Transcript Thrombocytopenia

Hematology in the ICU
Jonathan Bleeker, M.D.
Sanford Health
12 January 2015
Objectives
• Discuss etiology/management of
thrombocytopenias in ICU
• Discuss etiology/management of
coagulapathies in ICU
• Discuss blood product administration in the
ICU
Thrombocytopenia in the ICU
• Approximately 40% of ICU patients are
admitted with or develop thrombocytopenia
– 10-20% develop severe thrombocytopenia (<50K)
• Causes of thrombocytopenia in the ICU
Thrombocytopenia in the ICU
• Pseudothrombocytopenia
– Clotting in the tube, EDTA-associated platelet clumping
Thrombocytopenia in the ICU
• Pseudothrombocytopenia
• Hemodilution
– IVF and PRBC
• 10 units PRBC can decrease platelets by 50%
Thrombocytopenia in the ICU
• Pseudothrombocytopenia
• Hemodilution
• Increased consumption
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Bleeding
Sepsis
Disseminated intravascular coagulation (DIC)
Thrombotic thrombocytopenic purpura (TTP/HUS)
Intravascular devices (balloon pump, VAD, etc.)
Large thrombotic burden
Thrombocytopenia in the ICU
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Pseudothrombocytopenia
Hemodilution
Increased consumption
Increased destruction
– Heparin induced thrombocytopenia (HIT)
– Immune thrombocytopenic purpura (ITP)
– Some drug-dependent thrombocytopenias
Thrombocytopenia in the ICU
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Pseudothrombocytopenia
Hemodilution
Increased consumption
Increased destruction
Decreased production
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Drug impact on bone marrow (chemotherapy, alcohol, etc)
Severe infection
Malignancy (both hematologic and solid tumor)
Nutritional deficiencies
Thrombocytopenia in the ICU
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Pseudothrombocytopenia
Hemodilution
Increased consumption
Increased destruction
Decreased production
Platelet sequestration
– Hypersplenism
Thrombocytopenia in the ICU
• Management
– For most—treat the underlying cause
• Infection, cancer, thrombosis
• Withdrawal of offending agents
– Specific causes
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ITP
TTP/HUS
DIC
HIT
ITP
• Mechanism
• Not completely understood—often postviral in children
Cines, et al. NEJM. 2002;346(13):995-1008
ITP
• Clinical presentation
– Thrombocytopenia (often severe--<10K)
– Petechiae/purpura
– Mucosal bleeding (nose, oral cavity, vaginal, GI, CNS)
• Only 1.5% of patients present with significant bleeding1
• Diagnosis
– Diagnosis of exclusion
– Rule out TTP/HUS, DIC, medications (HIT), HIV/Hep C
– Do NOT need a bone marrow biopsy to make initial diagnosis
1Moulis,
et al. Blood. 2014;124(22):3308-3315
ITP
• Treatment
– Decrease clearance of platelets
• Steroids, IVIG, splenectomy
– Decrease antibody production
• Rituxmab, steroids, immunosuppressives
– Increase platelet production
• Thrombopoietin agonists (romiplastim, eltrombopag)
Cines, et al. NEJM. 2002;346(13):995-1008
Thrombocytopenia in the ICU
• Management
– For most—treat the underlying cause
• Infection, cancer, thrombosis
• Withdrawal of offending agents
– Specific causes
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ITP
TTP/HUS
DIC
HIT
Thrombocytopenia in the ICU
• TTP
– Mechanism
• Interaction between von Willebrands factor, platelets and vessel
wall
Mechanism of TTP
Tsai, et al. Kidney International (2006) 70, 16–23
Mechanism of TTP
• TTP
– Mechanism
• Interaction between von Willebrands factor, platelets and vessel
wall
• Leads to microangiopathic hemolytic anemia
http://www.immunopaedia.org.za/index.php?id=685
Mechanism of TTP
ASH image bank. Accessed at
http://imagebank.hematology.org/AssetDetail.aspx?AssetID=4049
TTP
• Clinical presentation
– Fever
• Rare
– Anemia (microangiopathic hemolytic anemia)
• Schistocytes crucial to diagnosis
– Thrombocytopenia
• Usually severe (mean 25,000 in one series)1
– Renal dysfunction
• 70-80% with some evidence of renal dysfunction2
– Neurologic dysfunction
• Ranges from mild headaches to obtundation
1Rock,
et al. Br J Haematol. 1998;103(4):1031.
et al. Am J Nephrol. 1986;6(2):117-31.
