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DeLoughery, MD FACP
Professor of Medicine, Pathology, and Pediatrics
Oregon Health Sciences University
Portland, Oregon
delought@ohsu.edu
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
Thrombocytopenia
Differential Diagnosis of Thrombocytopenia
Diagnostic Clues to Coagulation Defects
CLINICAL SETTING DIFFERENTIAL DIAGNOSES
Cardiac Surgery Factor V inhibitor, heparin excess or rebound,
protamine excess, fibrinolysis
Sepsis Syndrome Isolated factor VII deficiency, DIC, vitamin K
deficiency,
Recent use of Quinine, Second or Third Drug induced Hemolysis/DIC syndrome
generation cephalosporin
Post-surgery Dilutional, DIC, thrombin inhibitors
Pregnancy 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
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!
COAGULATION DEFECTS
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
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
Not Bleeding:
INR Action
3-3.45 Hold dose until INR decreased
4.5-10 1 mg Vitamin K PO
> 10 2.5 -5 mg Vitamin K PO
Should see INR back in therapeutic range in 24 hours
Bleeding
INR Action
2-4.5 2.5 mg Vitamin K FFP
4.5-10 5 mg Vitamin K FFP
>10 5-10 mg Vitamin K FFP
Consider 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
APCC = active prothrombin complex concentrates, PCC = prothrombin complex concentrates, FFP =
fresh frozen plasma, rVIIa = recombinant active factor VII
Pregnancy Related Diseases -TTP/HUS, HELLP Syndrome, and Acute Fatty Liver of Pregnancy
(FLP)
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%.
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)
Points 2 1 0
Thrombocytopenia >50% fall or nadir 20- 30-50% fall or nadir Fall < 30% or
100,000/ul 10-19,000/ul nadir <10,000/ul
Timing of platelet fall Onset day 5-10 of Consistent but not Platelets falls <
heparin or < 1 day if clear records or 5 days and no
patient recently exposed count falls after day recent (100
to heparin 10 days) heparin
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
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.
* 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.
HUS-type syndrome seen up to 28 weeks post-partum which is severe, and permanent renal failure often
results despite aggressive therapy.
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.
Diagnosis is clinical - patients have high titer antiphospholipid antibodies. Biopsy demonstrates bland
thrombi
Therapy: Plasmapheresis with monthly bolus cyclophosphamide (1 gram/m2)
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.
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 Drug
Increasing activity of warfarin 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*
Anti-arrymthics
Procainamide
Quinidine
Antimicrobial
Amphotericin B
Linazolid
Rifampin
Trimethoprim-sulfamethoxzole
Vancomycin
H2-blockers
Cimetidine
Ranitidine
Acetaminophen
Amirone
Carbanzepine
Gold
Heparin
Hydrochlorothiazide
Non-steroidal antiinflammatory agents
Quinine