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• I have nothing to disclose.
• Platelet basics • Epidemiology – Time course – Prognos?c significance
• Causes and differen?al diagnosis – Sepsis – Drug-‐induced – HIT
• Inves?ga?on • Treatment
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• Hemostasis and thrombus forma?on • Modula?on of platelet and receptor func?on – Secre?on of pro-‐coagulant factors • Platelet ac?va?ng factors • Complement proteins
– Secre?on of pro-‐inflammatory factors • Cytokines • Oxidants
– An?gen presenta?on Akca S et al. Crit Care Med. 2002. 30(4): 753-‐6.
Mantovani A, et al. Nature Immunol. 2013. 14: 768-‐70.
• Beneficial – Wound healing and vascular remodeling – Enhanced integrity of endothelial membranes – Reduc?on in vascular permeability – Media?on of inflammatory processes and host defense
• Harmful – Impairment of microcirculatory flow – Propaga?on of inflammatory and coagula?on cascades Akca S et al. Crit Care Med. 2002. 30(4): 753-‐6.
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• Contribu?on to organ dysfunc?on • Bleeding or thrombosis – Complica?ons of treatment
• Influence on overall management – Avoidance of invasive procedures – Avoidance of thromboprophylaxis – Inves?ga?on of cause
• Marker of illness severity
• Platelet basics • Epidemiology – Time course – Prognos?c significance
• Causes and differen?al diagnosis – Sepsis – Drug-‐induced – HIT
• Inves?ga?on • Treatment
• Platelet count < 150,000/µL • The most common hemosta?c disorder in cri?cally ill pa?ents – Incidence approaches 50%
• Prognos?c significance – Mortality – Other ICU endpoints Hui P, et al. Chest. 2011. 139(2): 271-‐8. Williamson DR, et al. Chest. 2013. 144(4): 1207-‐15.
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Acka S, et al. Crit Care Med. 2002. (30)4:753-‐6.
Shaded = TCP White = no TCP
Thiele T, et al. Semin Hematol. 2013. 50(3): 239-‐50.
Number (%)
All Pa&ents
Nadir Plt > 150
Nadir Plt < 150
329
193 (59)
136 (41)
APACHE II
18 (12-‐25) 16 (10-‐22) 21 (15-‐27)
SAPS II
41 (32-‐53) 38 (30-‐50) 47 (36-‐58)
MODS
5 (2-‐7)
3 (1-‐6)
6 (4-‐9)
P
< .0005 < .0005 < 0.0005
Shaded bars = TCP White bars = no TCP
Vanderscheuren S, et al. Crit Care Med. 2000.
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Crowther, et al. J Crit Care. 2005. 20:348-‐53.
Plt < 150
Plt > 150
p
39
23.6
0.03
ICU LOS, median (IQR)
16 (8-‐26)
8 (5-‐13)
< 0.001
Hospital mortality (%)
55.9
48
0.005
Dura?on of ven?la?on
11 (5-‐17.5)
5 (2-‐11)
< 0.001
ICU mortality (%)
Platelet transfusions (%) FFP transfusions (%) PRBC transfusions (%)
15
0
0.001
44.1
24.3
0.006
61
38.6
0.004
Williamson DR, et al. Chest. 2013. 144(4):1207-‐15.
Moreau D, et al. Chest. 2007. 131(6):1735-‐41.
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• Platelet basics • Epidemiology – Time course – Prognos?c significance
• Causes and differen?al diagnosis – Sepsis – Drug-‐induced – HIT
• Inves?ga?on • Treatment
• Blood loss or hemodilu?on
• Increased destruc?on
• Decreased produc?on – Infec?on – Toxins (including drugs) – Inflammatory mediators – Bone marrow disorders – Liver disease
– Consump?on – Immune-‐mediated
• Sequestra?on – 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.
Lim SY, et al. J Korean Med Sci. 2012. 27:1418-‐23. Stasi R. Hematology. 2012. 2012(1):191-‐7.
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Cardiothoracic surgery or ECMO
Pregnancy
• Cardiac bypass or ECMO circuit • An?-‐platelet agents
• • • • •
– GP IIb/IIIa inhibitors – Plavix
• HIT • Dilu?onal
Gesta?onal TCP Immune-‐mediated HELLP syndrome Preeclampsia Abrup?o placentae
Stasi R. Hematology. 2012. 2012(1):191-‐7.
• Represents hematologic system dysfunc?on in sepsis • Results from ac?va?on of the host inflammatory response • Mechanisms of thrombocytopenia in sepsis – Pseudothrombocytopenia – Bone marrow suppression – Non-‐immune mechanisms • Consump?on • DIC
– Immune mediated mechanisms Warken?n TE, et al. Hematology. 2003. 2003(1): 497-‐519.