2 Eknoyan,
TTP
• Diagnosis
– Working diagnosis
• MAHA and thrombocytopenia without other cause (DIC)
– Confirmation
• ADAMTS13 testing
– Typically less than <10% in antibody mediated TTP
– Greater than >50%--need to evaluate as to potential other causes
TTP
• Treatment
– Plasmapheresis
• Removes anti-ADAMTS13 antibodies
• Replacement plasma contains ADAMTS13
– Plasma infusion
• Does not remove antibodies, but does provide ADAMTS13
– Steroids/rituximab
• Decrease antibody production
http://www.immunopaedia.org.za/index.php?id=685
TTP
• Initial treatment
– PLEX +/- steroids
• Continue daily PLEX until platelets and LDH are normal x 2 days
• Steroid taper starts 1-2 weeks after normalization
• Monitor closely for recurrence
Thrombocytopenia in the ICU
• DIC
– Mechanism
• Excessive activation of
coagulation cascade
• Eventual consumption
of clotting factors
• Fibrin forms
• Decreased fibrinogen
• MAHA
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Microvascular thrombi
Platelet consumption
• Fibrinolysis
• Increased FDP
DIC
• Clinical presentation1
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1Siegal,
Bleeding (64%)
Renal dysfunction (25%)
Liver dysfunction (19%)
Respiratory dysfunction (16%)
Shock (14%)
Thromboembolism (7%)
Central nervous system involvement (2%)
et al. Thromb Haemost. 1978;39(1):122.
DIC
• Diagnosis
– Working diagnosis
• MAHA and coagulopathy (unlike TTP)
• Management
– TREAT THE UNDERLYING PROCESS
– Bleeding
• Maintain platelets >20K (50K with bleeding)
• Maintain fibrinogen >100
• FFP as needed if aPTT prolonged and bleeding
– Thrombosis
• ? Role of heparin
• ? Role of antithrombin
HIT
• Mechanism
Kelton, et al. Blood. 2008; 113(17):2607-2615
HIT
• Risk factors
– Type of heparin used
• UFH: 2.6% v LMWH: 0.2% in surgical population1
– Dose of heparin used
• Therapeutic: 0.76% v prophylactic <0.1%2
– Gender
• Women > Men
– Surgical v. Medical patient
• Surgical > Medical
1Martel,
et al. Blood. 2005;106(8):2710.
2Smythe, et al. Chest. 2007;131(6):1644.
HIT
• Relatively rare cause of thrombocytopenia in ICU
– 9.4% of 524 ICU patients had significant thrombocytopenia
while on heparin
– Only 2 of these patients (0.4%) actually had HIT
– How can we sort this out?
– When should we suspect HIT?
Crowther, et al. J Crit Care (2010) 25, 287–293.
HIT
• Clinical manifestations
– Thrombocytopenia
• >50% drop in platelets
• Typically not below 20,000 (thus, bleeding is unusual)
– Timing
• Typically 5-10 days after heparin exposure
– Thrombosis
• 25-50% of patients with HIT have thrombosis
HIT
• 67 year old female with prosthetic aortic valve
admitted with fever 3 weeks after hip
replacement
– Platelet counts
• 3 weeks ago: 145,000
• Admission: 154,000
• Day after admission: 56,000
– Medication review
• Aspirin, heparin gtt, TMP/SMX, omeprazole,
Pipercillin/Tazobactam, lamotrigine, phenytoin
– Exam: Unremarkable
Lo, et al. J Thromb Haemost. 2006;4(4):759.
