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

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.

5/31/2014 2

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

5/31/2014 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. 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.

5/31/2014 4

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.

5/31/2014 5

DIFFERENTIAL DIAGNOSIS IN THE ICU

• Infectious

– Sepsis** – 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. 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.

5/31/2014 6

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).

5/31/2014 7

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?

5/31/2014 8

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).

5/31/2014 9

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
• ther 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.

5/31/2014 10

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.

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):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. 20. 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):1207-1215. 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.

REFERENCES