• An?bio?cs – – – –
PCN β-‐lactamase inhibitors Carbapenems Cephalosporins
• An?-‐epilep?cs – – – –
Valproate Carbamazepine Phenobarbital Phenytoin
• Heparin
• Alcohol • Acetaminophen (overdose) • Herbals • An?-‐platelet agents • NSAIDs • Chemotherapy • H2 blockers • Quinolones • 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.
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Levine RL, et al. J Thromb Thrombolysis. 2010. 30:142-‐8. Thiele T, et al. Semin Hematol. 2013. 50(3): 239-‐50.
• Fall in platelet count > 50% • Platelet count nadir 50-‐80,000 • Associated with thrombo?c complica?ons – Pa?ents with vs. without HIT have OR 12-‐41 for developing thrombosis1
• Onset 5-‐14 days amer star?ng heparin – Within 24h if previous exposure (within 90 days) 1. Warken?n TE. Thromb Res. 2003. 110:73-‐82.
Warken?n TE, et al. Hematology. 2003. 2003(1): 497-‐519.
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• Platelet basics • Epidemiology – Time course – Prognos?c significance
• Causes and differen?al diagnosis – Sepsis – Drug-‐induced – HIT
• Inves?ga?on • Treatment
• Platelet count 30% decrease in platelet count • Rapid decline in platelet count (24-‐48 hours) • Failure to rebound amer 5-‐7 days • Decline in platelet count amer ini?al recovery • Other appropriate clinical situa?ons 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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Van der Linden T, et al. Ann Intensive Care. 2012. 2(42).
• Platelet basics • Epidemiology – Time course – Prognos?c significance
• Causes and differen?al diagnosis – Sepsis – Drug-‐induced – HIT
• Inves?ga?on • Treatment
• Target of treatment is the underlying process • Suppor?ve care may include – Platelet transfusion – An?coagula?on – E?ology-‐specific treatments
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• Is this condi?on pro-‐hemorrhagic? • Is this condi?on pro-‐thrombo?c? • Are addi?onal therapies or specialized studies necessary?
• Mul?ple studies have shown that thrombocytopenic pa?ents: – Bleed more – Receive more transfusions
• Many confounders or other factors contribu?ng to bleeding in these studies • There is s?ll controversy surrounding the prac?ce of prophylac?c platelet transfusion
– For further review: Stanworth SJ, et al. Platelet transfusion prophylaxis for pa?ents with hematologic malignancies: Where to now? Br J Hematology. 2005. 131:588-‐95. 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.
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• Decision to transfuse should be based on: – Platelet count – Presence of ac?ve bleeding • Site • Severity
– E?ology – Risk of thrombosis – Risk of hemorrhage
• Platelet func?on • Invasive procedures or surgery
– Associated treatment
Van der Linden T, et al. Ann Intensive Care. 2012. 2(42).
Transfusion threshold Pa&ent popula&on < 20,000
Central thrombocytopenia Chemotherapy*
< 50,000
Severe hemorrhage* Severe sepsis with risk of hemorrhage Invasive procedure Pre-‐ or post-‐surgical sepng
< 100,000
Post-‐op CNS, liver, eye, vascular Polytrauma * = strong agreement
Van der Linden T, et al. Ann Intensive Care. 2012. 2(42).
• Is this condi?on pro-‐hemorrhagic? • Is this condi?on pro-‐thrombo?c? • Are addi?onal therapies or specialized studies necessary?
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• Risk-‐benefit decision • An?coagula?on has been reported without increased bleeding incidence in cancer pa?ents with platelet count < 50,000 • Transfusion (probably) not recommended… – TTP/HUS – Catastrophic APLS – HIT – DIC Pemmaraju N, et al. Blood. 2012. 120. Van der Linden T, et al. Ann Intensive Care. 2012. 2(42).
• Is this condi?on pro-‐hemorrhagic? • Is this condi?on pro-‐thrombo?c? • Are addi?onal therapies or specialized studies necessary?
Condi&on
Therapy
Drug induced thrombocytopenia
Withdrawal of offending agent
HIT
Cessa?on of heparin, ini?a?on of non-‐heparin an?coagulant
CRRT
Citrate an?coagula?on
Thrombo?c microangiopathy
Plasma exchange
TTP
Cor?costeroids +/-‐ plasma exchange
Atypical HUS
Immunomodulators
Catastrophic APLS
An?coagula?on, an?-‐platelets, cor?costeroids, IVIG, plasma exchange
Van der Linden T, et al. Ann Intensive Care. 2012. 2(42).
