assessing thrombocytopenia in the intensive care unit · assessing thrombocytopenia in the...
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Assessing thrombocytopenia in the intensive care unit:
The past, present, and future
Ryan Zarychanski MD MSc FRCPC
Sections of Critical Care and of Hematology,
University of Manitoba
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Disclosures
FINANCIAL DISCLOSURE RELEVANT TO THIS PRESENTATION:
Grants/Research Support: None
Speaker bureau/Honoraria: None
Consulting fees: None
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Objectives
1. Characterize the multiple mechanisms that can contribute to thrombocytopenia in the ICU
2. Evaluate the trajectory of the patient’s platelet count and apply this information to establish a diagnosis and inform prognosis
3. Transfuse platelets appropriately to prevent and manage bleeding in thrombocytopenic patients admitted to the ICU
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Epidemiology of thrombocytopenia in ICU
• Prevalence at ICU admission ranges from 8% to 68%
• Incidence of developing thrombocytopenia in the ICU ranges from 14% to 44%
• Variability reflect variation in patient population, ICU characteristics, and the definition of thrombocytopenia
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Epidemiology of thrombocytopenia in ICU
• PROTECT Trial (n = 3,639)
– Prevalence of thrombocytopenia 26.2% (952 patients)
– Incidence of Thrombocytopenia
• Mild (100–149 × 109/L) 15.3% (417 patients)
• Moderate (50–99 × 109/L) 5.1% (140 patients)
• Severe (< 50 × 109/L) 1.6% (44 patients)
Williamson DR et al. Thrombocytopenia in critically ill patients receiving thromboprophylaxis: frequency, risk factors, and outcomes. Chest. 2013;144(4):1207-1215.
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Risk factors for thrombocytopenia in ICU
• Risk factors commonly associated with ICU-acquired thrombocytopenia (multivariate analyses)
– Severity of illness
– Organ dysfunction
– Sepsis
– Vasopressor use
– Renal failure.
Williamson DR et al. Thrombocytopenia in critically ill patients receiving thromboprophylaxis: frequency, risk factors, and outcomes. Chest. 2013;144(4):1207-1215.
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Consequences of thrombocytopenia in ICU
• Bleeding and Transfusion
– PROTECT
• Any thrombocytopenia associated with major hemorrhage and transfusion of RBCs, PLTs, FFP, or cryoprecipitate
– Observational studies
• Thrombocytopenia (incident or prevalent) is associated with bleeding and transfusion
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Consequences of thrombocytopenia in ICU
• Mortality
– PROTECT
• Severe thrombocytopenia associated with increased ICU and hospital mortality (1.6% of patients)
– Observational studies
• 6/8 observational studies thombocytopenia was found to independently predict mortality
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Thrombocytopenia as a marker of illness
• Thrombocytopenia also associated with:
– Increased ICU and hospital LOS
– Need for organ support
• Blunted recovery predicts death
• Deaths are not typically due to bleeding
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Causes
• Common
• Uncommon
• Rare
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Causes
• Common
– Sepsis
– Disseminated intravascular coagulation
– Consumption (eg major trauma, cardiopulmonary bypass)
– Dilution (with massive transfusion)
– Myelosuppressive chemotherapy
– Mechanical circulatory support
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Causes
• Uncommon
– Heparin-induced thrombocytopenia
– Hemophagocytic syndrome
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Causes
• Rare
– Drug-induced thrombocytopenia (other than heparin or cytotoxic chemotherapy)
– Leukemia, myelodysplasia, aplastic anemia, etc, unless abnormalities were already present before ICU admission
– Thrombotic thrombocytopenic purpura
– Immune/idiopathic thrombocytopenia
– Post-transfusion purpura
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Mechanisms
• Poorly understood
• May have multiple possible causes
• Tools to distinguish between them are limited
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Mechanisms
• Decreased Production– Note** Inflammatory cytokines stimulate thrombopoiesis
– Unlikely to be the dominant factor
• Exceptions include preexisting marrow disease or cytotoxic chemotherapy.
• Sequestration– Only if preexisting (eg, liver disease with portal hypertension)
– May contribute to the severity of thrombocytopenia and reduce post-transfusion platelet increments
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Mechanisms
• Destruction and/or Consumption
– Explains the bulk of thrombocytopenia in the ICU
– Thrombin
– Antibodies
– Hemophagocytosis
– Histones
– ADAMTS13 depletion
– Complement activation
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Thrombocytopenia in Sepsis
Sepsis• 10% of ICU admissions• 50% of TCP in ICU
• Thrombocytopenia may modify the host immune response to Infection
• Consideration mechanisms suggests directions for therapeutic trials.
