5/31/2014 1 THROMBOCYTOPENIA IN THE ICU Anne Donovan Critical Care Medicine & Trauma May 31, 2014 DISCLOSURES • I have nothing to disclose. OVERVIEW • Platelet basics • Epidemiology – Time course – Prognostic significance • Causes and differential diagnosis – Sepsis – Drug-induced – HIT • Investigation • Treatment FUNCTION OF PLATELETS • Hemostasis and thrombus formation • Modulation of platelet and receptor function – Secretion of pro-coagulant factors • Platelet activating factors • Complement proteins – Secretion of pro-inflammatory factors • Cytokines • Oxidants – Antigen presentation Akca S et al. Crit Care Med. 2002. 30(4): 753-6.
Transcript
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THROMBOCYTOPENIA IN THE ICU
Anne Donovan
Critical Care Medicine & Trauma
May 31, 2014
DISCLOSURES
• I have nothing to disclose.
OVERVIEW
• Platelet basics
• Epidemiology – Time course
– Prognostic significance
• Causes and differential diagnosis – Sepsis
– Drug-induced
– HIT
• Investigation
• Treatment
FUNCTION OF PLATELETS
• Hemostasis and thrombus formation
• Modulation of platelet and receptor function
– Secretion of pro-coagulant factors • Platelet activating factors
• Complement proteins
– Secretion of pro-inflammatory factors • Cytokines
• Oxidants
– Antigen presentation
Akca S et al. Crit Care Med. 2002. 30(4): 753-6.
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Mantovani A, et al. Nature Immunol. 2013. 14: 768-70.
CONSEQUENCES OF PLATELET ACTIVATION
• Beneficial – Wound healing and vascular remodeling
– Enhanced integrity of endothelial membranes
– Reduction in vascular permeability
– Mediation of inflammatory processes and host defense
• Harmful – Impairment of microcirculatory flow
– Propagation of inflammatory and coagulation cascades
Akca S et al. Crit Care Med. 2002. 30(4): 753-6.
WHY IS PLATELET PATHOLOGY HARMFUL?
• Contribution to organ dysfunction
• Bleeding or thrombosis
– Complications of treatment
• Influence on patient management – Avoidance of invasive procedures
– Avoidance of thromboprophylaxis
– Investigation of cause
• Marker of illness severity
OVERVIEW
• Platelet basics
• Epidemiology – Time course
– Prognostic significance
• Causes and differential diagnosis – Sepsis
– Drug-induced
– HIT
• Investigation
• Treatment
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THROMBOCYTOPENIA IN THE ICU
• Platelet count < 150,000/mL
• The most common hemostatic disorder in critically ill patients
– Incidence approaches 50%
• Association between thrombocytopenia and
– Mortality
– Poor ICU outcomes
Hui P, et al. Chest. 2011. 139(2): 271-8. Williamson DR, et al. Chest. 2013. 144(4): 1207-15.
A MARKER OF ILLNESS SEVERITY AND A PREDICTOR OF MORTALITY
• Patients with thrombocytopenia have:
– Higher admission APACHE II, SAPS II, MODS II scores
– Higher mortality within the same APACHE II or SAPS II quartiles
– Higher ICU (39% vs. 24%, p<0.0005) and hospital (56% vs 48%, p<0.0005) mortality
– Longer duration of mechanical ventilation (11 vs. 5 days, p<0.0005)
– Receive more PRBC, FFP, platelet transfusions
Vanderscheuren S, et al. Crit Care Med. 2000. Crowther, et al. J Crit Care. 2005. 20:348-53.
Williamson DR, et al. Chest. 2013. 144(4):1207-15. Moreau D, et al. Chest. 2007. 131(6):1735-41.
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Acka S, et al. Crit Care Med. 2002. (30)4:753-6.
Shaded = non-survivors White = survivors
VARIATION BASED ON PATIENT POPULATION
Thiele T, et al. Semin Hematol. 2013. 50(3): 239-50.
OVERVIEW
• Platelet basics
• Epidemiology – Time course
– Prognostic significance
• Causes and differential diagnosis – Sepsis
– Drug-induced
– HIT
• Investigation
• Treatment
MECHANISMS OF THROMBOCYTOPENIA
• Blood loss or hemodilution
• Decreased production
– Infection
– Toxins (including drugs)
– Inflammatory mediators
– Bone marrow disorders
– Liver disease
• Increased destruction
– Consumption
– Immune-mediated
• Sequestration – Spleen
– Liver
– Lungs (ARDS)
• Pseudothrombocytopenia
Akca S, et al. Crit Care Med. 2002. 30(4): 753-6.
Vanderscheuren S, et al. Crit Care Med. 2000. 28(6): 1871-6.
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DIFFERENTIAL DIAGNOSIS IN THE ICU
• Infectious – Sepsis** – HIV – HCV – Other viral infections
Lim SY, et al. J Korean Med Sci. 2012. 27:1418-23. Stasi R. Hematology. 2012. 2012(1):191-7.