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• Platelets have diverse roles in coagula?on, inflamma?on, 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 Dilu?onal
• Diagnosis of HIT should be made using a combina?on of clinical and laboratory data
• Certain features of thrombocytopenia should prompt inves?ga?on – – – –
< 100,000 or decrease > 30% Rapid decline Failure to rebound amer 5-‐7 days Decline amer ini?al recovery
• Ini?al inves?ga?on should include peripheral smear and other labs as clinically indicated • Decision to transfuse depends on platelet count, e?ology, bleeding risk, thrombo?c risk, other factors • Consider an?coagula?on and other e?ology-‐specific treatments depending on clinical scenario
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1. 2. 3. 4. 5. 6.
7.
8. 9. 10. 11.
12.
13.
Akca S, Haji Michael P, de-‐MendonÃa A, Suter P, Levi M, et al. Time course of platelet counts in cri?cally ill pa?ents. Cri?cal care medicine. 2002;30(4): 753-‐756. Berry C, Tcherniantchouk O, Ley E J, Salim A, Mirocha J, et al. Overdiagnosis of heparin-‐induced thrombocytopenia in surgical ICU pa?ents. Journal of the American College of Surgeons. 2011;213(1):10-‐7. Crowther M A, Cook D J, Meade M O, Griffith L E, Guyaw G H, et al. Thrombocytopenia in medical-‐surgical cri?cally ill pa?ents: prevalence, incidence, and risk factors. Journal of cri?cal care. 2005;20(4):348-‐353. 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 pa?ents. Journal of cri?cal care. 2010;25(2):287-‐293. Hui P, Cook D J, Lim W, Fraser G A, & Arnold D M. The frequency and clinical significance of thrombocytopenia complica?ng cri?cal illness: a systema?c review. Chest. 2011;139(2):271-‐278. Levine R L, Hergenroeder G W, Francis J L, Miller C, & Hurs?ng M J. Heparin-‐ platelet factor 4 an?bodies in intensive care pa?ents: an observa?onal seroprevalence study. Journal of thrombosis and thrombolysis. 2010;30(2): 142-‐148. Lim S Y, Jeon E J, Kim H, Jeon K, Um S, et al. The incidence, causes, and prognos?c significance of new-‐onset thrombocytopenia in intensive care units: a prospec?ve cohort study in a Korean hospital. Journal of Korean medical science. 2012;27(11):1418-‐1423.
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. Mantovani A and Garlanda C. Platelet-‐macrophage partnership in innate immunity. Nature Immunology. 2013;14:768-‐770. Moreau D, Timsit J, Vesin A, Garrouste-‐Orgeas M, de Lassence A, et al. Platelet count decline: an early prognos?c marker in cri?cally ill pa?ents with prolonged ICU stays. Chest. 2007;131(6):1735-‐1741. Pemmeraju N, Kroll MH, Afshar-‐Kharghan V, Oo TH. Bleeding risk in thrombocytopenic cancer pa?ents with venous thromboembolism (VTE) receiving an?coagula?on. Blood (ASH Annual Mee?ng Abstracts). 2012. 120;Abstract 3408. Rios F G, Estenssoro E, Villarejo F, Valen?ni R, Aguilar L, et al. Lung func?on and organ dysfunc?ons in 178 pa?ents requiring mechanical ven?la?on during the 2009 influenza A (H1N1) pandemic. Cri?cal care. 2011;15(4):R201-‐R201. Stasi R. How to approach thrombocytopenia. Hematology. 2012;2012(1): 191-‐7.
14. Thiele T, Selleng K, Selleng S, Greinacher A, & Bakchoul T. Thrombocytopenia in the intensive care unit-‐diagnos?c 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. Cri?cal care medicine. 2000;28(6):1871-‐1876. 17. Warken?n T E. Management of heparin-‐induced thrombocytopenia: a cri?cal comparison of lepirudin and argatroban. Thrombosis research. 2003;110(2-‐3): 73-‐82. 18. Warken?n T E, Aird W C, & Rand J H. Platelet-‐endothelial interac?ons: sepsis, HIT, and an?phospholipid syndrome. Hematology. 2003;:497-‐519. 19. Warken?n T E, Sheppard J I, Heels Ansdell D, Marshall J C, McIntyre L, et al. Heparin-‐induced thrombocytopenia in medical surgical cri?cal illness. Chest. 2013;144(3):848-‐858. 20. Williamson D R, Albert M, Heels Ansdell D, Arnold D M, Lauzier F, et al. Thrombocytopenia in cri?cally ill pa?ents receiving thromboprophylaxis: frequency, risk factors, and outcomes. Chest. 2013;144(4):1207-‐1215. 21. Williamson D R, Lesur O, TÃtrault J, Nault V, & Pilon D. Thrombocytopenia in the cri?cally ill: prevalence, incidence, risk factors, and clinical outcomes. Canadian journal of anesthesia. 2013;60(7):641-‐651.
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