Could this be HIT?
Low prob (0-3): 1% risk of HIT
Int prob (4-5): 11.4% risk of HIT
High prob (6-8): 34% risk of HIT
Lo, et al. J Thromb Haemost. 2006;4(4):759.
HIT
• Clinical diagnosis
– 4T score—does is work in the ICU?1
• 50 patients investigated for HIT
• 39/50 had a low (0-3) 4T score
– None were confirmed to have HIT
• 11/50 had moderate or high 4T score
– 2/11 had HIT
– OK, so a patient has a mod/high 4T score….
1Crowther,
et al. J Crit Care (2010) 25, 287–293.
OK…what test(s) do we order now?
• Heparin-PF4 antibody
• Pros: Quick, cheap, high sensitivity (>90%)
• Cons: Low specificity (75-85%)
• Seratonin release assay
• Pros: High sensitivity and specificity (95+%)
• Cons: Expense, availability, timing
• Practical summary
– Start with Hep-PF4 ab: If negative, believe it. If positive
and high risk, believe it. If questionable clinical scenario,
send SRA to confirm.
Treatment of HIT
• Immediate discontinuation of ALL heparin products
• Start alternative anticoagulant
– Argatroban (do not choose in liver dysfunction)
– Bivalirudin (do not choose in renal dysfunction)
– Fondiparinux
• Pentasaccharide which binds to heparin’s binding site
on antithrombin
• Does not appear to stimulate Hep-PF4 ab production
Treatment of HIT
• Continue alternative anticoagulant alone until…
– Platelets reach normal range
– Then, warfarin can be started and combined therapy
continued until INR therapeutic
• Starting earlier increases risk of warfarin skin necrosis
Deciperhing thrombocytopenias
Plts Hgb Schistos PT/aPTT
ITP
Nl
No
Nl
HIT
Nl
No
Nl
TTP
Nl/
Yes
Nl
DIC
Nl/
Yes
Objectives
• Discuss etiology/management of
thrombocytopenias in ICU
• Discuss etiology/management of
coagulapathies in ICU
• Discuss blood product administration in the
ICU
Coagulopathy in the ICU
Coagulopathy in the ICU
Prolonged PT
Warfarin effect
Other anticoagulants
FVII deficiency/inhibitor
Mild vit K deficiency
Liver disease
Coagulopathy in the ICU
Prolonged aPTT
FVIII deficiency/inhibitor
FIX deficiency inhibitor
Factor XI deficiency
Heparin
Argatroban/dabigatran
Lupus inhibitor
Coagulopathy in the ICU
Both prolonged
Deficiencies of II, V, X, fibrinogen
Xa inhibitors (rivaroxban)
DIC
Supratherapeutic anticoagulation
Heparin + Warfarin
Liver disease
Coagulopathy in the ICU
• Liver disease
• Anticoagulant reversal
– Warfarin
– Direct thrombin inhibitors (dabigatran)
– Xa inhibitors (rivaroxaban)
Coagulopathy in the ICU
• Liver disease
– Coagulation tests are not an accurate predictor of bleeding
risk in patients with liver disease
– Procoagulant proteins made in liver
• Factors II, V, VII, IX, X, XI, XII
• Reflected in PT, aPTT, etc
– Anticoagulant proteins made in liver
• Protein C, protein S, antithrombin, plasminogen
• Not terribly well reflected in any of our standard testing
Coagulopathy in the ICU
• Don’t chase abnormal coags with FFP in a cirrhotic pt
– Coags are not an accurate measure of actual bleeding risk
– “Chasing” coags with FFP does not work1
• 80 patients—got 2-6 units of FFP
• Only 12.5% got PT to within 3 seconds of normal
– Enormous volumes of FFP would be required
• Recommended FFP dose to correct PT is 10-15 ml/kg
• Average pt=1200 mL FFP (6 units)
– FFP won’t last that long anyway…
• Half life of factor VII FFP is 4-8 hours
1Youssef,
et al. Am J Gastroenterol. 2003;98(6):1391.