SEPSIS
• Represents hematologic system dysfunction in sepsis
• Results from activation of the host inflammatory response
• Mechanisms of thrombocytopenia in sepsis – Pseudothrombocytopenia – Bone marrow suppression – Non-immune mechanisms
• Consumption • DIC
– Immune mediated mechanisms
Warkentin TE, et al. Hematology. 2003. 2003(1): 497-519.
DRUG-INDUCED THROMBOCYTOPENIA
• Antibiotics – PCN
– β-lactamase inhibitors
– Carbapenems
– Cephalosporins
– Quinolones
• Anti-epileptics – Valproate
– Carbamazepine
– Phenobarbital
– Phenytoin
• Alcohol
• Acetaminophen (overdose)
• Anti-platelet agents
• NSAIDs
• Heparin
• H2 blockers
• Chemotherapy
• Herbals
• Snake venom
Lim SY, et al. J Korean Med Sci. 2012. 27:1418-23. Thiele T, et al. Semin Hematol. 2013. 50(3): 239-50.
HEPARIN-INDUCED THROMBOCYTOPENIA
• Uncommon cause of thrombocytopenia in the ICU
• Formation of antibodies against PF4-heparin complexes activation of platelets
• Detection is more complicated in ICU patients
• Seroprevalence of Anti-PF4 is high in ICU patients – 10.8% on admission 29.4% on day 7
– Not all develop TCP or thrombosis!
Levine RL, et al. J Thromb Thrombolysis. 2010. 30:142-8. Thiele T, et al. Semin Hematol. 2013. 50(3): 239-50.
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CLINICAL FEATURES OF HIT
• Fall in platelet count > 50%
• Platelet count nadir 50-80,000
• Associated with thrombotic complications – Patients with vs. without HIT have OR 12-41 for
developing thrombosis1
• Onset 5-14 days after starting heparin – Within 24h if previous exposure (within 90 days)
1. Warkentin TE. Thromb Res. 2003. 110:73-82.
“A CLINICOPATHOLOGIC DIAGNOSIS”
Warkentin TE, et al. Hematology. 2003. 2003(1): 497-519.
OVERVIEW
• Platelet basics
• Epidemiology – Time course
– Prognostic significance
• Causes and differential diagnosis – Sepsis
– Drug-induced
– HIT
• Investigation
• Treatment
WHEN SHOULD WE INVESTIGATE?
• Platelet count < 100,000
• > 30% decrease in platelet count
• Rapid decline in platelet count (24-48 hours)
• Failure to rebound after 5-7 days
• Decline in platelet count after initial recovery
• Other appropriate clinical situations
Thiele T, et al. Semin Hematol. 2013. 50(3): 239-50.
Van der Linden T, et al. Ann Intensive Care. 2012. 2(42).
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INITIAL INVESTIGATION
Van der Linden T, et al. Ann Intensive Care. 2012. 2(42).
OVERVIEW
• Platelet basics
• Epidemiology – Time course
– Prognostic significance
• Causes and differential diagnosis – Sepsis
– Drug-induced
– HIT
• Investigation
• Treatment
TREATMENT
• Target of treatment is the underlying process
• Supportive care may include
– Platelet transfusion
– Anticoagulation
– Etiology-specific treatments
3 QUESTIONS TO GUIDE TREATMENT…
• Is this condition pro-hemorrhagic?
• Is this condition pro-thrombotic?
• Are additional therapies or specialized studies necessary?
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BLEEDING AND THROMBOCYTOPENIA
• Thrombocytopenic patients:
– Bleed more often
– Receive more transfusions
• There is still controversy surrounding the practice of prophylactic platelet transfusion
Stanworth SJ, et al. NEJM. 2013. 368(19). Vanderscheuren S, et al. Crit Care Med. 2000. 28(6): 1871-6.
Williamson DR, et al. Chest. 2013. 144(4):1207-15.
FOR FURTHER REVIEW…
2012
CONSENSUS RECOMMENDATIONS FOR TREATMENT
Decision to transfuse should be based on:
– Platelet count
– Presence of active bleeding
• Site
• Severity
– Etiology
– Risk of thrombosis
– Risk of hemorrhage
• Platelet function
• Invasive procedures or surgery
– Associated treatment
Van der Linden T, et al. Ann Intensive Care. 2012. 2(42).