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Thrombocytopenia in Sepsis
• Retrospective cohort study of septic shock (n = 980; APACHE II = 25)
• Prevalence of TCP at ICU admission: 17% (n = 165)
• Incident of TCP in ICU: 28% (n = 271)
• Median time to TCP (PLT < 100): 2 days (IQR 1 to 3)
• Median time from TCP to platelet recovery: 6 days (IQR 4 – 8)
• Average platelet nadir: 62 (SD 24.6) in survivors
Menard C, Kumar A, Zarychanski et al. Evolution and impact of thrombocytopenia in septic shock: a retrospective cohort study. (Submitted to CCM, 2017)
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Thrombocytopenia in Sepsis
• In a propensity-matched cohort analysis– TCP not associated with hospital mortality (OR 1.17; 95% CI 0.81-1.69)
– TCP is associated with:
• ICU length of stay 9 vs. 6 days; p<0.01
• Duration of mechanical ventilation 7 vs. 4 days; p<0.01
• Duration of vasopressor use 4 vs. 3 days; p<0.01
• Major bleeding events 41% vs 18%; p<0.01
Menard C, Kumar A, Zarychanski et al. Evolution and impact of thrombocytopenia in septic shock: a retrospective cohort study. (Submitted to CCM, 2017)
(41.2% vs. 17.6%; p<0.01).
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Thrombocytopenia in Sepsis
• Thrombin
– Sepsis is a well-recognized trigger of DIC
– Driven by upregulation of tissue factor expression on monocytes
– Several targeted anticoagulants (TFPI, AT, APC) have been evaluated in the treatment of sepsis…largely negative results
– ACTIVE RESEARCH:
• ’Less targeted’ anticoagulants may be beneficial to reduce thrombin-mediated platelet activation and DIC
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Propensity Matched Cohort Study
National SurveyMeta-Analysis
Pilot Randomized
Feasibility Trial
Phase IIInternational
RCT
Cytokine AnalysisActivation of CoagulationCell free DNA
Phase III International RCT
Exit survey
HALO
Heparin Anticoagulation to improve outcomes in septic shock
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Thrombocytopenia in Sepsis
• Hemophagocytosis (HPS)
– Evolving knowledge base pertaining to the definition & diagnosis
– Evidence to inform treatment is lacking
– Current therapies target T cells (steroids, cyclosporine) and macrophages (etoposide)
– IVIG may support defective humoral immunity and reduce systematic inflammation
– RCTs suggest a survival benefit of IVIG
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Modeled Economic Evaluation of IVIG in
Sepsis
International Survey• Utility, Utilization• Barriers/facilitators• Willingness to study
Population Cohort• Long-term sepsis-mortality• Health-care utilization
Integrated Economic Evaluation
PS Matched Cohort• Mortality• Utilization• Dosing
Pilot RCT 2B Adaptive RCTPhase 3 International
Multicentre RCT
Translational Biology
InVIGIS
IntraVenous Immune Globulin In Severe Sepsis
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Thrombocytopenia in Sepsis
• ADAMTS13 deficiency
– Possible contribution to thrombocytopenia and microvascular injury should lead to consideration of future trials evaluating plasma exchange or infusion of recombinant ADAMTS13
– Meta-analysis of plasma exchange suggests benefit in adults
– Considerable European interest in non-centrifugal plasma filtration
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How I approach thrombocytopenia in the ICU
Past
Present
Future
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Approaching thrombocytopenia in the ICU
• Past– What is the context of the patient’s ICU admission?
– Is there evidence of a preexisting illness or the use of a drug known to cause thrombocytopenia?
– Could the ICU admission have been precipitated by a catastrophic illness associated with thrombocytopenia, such as thrombotic thrombocytopenic purpura, hemophagocyticsyndrome, or acute leukemia?
– Was there major trauma or surgery that would consume platelets, or transfusion and fluid resuscitation that would cause dilution?
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Approaching thrombocytopenia in the ICU
• Present
• What is the trajectory of the platelet count, and how does it relate to the patient’s clinical course?
• How low is the platelet count?
• Is there thrombosis?
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Trajectory #1: Present low…stay low
• Suggests an independent cause of thrombocytopenia– marrow failure– Hypersplenism
• Investigation could include assessment of spleen size, review of the peripheral blood film, and bone marrow examination
Pla
tele
t co
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t x
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9/L
0
20
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1 2 3 4 5 6 7
Days in ICU
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Trajectory #2: Falls immediate; recovers quicklyP
late
let
cou
nt
x 1
09/L
0
20
40
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1 2 3 4 5 6 7
Days in ICU
• Seen in major surgery (esp. CPB) or massive transfusion.