Coagulopathy in the ICU
• Liver disease
• Anticoagulant reversal
– Warfarin
– Direct thrombin inhibitors (dabigatran)
– Xa inhibitors (rivaroxaban)
Anticoagulant reversal
• Warfarin
– Inhibits vitamin K dependent “activation” of multiple
clotting factors (II, VII, IX, X)
– Reversal
• Factor replacement
– FFP
» Effective, but a lot of volume and relatively low factor concentrations
– Unactivated prothrombin complex concentrates (PCC)
» Contain factors II, VII (some), IX, X
» Lower volume than FFP, given much faster
• Vitamin K—allows for re-“activation” of these clotting factors
– Non-life threatening bleeding—Oral=IV >SQ routes
– Life threatening bleeding—recommend IV route
Anticoagulant reversal
• Warfarin
– No bleeding
• INR <5—hold warfarin and change dose
• INR 5-10—hold warfarin, change dose and consider low dose vit K
• INR >10—hold warfarin, vit K and change dose
– Major bleeding
• PCC +/- FFP or rFVIIa
– PCC dosing: 30-50 IU/kg
– FFP: 1-2 units to ensure FVII administered (rFVIIa an
alternative)
• Vit K: 10 mg IV
Anticoagulant reversal
• Direct thrombin inhibitors (dabigatran)
Hankey G J , et al. Circulation. 2011;123:1436-1450
Anticoagulant reversal
• Direct thrombin inhibitors (dabigatran)
– No specific antidote
– Activated PCC (FEIBA)
• Rapid onset hemostasis, short duration of action, high clot risk
– Unactivated PCC
– Antifibrinolytics to prevent clot breakdown
– Activated charcoal to prevent absorption
– Drug is dialyzable
Anticoagulant reversal
• Xa inhibitors (Rivaroxaban)
Hankey G J , et al. Circulation. 2011;123:1436-1450
Anticoagulant reversal
• Xa inhibitors (Rivaroxaban)
– No specific antidote
– Unactivated PCC
– Antifibrinolytics to prevent clot breakdown
– Activated charcoal to prevent further absorption
– Drug is not dialyzable
Objectives
• Discuss etiology/management of
thrombocytopenias in ICU
• Discuss etiology/management of
coagulapathies in ICU
• Discuss blood product administration in the
ICU
Blood products in the ICU
• PRBC
• Platelets
• FFP
• Cryoprecipitate
Blood products in the ICU
• Indications for PRBC
– Hemorrhagic shock
– Bleeding with evidence of hypoperfusion
– Hemoglobin <7 g/dl
• Response
– 1 unit PRBC should raise HCT 3% and Hgb 1 g/dL
Blood products in the ICU
• Indications for platelets
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Any clinically significant active bleeding
Plts <10,000 if no bleeding or procedures
Plts <50,000 if procedure planned
Plts <100,000 if neurosurgical procedure planned
• Platelet preparations
– “6 pack”—pooled from 6 different donors
– “Apheresis”—single donor platelets
Blood products in the ICU
• Expected response
– Platelets should increase 10-30K with a 6 pack of plts or
apheresis unit
– Why won’t the platelets go up?
• Consumption due to illness vs. alloantibodies
• Draw a 1 hour post infusion platelet level and if…
– Platelets bump and then drop, they are being consumed (sepsis, DIC, etc)
– Platelets do not bump, due to alloantibodies
• Consider single donor platelets or ABO matched platelets if
concerned for alloantibodies
Blood products in the ICU
• Indications for FFP
– Reversal of factor deficiencies
• Including those due to anticoagulants
– Degree of impact based on severity of factor deficiency
• Indications for cryoprecipitate
– Replace fibrinogen
• Goal fibrinogen often >100 in DIC, etc.
– Given in “10 packs”
• 10 pack of cryoprecipitate should raise fibrinogen 60-80 mg/dL
Hematology in the ICU
QUESTIONS?