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CONCLUSIONS
• Platelets have diverse roles in coagulation, inflammation, and the immune response
• Thrombocytopenia is common in the ICU
• Mild decrease in platelet count early in the ICU stay is predictable and physiologic
• The most common causes of thrombocytopenia in the ICU are – Sepsis – Drug-induced – Liver disease – Dilutional
• Diagnosis of HIT should be made using a combination of clinical and laboratory data
CONCLUSIONS
• Certain features of thrombocytopenia should prompt investigation – < 100,000 or decrease > 30% – Rapid decline – Failure to rebound after 5-7 days – Decline after initial recovery
• Initial investigation should include peripheral smear and other labs as clinically indicated
• Decision to transfuse depends on platelet count, etiology, bleeding risk, thrombotic risk, other factors
• Consider anticoagulation and other etiology-specific treatments depending on clinical scenario
QUESTIONS?
REFERENCES 1. Akca S, Haji Michael P, de-MendonÃa A, Suter P, Levi M, et al. Time course of
platelet counts in critically ill patients. Critical care medicine. 2002;30(4):753-756.
2. Berry C, Tcherniantchouk O, Ley E J, Salim A, Mirocha J, et al. Overdiagnosis of heparin-induced thrombocytopenia in surgical ICU patients. Journal of the American College of Surgeons. 2011;213(1):10-7.
3. Crowther M A, Cook D J, Meade M O, Griffith L E, Guyatt G H, et al. Thrombocytopenia in medical-surgical critically ill patients: prevalence, incidence, and risk factors. Journal of critical care. 2005;20(4):348-353.
4. Crowther M A, Cook D J, Albert M, Williamson D, Meade M, et al. The 4Ts scoring system for heparin-induced thrombocytopenia in medical-surgical intensive care unit patients. Journal of critical care. 2010;25(2):287-293.
5. Hui P, Cook D J, Lim W, Fraser G A, & Arnold D M. The frequency and clinical significance of thrombocytopenia complicating critical illness: a systematic review. Chest. 2011;139(2):271-278.
6. Levine R L, Hergenroeder G W, Francis J L, Miller C, & Hursting M J. Heparin-platelet factor 4 antibodies in intensive care patients: an observational seroprevalence study. Journal of thrombosis and thrombolysis. 2010;30(2):142-148.
7. Lim S Y, Jeon E J, Kim H, Jeon K, Um S, et al. The incidence, causes, and prognostic significance of new-onset thrombocytopenia in intensive care units: a prospective cohort study in a Korean hospital. Journal of Korean medical science. 2012;27(11):1418-1423.
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8. Lopez Delgado J C, Rovira A, Esteve F, Rico N, MaÃez-Mendiluce R, et al. Thrombocytopenia as a mortality risk factor in acute respiratory failure in H1N1 influenza. Swiss medical weekly. 2013;143:w13788-w13788.
9. Mantovani A and Garlanda C. Platelet-macrophage partnership in innate immunity. Nature Immunology. 2013;14:768-770.
10. Moreau D, Timsit J, Vesin A, Garrouste-Orgeas M, de Lassence A, et al. Platelet count decline: an early prognostic marker in critically ill patients with prolonged ICU stays. Chest. 2007;131(6):1735-1741.
11. Pemmeraju N, Kroll MH, Afshar-Kharghan V, Oo TH. Bleeding risk in thrombocytopenic cancer patients with venous thromboembolism (VTE) receiving anticoagulation. Blood (ASH Annual Meeting Abstracts). 2012. 120;Abstract 3408.
12. Rios F G, Estenssoro E, Villarejo F, Valentini R, Aguilar L, et al. Lung function and organ dysfunctions in 178 patients requiring mechanical ventilation during the 2009 influenza A (H1N1) pandemic. Critical care. 2011;15(4):R201-R201.
13. Stasi R. How to approach thrombocytopenia. Hematology. 2012;2012(1):191-7.
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the intensive care unit-diagnostic approach and management. Seminars in hematology. 2013;50(3):239-250.
15. Van der Linden T, Souweine B, Dupic L, Soufir L, & Meyer P. Management of thrombocytopenia in the ICU (pregnancy excluded). Annals of Intensive Care. 2012;2(1):42-42.
16. Vanderschueren S, De Weerdt A, Malbrain M, Vankersschaever D, Frans E, et al. Thrombocytopenia and prognosis in intensive care. Critical care medicine. 2000;28(6):1871-1876.
17. Warkentin T E. Management of heparin-induced thrombocytopenia: a critical comparison of lepirudin and argatroban. Thrombosis research. 2003;110(2-3):73-82.
18. Warkentin T E, Aird W C, & Rand J H. Platelet-endothelial interactions: sepsis, HIT, and antiphospholipid syndrome. Hematology. 2003;:497-519.
19. Warkentin T E, Sheppard J I, Heels Ansdell D, Marshall J C, McIntyre L, et al. Heparin-induced thrombocytopenia in medical surgical critical illness. Chest. 2013;144(3):848-858.
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21. Williamson D R, Lesur O, TÃtrault J, Nault V, & Pilon D. Thrombocytopenia in the critically ill: prevalence, incidence, risk factors, and clinical outcomes. Canadian journal of anesthesia. 2013;60(7):641-651.
