5/31/2014

DISCLOSURES

• I have nothing to disclose.

THROMBOCYTOPENIA IN THE ICU

Anne Donovan Critical Care Medicine & Trauma May 31, 2014

OVERVIEW FUNCTION OF PLATELETS

• Platelet basics • Hemostasis and thrombus formation • Epidemiology – Time course • Modulation of platelet and receptor function – 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

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. 2013. 14: 768-70. Akca S et al. Crit Care Med. 2002. 30(4): 753-6.

WHY IS PLATELET PATHOLOGY HARMFUL? OVERVIEW

• 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 • Marker of illness severity • Treatment

2 5/31/2014

A MARKER OF ILLNESS SEVERITY AND THROMBOCYTOPENIA IN THE ICU A PREDICTOR OF MORTALITY • Platelet count < 150,000/mL • Patients with thrombocytopenia have: – Higher admission APACHE II, SAPS II, MODS II scores • The most common hemostatic disorder in critically ill patients – Higher mortality within the same APACHE II or SAPS II quartiles – Incidence approaches 50% – Higher ICU (39% vs. 24%, p<0.0005) and hospital (56% • Association between thrombocytopenia and vs 48%, p<0.0005) mortality – Mortality – Longer duration of mechanical ventilation (11 vs. 5 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

ARIATION BASED ON PATIENT POPULATION Acka S, et al. Crit Care Med. 2002. (30)4:753-6. V

Shaded = non-survivors White = survivors

Thiele T, et al. Semin Hematol. 2013. 50(3): 239-50.

OVERVIEW MECHANISMS OF THROMBOCYTOPENIA

• Platelet basics • Blood loss or • Increased destruction • Epidemiology hemodilution – Consumption – Time course – Immune-mediated – Prognostic significance • Decreased production • Causes and differential diagnosis – Infection • Sequestration – Sepsis – Toxins (including drugs) – Spleen – 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

DIFFERENTIAL DIAGNOSIS IN THE ICU SEPSIS

• Infectious • Liver disease • Represents hematologic system dysfunction in – Sepsis** • sepsis – HIV DIC – HCV • Massive transfusion • Results from activation of the host inflammatory – Other viral infections (dilutional) response • Drug-induced • Rheumatologic disease • Mechanisms of thrombocytopenia in sepsis • Hematologic disease – Pseudothrombocytopenia – TTP/HUS • Idiopathic/unknown – Bone marrow suppression – 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.

DRUG-INDUCED THROMBOCYTOPENIA HEPARIN-INDUCED THROMBOCYTOPENIA

• Antibiotics • Alcohol • Uncommon cause of thrombocytopenia in the – PCN • Acetaminophen ICU – β-lactamase inhibitors (overdose) – Carbapenems • Anti-platelet agents • Formation of antibodies against PF4-heparin – Cephalosporins • NSAIDs complexes  activation of platelets – Quinolones • Heparin • Anti-epileptics • • H2 blockers Detection is more complicated in ICU patients – Valproate • Chemotherapy – Carbamazepine • Herbals • Seroprevalence of Anti-PF4 is high in ICU patients – Phenobarbital – 10.8% on admission  29.4% on day 7 – Phenytoin • Snake venom – 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 CLINICOPATHOLOGIC DIAGNOSIS” 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. Warkentin TE, et al. Hematology. 2003. 2003(1): 497-519.

OVERVIEW WHEN SHOULD WE INVESTIGATE?

• Platelet basics • Platelet count < 100,000 • Epidemiology – Time course • > 30% decrease in platelet count – Prognostic significance • • Causes and differential diagnosis Rapid decline in platelet count (24-48 hours) – Sepsis • Failure to rebound after 5-7 days – Drug-induced – HIT • Decline in platelet count after initial recovery • Investigation • Treatment • 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).

6 5/31/2014

INITIAL INVESTIGATION OVERVIEW

• 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).

TREATMENT 3 QUESTIONS TO GUIDE TREATMENT… • Target of treatment is the underlying process

• Supportive care may include • Is this condition pro-hemorrhagic? – Platelet transfusion • Is this condition pro-thrombotic? – Anticoagulation – Etiology-specific treatments • Are additional therapies or specialized studies necessary?