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Trajectory #3: Falls in first few days; recovers with improvement of the clinical condition
Pla
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t x
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9/L
0
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1 2 3 4 5 6 7 8
Days in ICU
• Seen in sepsis, pancreatitis, burns, multi-organ dysfunction
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Thrombocytopenia in sepsisMenard C, Kumar A, Zarychanski et al. Evolution and impact of thrombocytopenia in septic shock: a retrospective cohort study. (Submitted to CCM, 2017)
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Trajectory #4: Fall and stay low in a patient whose clinical course is otherwise recovering
Pla
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t co
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t x
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9/L
0
20
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1 2 3 4 5 6 7 8
Days in ICU
• Consider iatrogenic causes
– HIT, other drugs, (post-transfusion purpura)
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Trajectory #5: Falls in first few daysj; stays low in a patient with persistent multi-organ failure
Pla
tele
t co
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t x
10
9/L
0
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1 2 3 4 5 6 7 8
Days in ICU
• Observed in the sickest of patients who have the worst prognosis. – Sepsis, DIC, HPS, and shock are possible.
• It is not clear to what extent the thrombocytopenia contributes to poor outcomes
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Approaching thrombocytopenia in the ICU
• Present
• What is the trajectory of the platelet count, and how does it relate to the patient’s clinical course?
• How low is the platelet count?
• Is there thrombosis?
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Approaching thrombocytopenia in the ICU
• Present
• What is the trajectory of the platelet count, and how does it relate to the patient’s clinical course?
• How low is the platelet count?
• Is there thrombosis?
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Approaching thrombocytopenia in the ICU
• Future
– Is the platelet count following the expected trajectory, given your analysis of the cause?
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Management of thrombocytopenia in ICU
• Treat the underlying cause!
• Manage expectations
– Sepsis: improvement not expected until 2 days after discontinuation of pressors
– ECMO/VAD: likely to persist until device removal
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Management of thrombocytopenia in ICU
• Platelet transfusion
– Risk:Benefit of platelet transfusion is unknown
• Effectiveness of platelet transfusion to stop bleeding, reduce transfusion, or improve clinical outcomes is uncertain
• Harms associated with PLT transfusion are well documented
– Nosocomial infection, thrombosis, acute lung injury
– High quality trials are warranted
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Eminence-based recommendations
Indication Platelet threshold‡ Strength of recommendation
Quality of evidence
Severe bleeding Maintain PLT > 50 x109/L; consider using an MTP
Strong Low
Prophylaxis in adults 10 x109/L Moderate LowPrior to elective central venous catheter 20 x109/L§ Weak LowPrior to chest tube insertion or thoracentesis
50 x109/L Weak Low
Prior to bronchoscopy with lavage 20 x109/L Weak LowPrior to paracentesis Not routinely required Weak LowPrior to bone marrow biopsy Not routinely required Weak LowPrior to elective diagnostic lumbar puncture
50 x109/L Weak Very low
Prior to urgent diagnostic lumbar puncture
20 x109/L Weak Very low
Prior to major elective surgery (excluding neurosurgery)
50 x109/L Weak Very low
Prior to neurosurgery 100 x109/L Weak Very lowTraumatic brain injury, Intracranial hemorrhage
100 x109/L Weak Low
Prior to insertion of an intraventricular drain (EVD)
100 x109/L Weak Very Low
Zarychanski R, Houston DS. Hematology Am Soc Hematol Educ Program. 2017 (in press)
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Conclusions
• Thrombocytopenia in the ICU is common and correlates with an adverse prognosis
• Multiple mechanisms may contribute to thrombocytopenia; Differentiating the pertinent cause (or causes) in individual patients is challenging
• Looking back at the patient’s medical history and presenting illness, while observing the platelet trajectory and the clinical course, offers clues to the diagnosis and prognosis.
• Optimal platelet transfusion strategies to prevent or treat bleeding in thrombocytopenic ICU patients remain to be defined
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Objectives
1. Characterize the multiple mechanisms that can contribute to thrombocytopenia in the ICU
2. Evaluate the trajectory of the patient’s platelet count and apply this information to establish a diagnosis and inform prognosis
3. Transfuse platelets appropriately to prevent and manage bleeding in thrombocytopenic patients admitted to the ICU
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For further details:
Zarychanski R, Houston DS. Assessing thrombocytopenia in the intensive care unit: The past, present, and future. Hematology Am Soc Hematol Educ Program. Dec, 2017.