. Hepatically cleared. Dose at 2 ug/kg/min infusion with dose
adjustments to keep aPTT 1.5 - 3 times normal. No dose adjustment for renal disease but for severe liver
disease dose is 0.5 ug/kg/min. Also for patients with MOSF use 1ug/kg/min. Will also raise INR to 2-4.
Lepirudin: Direct thrombin inhibitor – renal cleared. Less bleeding with following dosing
schedule”
Therapy: bolus of 0.4 Mg/kg followed by 0.15 Mg/kg/hour to maintain an aPTT of 1.5-3.0 times normal.
For creatine of 1.6-2.0 mg/dl: bolus of 0.2 mg/kg followed by a 50% reduction in infusion rate.
For creatine of 2.0-2.5: bolus of 0.2 mg/kg followed by a 75% reduction in infusion rate.
For creatine of 2.6-6.0:bolus of 0.2 mg/kg followed by a 90% reduction in infusion rate.
For creatine of greater than 6.0 mg/ml: Bolus of o.1 mg/kg on alternate days only when the aPTT is less
than 1.5 times normal and no infusion.
Fondaparinux:
Increasing use for HIT – has long half-life and renal clearance
Prophylactic: 2.5 mg/day
Therapeutic: 7.5 mg/day (< 50 kg - 5.0, > 100 kg - 10mg/day)
Suggested HIT Scoring system
Points
2
1
0
Thrombocytopenia
>50% fall or nadir 20100,000/ul
30-50% fall or nadir
10-19,000/ul
Fall < 30% or
nadir <10,000/ul
Timing of platelet fall
Onset day 5-10 of
heparin or < 1 day if
patient recently exposed
to heparin
Consistent but not
clear records or
count falls after day
10
Platelets falls <
5 days and no
recent (100
days) heparin
Thrombosis
New thrombosis or skin
necrosis or systemic
reaction with heparin
Progressive or
recurrent thrombosis
or suspected but not
proven thrombosis
None
oTher cause for
thrombocytopenia
No
Possible
Definite
Pretest Score 6-8=high, 4-5 intermediate, 0-3 low
Warkentin, Heddle Current Hematology Reports 2:148 2003
If HIT score is >6 or
Patient has documented new thrombosis on heparin or
Platelets fall by over 50% for no other reason than heparin exposure
Then stop heparin and substitute argatroban or other agent
If HIT score is 4-5 than obtain HIT test. If test positive then stop heparin and substitute argatroban
If HIT score is 0-3 consider not testing for HIT
Thrombotic Thrombocytopenic Purpura
TTP should be suspected when any patient presents with any combination of renal insufficiency,
thrombocytopenia, and central nervous system symptoms.
There is currently no diagnostic test for TTP - diagnosis is based on the clinical presentation. TTP should
be considered in any patients who presents with multi-system illness and thrombocytopenia.
* Microangiopathic hemolytic anemia - schistocytes on the blood smear
* Thrombocytopenia - usually 20-60,000/ul range
* Renal insufficiency - often mild, frank renal failure rare. UA usually abnormal with red cells and
proteinuria
* Fevers - seen in less than half of TTP
* Mental status changes - can range from confusion to coma. Seizures can also be seen.
* Pulmonary - patients can infiltrates and hypoxia
* Cardiac - coronary microthrombi common - can lead to ischemia and dysrhythmia's
* GI - pancreatitis is a common complication.
One helpful clue is the presence of a raised LDH. LDH levels are often over 2 times normal in TTP and
on fractionation is from all isoenzymes representing widespread tissue damage
Although inhibitors to ADAMTS13 are responsible for many if not most cases of TTP, rapid assays are not
clinical available so the diagnosis remains clinical.
Therapy:
Untreated TTP is rapidly fatal. Mortality in the pre-plasma exchange era ranged from 95-100%.
Today plasma exchange therapy is the cornerstone of TTP treatment and has reduced mortality to less
than 20%.
** Plasma exchange (1-1.5 plasma volumes) is essential and has been shown to be superiors to simple
plasma infusion. Patients should get 5 days of therapy and then exchange is tapered based on LDH and
platelet counts. If there is delay in plasma exchange plasma (units/4-6 hours) should be given.
* Glucocorticosteroid therapy, equivalent to 60-120 mg of prednisone is often used.
* Platelet transfusions are contraindicated in most patients with TTP and in most patients there is little
justification for platelet transfusion.
* For patients not responding rapidly to therapy vincristine 1 mg/meter squared days 1, 4, 7, 10 can be
tried.
* Increasing reports that rituximab may be effective in recalcitrant TTP but dosing and timing is uncertain.
The role for plasma therapy in adults who present with "classic" post-diarrhea HUS is less certain
but experience suggests that plasma exchange may also be of benefit. These patients do seem to have a
higher risk of long-term renal damage. Patients suffering extra-renal problems such as pancreatitis or
neurologic syndromes should receive aggressive plasma exchange.