7 5/31/2014

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. 2013. 368(19). Vanderscheuren S, et al. Crit Care Med. 2000. 28(6): 1871-6. 2012 Williamson DR, et al. Chest. 2013. 144(4):1207-15.

CONSENSUS 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 – Etiology – Associated treatment

Van der Linden T, et al. Ann Intensive Care. 2012. 2(42).

8 5/31/2014

CONCLUSIONS CONCLUSIONS

• Platelets have diverse roles in coagulation, inflammation, and the • Certain features of thrombocytopenia should prompt immune response investigation • Thrombocytopenia is common in the ICU – < 100,000 or decrease > 30% – Rapid decline • Mild decrease in platelet count early in the ICU stay is predictable – Failure to rebound after 5-7 days and physiologic – Decline after initial recovery • The most common causes of thrombocytopenia in the ICU are – Sepsis • Initial investigation should include peripheral smear and – Drug-induced other labs as clinically indicated – Liver disease • Decision to transfuse depends on platelet count, etiology, – Dilutional bleeding risk, thrombotic risk, other factors • Diagnosis of HIT should be made using a combination of clinical and laboratory data • Consider anticoagulation and other etiology-specific treatments depending on clinical scenario

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, QUESTIONS? 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.

9 5/31/2014

REFERENCES REFERENCES 14. Thiele T, Selleng K, Selleng S, Greinacher A, & Bakchoul T. Thrombocytopenia in 8. Lopez Delgado J C, Rovira A, Esteve F, Rico N, MaÃez-Mendiluce R, et al. the intensive care unit-diagnostic approach and management. Seminars in Thrombocytopenia as a mortality risk factor in acute respiratory failure hematology. 2013;50(3):239-250. in H1N1 influenza. Swiss medical weekly. 2013;143:w13788-w13788. 15. Van der Linden T, Souweine B, Dupic L, Soufir L, & Meyer P. Management of 9. Mantovani A and Garlanda C. Platelet-macrophage partnership in innate thrombocytopenia in the ICU (pregnancy excluded). Annals of Intensive Care. immunity. Nature Immunology. 2013;14:768-770. 2012;2(1):42-42. 16. Vanderschueren S, De Weerdt A, Malbrain M, Vankersschaever D, Frans E, et al. 10. Moreau D, Timsit J, Vesin A, Garrouste-Orgeas M, de Lassence A, et al. Thrombocytopenia and prognosis in intensive care. Critical care medicine. Platelet count decline: an early prognostic marker in critically ill patients 2000;28(6):1871-1876. with prolonged ICU stays. Chest. 2007;131(6):1735-1741. 17. Warkentin T E. Management of heparin-induced thrombocytopenia: a critical 11. Pemmeraju N, Kroll MH, Afshar-Kharghan V, Oo TH. Bleeding risk in comparison of lepirudin and argatroban. Thrombosis research. 2003;110(2-3):73- thrombocytopenic cancer patients with venous thromboembolism (VTE) 82. receiving anticoagulation. Blood (ASH Annual Meeting Abstracts). 2012. 18. Warkentin T E, Aird W C, & Rand J H. Platelet-endothelial interactions: sepsis, 120;Abstract 3408. HIT, and antiphospholipid syndrome. Hematology. 2003;:497-519. 12. Rios F G, Estenssoro E, Villarejo F, Valentini R, Aguilar L, et al. Lung 19. Warkentin T E, Sheppard J I, Heels Ansdell D, Marshall J C, McIntyre L, et al. function and organ dysfunctions in 178 patients requiring mechanical Heparin-induced thrombocytopenia in medical surgical critical illness. Chest. ventilation during the 2009 influenza A (H1N1) pandemic. Critical care. 2013;144(3):848-858. 2011;15(4):R201-R201. 20. Williamson D R, Albert M, Heels Ansdell D, Arnold D M, Lauzier F, et al. Thrombocytopenia in critically ill patients receiving thromboprophylaxis: 13. Stasi R. How to approach thrombocytopenia. Hematology. frequency, risk factors, and outcomes. Chest. 2013;144(4):1207-1215. 2012;2012(1):191-7. 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.

10