DISCLOSURES THROMBOCYTOPENIA IN THE ICU OVERVIEW FUNCTION OF PLATELETS 5/31/2014. I have nothing to disclose.

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1 DISCLOSURES I have nothing to disclose. THROMBOCYTOPENIA IN THE ICU Anne Donovan Critical Care Medicine & Trauma May 31, 2014 Platelet basics Epidemiology Time course Prognostic significance OVERVIEW Causes and differential diagnosis 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 (4):

2 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 Mantovani A, et al. Nature Immunol : Akca S et al. Crit Care Med (4): 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 Platelet basics Epidemiology Time course Prognostic significance OVERVIEW Causes and differential diagnosis HIT Investigation Treatment 2

3 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 (2): Williamson DR, et al. Chest (4): 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 Crowther, et al. J Crit Care : Williamson DR, et al. Chest (4): Moreau D, et al. Chest (6):

4 Acka S, et al. Crit Care Med (30)4: VARIATION BASED ON PATIENT POPULATION Shaded = non-survivors White = survivors Thiele T, et al. Semin Hematol (3): OVERVIEW MECHANISMS OF THROMBOCYTOPENIA Platelet basics Epidemiology Time course Prognostic significance Causes and differential diagnosis HIT Investigation Treatment 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 (4): Vanderscheuren S, et al. Crit Care Med (6):

5 DIFFERENTIAL DIAGNOSIS IN THE ICU SEPSIS Infectious ** HIV HCV Other viral infections Drug-induced Hematologic disease TTP/HUS ITP Bone marrow disorders Macrophage activation syndrome Liver disease DIC Massive transfusion (dilutional) Rheumatologic disease Idiopathic/unknown Lim SY, et al. J Korean Med Sci : Stasi R. Hematology (1): 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 (1): DRUG-INDUCED THROMBOCYTOPENIA HEPARIN-INDUCED THROMBOCYTOPENIA Antibiotics PCN β-lactamase inhibitors Carbapenems Cephalosporins Quinolones Anti-epileptics Valproate Carbamazepine Phenobarbital Phenytoin Alcohol Acetaminophen (overdose) Anti-platelet agents NSAIDs Heparin H 2 blockers Chemotherapy Herbals Snake venom Lim SY, et al. J Korean Med Sci : Thiele T, et al. Semin Hematol (3): 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 : Thiele T, et al. Semin Hematol (3):

6 CLINICAL FEATURES OF HIT A CLINICOPATHOLOGIC DIAGNOSIS Fall in platelet count > 50% Platelet count nadir 50-80,000 Associated with thrombotic complications Patients with vs. without HIT have OR for developing thrombosis 1 Onset 5-14 days after starting heparin Within 24h if previous exposure (within 90 days) 1. Warkentin TE. Thromb Res : Warkentin TE, et al. Hematology (1): Platelet basics Epidemiology Time course Prognostic significance OVERVIEW Causes and differential diagnosis 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 (3): Van der Linden T, et al. Ann Intensive Care (42). 6

7 INITIAL INVESTIGATION Platelet basics Epidemiology Time course Prognostic significance OVERVIEW Causes and differential diagnosis HIT Investigation Treatment Van der Linden T, et al. Ann Intensive Care (42). TREATMENT Target of treatment is the underlying process 3 QUESTIONS TO GUIDE TREATMENT Supportive care may include Platelet transfusion Anticoagulation Etiology-specific treatments Is this condition pro-hemorrhagic? Is this condition pro-thrombotic? Are additional therapies or specialized studies necessary? 7

8 BLEEDING AND THROMBOCYTOPENIA FOR FURTHER REVIEW Thrombocytopenic patients: Bleed more often Receive more transfusions There is still controversy surrounding the practice of prophylactic platelet transfusion Stanworth SJ, et al. NEJM (19). Vanderscheuren S, et al. Crit Care Med (6): Williamson DR, et al. Chest (4): 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 (42). 8

9 CONCLUSIONS 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 Liver disease Dilutional Diagnosis of HIT should be made using a combination of clinical and laboratory data 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 REFERENCES QUESTIONS? 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): 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): 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): 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): 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): Levine R L, Hergenroeder G W, Francis J L, Miller C, & Hursting M J. Heparinplatelet factor 4 antibodies in intensive care patients: an observational seroprevalence study. Journal of thrombosis and thrombolysis. 2010;30(2): 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):

10 REFERENCES 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-w Mantovani A and Garlanda C. Platelet-macrophage partnership in innate immunity. Nature Immunology. 2013;14: 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): 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) ;Abstract 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-R Stasi R. How to approach thrombocytopenia. Hematology. 2012;2012(1): REFERENCES 14. Thiele T, Selleng K, Selleng S, Greinacher A, & Bakchoul T. Thrombocytopenia in the intensive care unit-diagnostic approach and management. Seminars in hematology. 2013;50(3): 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): 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): Warkentin T E. Management of heparin-induced thrombocytopenia: a critical comparison of lepirudin and argatroban. Thrombosis research. 2003;110(2-3): Warkentin T E, Aird W C, & Rand J H. Platelet-endothelial interactions: sepsis, HIT, and antiphospholipid syndrome. Hematology. 2003;: 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): Williamson D R, Albert M, Heels Ansdell D, Arnold D M, Lauzier F, et al. Thrombocytopenia in critically ill patients receiving thromboprophylaxis: frequency, risk factors, and outcomes. Chest. 2013;144(4): 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):