D ISCLOSURES I have nothing to disclose. T HROMBOCYTOPENIA IN THE - PDF document

5/31/2014 D ISCLOSURES • I have nothing to disclose. T HROMBOCYTOPENIA IN THE ICU Anne Donovan Critical Care Medicine & Trauma May 31, 2014 O VERVIEW F UNCTION OF P LATELETS • Platelet basics • Hemostasis and thrombus formation • Epidemiology • Modulation of platelet and receptor function – Time course – Prognostic significance – Secretion of pro-coagulant factors • Causes and differential diagnosis • Platelet activating factors – Sepsis • Complement proteins – Drug-induced – Secretion of pro-inflammatory factors – HIT • Cytokines • Investigation • Oxidants • Treatment – Antigen presentation Akca S et al . Crit Care Med. 2002. 30(4): 753-6. 1

5/31/2014 C ONSEQUENCES 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. Mantovani A, et al . Nature Immunol. 2013. 14: 768-70. O VERVIEW W HY IS PLATELET PATHOLOGY HARMFUL ? • Contribution to organ dysfunction • Platelet basics • Epidemiology • Bleeding or thrombosis – Time course – Complications of treatment – Prognostic significance • Causes and differential diagnosis • Influence on patient management – Sepsis – Avoidance of invasive procedures – Drug-induced – Avoidance of thromboprophylaxis – HIT – Investigation of cause • Investigation • Treatment • Marker of illness severity 2

5/31/2014 A MARKER OF ILLNESS SEVERITY AND T HROMBOCYTOPENIA IN THE ICU A PREDICTOR OF MORTALITY • Platelet count < 150,000/ m L • Patients with thrombocytopenia have: – Higher admission APACHE II, SAPS II, MODS II scores • The most common hemostatic disorder in – Higher mortality within the same APACHE II or SAPS II critically ill patients quartiles – Incidence approaches 50% – Higher ICU (39% vs. 24%, p<0.0005) and hospital (56% vs 48%, p<0.0005) mortality • Association between thrombocytopenia and – Longer duration of mechanical ventilation (11 vs. 5 – Mortality days, p<0.0005) – Poor ICU outcomes – Receive more PRBC, FFP, platelet transfusions Hui P, et al. Chest. 2011. 139(2): 271-8. Vanderscheuren S, et al . Crit Care Med . 2000. Williamson DR, et al . Chest. 2013. 144(4): 1207-15. 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. 3

5/31/2014 V ARIATION BASED ON PATIENT POPULATION Acka S, et al . Crit Care Med. 2002. (30)4:753-6. Shaded = non-survivors White = survivors Thiele T, et al . Semin Hematol. 2013. 50(3): 239-50. O VERVIEW M ECHANISMS OF THROMBOCYTOPENIA • Platelet basics • Blood loss or • Increased destruction • Epidemiology hemodilution – Consumption – Time course – Immune-mediated • Decreased production – Prognostic significance • Sequestration – Infection • Causes and differential diagnosis – Toxins (including drugs) – Spleen – Sepsis – Drug-induced – Inflammatory mediators – Liver – HIT – Bone marrow disorders – Lungs (ARDS) • Investigation – Liver disease • Pseudothrombocytopenia • Treatment Akca S, et al . Crit Care Med. 2002. 30(4): 753-6. Vanderscheuren S, et al . Crit Care Med. 2000. 28(6): 1871-6. 4

5/31/2014 D IFFERENTIAL DIAGNOSIS IN THE ICU S EPSIS • Infectious • Liver disease • Represents hematologic system dysfunction in – Sepsis** sepsis • DIC – HIV • Results from activation of the host inflammatory – HCV • Massive transfusion response – Other viral infections (dilutional) • Drug-induced • Mechanisms of thrombocytopenia in sepsis • Rheumatologic disease • Hematologic disease – Pseudothrombocytopenia • Idiopathic/unknown – Bone marrow suppression – TTP/HUS – ITP – Non-immune mechanisms – Bone marrow disorders • Consumption – Macrophage activation • DIC syndrome – Immune mediated mechanisms Lim SY , et al . J Korean Med Sci. 2012. 27:1418-23. Stasi R. Hematology. 2012. 2012(1):191-7. Warkentin TE, et al . Hematology. 2003. 2003(1): 497-519. D RUG -I NDUCED THROMBOCYTOPENIA H EPARIN -I NDUCED THROMBOCYTOPENIA • Antibiotics • Alcohol • Uncommon cause of thrombocytopenia in the – PCN • Acetaminophen ICU – β -lactamase inhibitors (overdose) – Carbapenems • Formation of antibodies against PF4-heparin • Anti-platelet agents – Cephalosporins complexes  activation of platelets • NSAIDs – Quinolones • Heparin • Anti-epileptics • Detection is more complicated in ICU patients • H 2 blockers – Valproate • Chemotherapy – Carbamazepine • Seroprevalence of Anti-PF4 is high in ICU patients • Herbals – Phenobarbital – 10.8% on admission  29.4% on day 7 • Snake venom – Phenytoin – Not all develop TCP or thrombosis! Lim SY , et al . J Korean Med Sci. 2012. 27:1418-23. Levine RL, et al . J Thromb Thrombolysis. 2010. 30:142-8. Thiele T, et al . Semin Hematol. 2013. 50(3): 239-50. Thiele T, et al . Semin Hematol. 2013. 50(3): 239-50. 5

5/31/2014 “A C LINICOPATHOLOGIC DIAGNOSIS ” C LINICAL 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 thrombosis 1 • Onset 5-14 days after starting heparin – Within 24h if previous exposure (within 90 days) 1. Warkentin TE. Thromb Res. 2003. 110:73-82. Warkentin TE, et al . Hematology. 2003. 2003(1): 497-519. O VERVIEW W HEN SHOULD WE INVESTIGATE ? • Platelet basics • Platelet count < 100,000 • Epidemiology • > 30% decrease in platelet count – Time course – Prognostic significance • Rapid decline in platelet count (24-48 hours) • Causes and differential diagnosis – Sepsis • Failure to rebound after 5-7 days – Drug-induced – HIT • Decline in platelet count after initial recovery • Investigation • Other appropriate clinical situations • Treatment Thiele T, et al . Semin Hematol. 2013. 50(3): 239-50. Van der Linden T, et al . Ann Intensive Care. 2012. 2(42). 6

5/31/2014 I NITIAL INVESTIGATION O VERVIEW • Platelet basics • Epidemiology – Time course – Prognostic significance • Causes and differential diagnosis – Sepsis – Drug-induced – HIT • Investigation • Treatment Van der Linden T, et al . Ann Intensive Care. 2012. 2(42). T REATMENT 3 QUESTIONS TO GUIDE TREATMENT … • Target of treatment is the underlying process • Is this condition pro-hemorrhagic? • Supportive care may include – Platelet transfusion • Is this condition pro-thrombotic? – Anticoagulation • Are additional therapies or specialized studies – Etiology-specific treatments necessary? 7

5/31/2014 B LEEDING AND THROMBOCYTOPENIA F OR 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. 2013. 368(19). 2012 Vanderscheuren S, et al . Crit Care Med. 2000. 28(6): 1871-6. Williamson DR, et al . Chest. 2013. 144(4):1207-15. C ONSENSUS RECOMMENDATIONS FOR TREATMENT Decision to transfuse should be based on: – Platelet count – Risk of thrombosis – Presence of active – Risk of hemorrhage bleeding • Platelet function • Site • Invasive procedures or • Severity surgery – Associated treatment – Etiology Van der Linden T, et al . Ann Intensive Care. 2012. 2(42). 8