Therapy Related TTP/HUS
TTP/HUS syndromes can complicate a variety of therapies including:
* Cyclosporine/FK506: TTP/HUS occurs within days after the agent is started with the appearance of a
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
* Adult respiratory distress syndrome (often with pulmonary hemorrhage)
* Cardiac failure
* Dramatic livido reticularis
* Thrombocytopenia.
Diagnosis is clinical - patients have high titer antiphospholipid antibodies. Biopsy demonstrates bland
thrombi
Therapy: Plasmapheresis with monthly bolus cyclophosphamide (1 gram/m2)
Post-Transfusion Purpura (PTP)
* Onset of severe thrombocytopenia (<10,000/ul)one to two weeks after receiving blood products.
* Occurs in patients who lack common platelet antigens such as PLA1.
* Diagnostic clue is thrombocytopenia in a patient, typical female, who has recently received a red cell or
platelet blood product in the past 7-10 days.
* Treatment: Intravenous immunoglobulin.
Cardiac By-pass
Cardiac bypass results in very complex and still poorly defined defects in all aspects of hemostasis.
* Activation of both the contact coagulation system and the tissue factor pathway.
* Platelets activation -excessive activation of platelets depletes their granules leading to the circulation of
"spent platelets"
* Platelet function is also inhibited by loss of their key receptors, GP Ib and GP IIb/IIIa.
* Activation of the fibrinolytic system both via the contact pathway and by release of endothelial tPA due to
the stress of surgery and hypothermia.
Operative bleeding
* Check the 5 basic coag tests
* If patient still on bypass, an infusion of desmopressin is indicated.
Postoperative bleeding
* In the immediate postoperative state a thrombin time should be checked to insure the patient is not
experiencing "heparin rebound".
* Ensure surgical hemostasis achieved.
* Check the 5 basic coag tests
* If bleeding persist and INR/aPTT/fibrinogen normal empirically transfuse platelets.
Uremia
*Life threatening bleeding is uncommon but dialysis patients have a high incidence of gastrointestinal
bleeding and subdural hematomas
* Defect in uremia appears to be a platelet function defect.
Uremic patients who are bleeding
* Basic 5 coag tests performed. Patients are prone to vitamin K deficiency.
* Heparin level - The half-life of both unfractionated and low molecular weight heparin is increased in renal
failure.
* Little utility in measuring bleeding time or platelet function tests
Therapy
ACUTE
Agressive dialysis
Desmopressin (DDAVP) 0.3 Ug/kg IV
Cryoprecipitate 10 units
LONG TERM
Congegated Estrogen 0.6 Mg/kg for five days
Erythropoietin to increase hematocrit > 30%
Table 1: Drugs and Hemostasis
Action
Increasing activity of warfarin
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*
Decrease activity of warfarin
Alcohol
Barbiturates*
Carbamazepine
Corticosteroids
Phenytoin (May Potentiate Warfarin with Initiation
of Drug)
Cholestyramine
Dicloxacillin
Estrogens
Griseofulvin
Nafcillin
Rifampin
Sucralfate
Vitamin K
Increase Prothrombin Time
N-methylthiotetrazole (NMTT) group contain
antibiotics: cefamandole, cefoperazone, cefotetan,
cefmenoxime and cefmetazole
TTP/HUS
Mitomycin C, Cyclosporine, FK 506, carbo- or cisplatinum, ticlopidine, clopidogrel
Hemolysis/DIC syndrome
Quinine, 2nd and 3rd Generation Cephlosporins
Thrombocytopenia
See Table 10
(*= Major Effect, Bold = Strongest Evidence for Effect)
Table 2: Common Critical Care Drugs Implicated in Thrombocytopenia
Anti-arrymthics
Procainamide
Quinidine
Anti GP IIb/IIIa agents
Abciximab
Eptifibatide
Tirofiban
Antimicrobial
Amphotericin B
Linazolid
Rifampin
Trimethoprim-sulfamethoxzole
Vancomycin
H2-blockers
Cimetidine
Ranitidine
Acetaminophen
Amirone
Carbanzepine
Gold
Heparin
Hydrochlorothiazide
Non-steroidal antiinflammatory agents
Quinine
Detailed references can be found in:
DeLoughery TG. Thrombocytopenia in the Intensive Care Unit. Journal of Intensive Care Medicine.
17:267-282, 2002
Deloughery, TG. Bleeding and Thrombosis in Critical Ill Patients. in Consultative Hemostasis and
Thrombosis. Kitchens Cs, Alving BM, and Kessler C. ed. W.B. Sanders. Chapter 32 pp 493-514. 2003
DeLoughery TG. Critical care clotting catastrophes. Crit Care Clin. 2005 Jul;21(3):531-62.
DeLoughery TG. Venous thromboembolism in the ICU and reversal of bleeding on anticoagulants.
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