The missing platelets… where did they go?

1. The missing platelets… where did they go? Hilary Rowe, BScPharm VIHA Pharmacy Resident 2009-10 Intensive Care Unit Rotation April 13, 2010

2. Outline • Objectives • Patient Case • Background • Clinical Question • Review of Evidence • Recommendation • Monitoring

3. Objectives • Be able to list the 4 SIRS criteria • Review pathophysiology for HIT, DIC & thrombocytopenia in sepsis • Name 2 risk factors for thrombocytopenia in the ICU • Quantify the risk of thrombocytopenia from Sepsis

4. Mrs. DG • ID: 75 yo Female, ht 166cm, wt 65kg • CC: April 6th- arrived at ER with family; weakness, ↓ oral intake, difficulty speaking • HPI: 4 days of abdominal pain, bloating & nausea • ICU Vitals: Temp 359, HR 120, RR 18, MAP <49, BP 95/60 mmHg, APACHE II =28

5. Mrs. DG • PMHx: Hypertension, Osteoarthritis • Meds PTA: Losartan 50mg od • Allergies: NKA • SH: From Saskatchewan-on vacation, 2-3 glasses of wine/day, non-smoker

6. Review of Systems

7. Review of Systems

8. Review of Systems

9. Review of Systems

10. Review of Systems

11. Review of Systems

12. Review of Systems

13. Review of Systems

14. SIRS • Presence of two or more of: • Temperature < 36 °C or > 38 °C • Heart rate > 90 beats per minute • Respiratory rate > 20 breaths per minute or a PaCO2 less than 32 mm Hg • White blood cell count < 4  × 109 cells/L or > 12 × 109 cells/L), or greater than 10% bands • DG Temp 359, HR 120, WBC 3.8 × 109 cells/L

15. Medical Problems List • Septic Shock-Urosepsis origin • Acute Renal Failure • Thrombocytopenia ? • HIT • DIC • Sepsis • Drug cause- Drotrecogen alfa • Ascites • ARDS (Pa02/FiO2=190)

16. DRP’s • DG is at risk of neurotoxicity (confusion, delirium, myoclonus) secondary to a toxic metabolite of hydromorphone in renal failure and would benefit from re-assessment of her pain and sedation therapy • DG is at risk of side effects (confusion) from ranitidine secondary to too high of a dose in acute renal failure

17. DRP’s • DG is at risk of a bleed secondary to having thrombocytopenia and being on APC and would benefit from re-assessment of her therapy

18. Thrombocytopenia • Defined as < 100 x 109 platelets/L • Most common ICU causes • Sepsis & DIC • April 7th • 03:22 85 x 109 platelets/L • 08:30-clumped, 15:30-19C, 22:00 13C • April 8th • 6:10 13C, 17:35 8C

19. Clinical Question Rounds • Could Xigris, DIC, Sepsis, HIT or a medication error have caused the thrombocytopenia and can we tell which one is the culprit?

20. HIT • Heparin can combine with a heparin-binding protein (platelet factor 4) and make an antigenic complex that causes IgG antibodies to be made • Antibodies bind platelets and cause aggregation = platelet consumption and thrombosis • >50% ↓in platelets 5-10d after 1st exposure • 5-10% get a redness around sc site • 25% get systemic reactions if given IV-fever, chills, ↑ RR, ↑ HR, SOB

21. DIC & Sepsis • Gram + & – organisms cause excessive activation of the clotting cascade • Platelets are consumed • Results in thrombocytopenia • In severe sepsis microvasculature is damaged by poor perfusion, hypoxia, stasis & acidosis • Platelets adhere to damage • Causes activation of platelets & aggregation • Leads to more platelet consumption

22. DIC • >5 points is required to consider DIC • DG has a score of 7 + some points for INR >1

23. Lee et al. Singapore Med J 1993

24. Lee et al. Singapore Med J 1993 DG’s APACHE II= 28, Platelets 85 x 109/L

25. Lee et al. Singapore Med J 1993

26. Lee et al. Singapore Med J 1993 DG had Streptococcus pyogenes

27. Lee et al. Singapore Med J 1993 Summary • Thrombocytopenia (57%) and DIC (35%) are common in sepsis • Thrombocytopenia presents early in sepsis and is a predictor of mortality, independent of APACHE II for Sepsis • Patients died of multi-organ failure not blood loss from thrombocytopenia

28. Clinical Question

29. Benefit of Xigris • 6.1% ARR (NNT=16, RRR 19.4% P=0.005) in all cause mortality • Due to reduction in refractory septic shock, respiratory failure and improvement in cardiac and respiratory function

31. Bernard et al. Critical Care 2003

32. Bernard et al. Critical Care 2003

33. Bernard et al. Critical Care 2003 Mortality rate • Controlled trials 25.2% (236/940; 95% CI 22.4-28) • Open-label studies 25.2% (398/1578; 95% CI 23.1-27.4) • Compassionate use 26.1% (70/268; 95% CI 21-31.8) • Clinical trials 25.3% (704/2786; 95% CI 23.7-26.9) • Placebo 31% (273/881; 95% CI 28-34.2)

34. Bernard et al. Critical Care 2003 • 58/79 SBE during infusion were considered related to the drug (2.1%; 58/2786) • 8/69 SBE post infusion were considered related to the drug (0.3% of all treated patients)

35. Bernard et al. Critical Care 2003 • 22/53 (42%) patients who experienced a SBE during the infusion period had thrombocytopenia

36. Bernard et al. Critical Care 2003 • High proportion of SBE was due to invasive procedures • 58/148 SBE’s were due to procedures in the drotrecogen alfa group • PROWESS trial • 53.5% (16/30) in drotrecogen alfa group vs. 23.5% (4/17) in placebo group had a SBE due to a procedure

37. Bernard et al. Critical Care 2003 • Non ICH SBE with fatal outcome • -3 events in drug group during infusion • -1 involved thrombocytopenia (19x109/L) and PTT >150 sec

38. Bernard et al. Critical Care 2003

39. Bernard et al. Critical Care 2003 Summary: • Heparin exposure • 75% of patients in PROWESS trial were exposed to heparin, 11/18 with SBE had used heparin • 14/49 in open-label trials and 3/10 in compassionate use trials who had SBE were exposed to heparin • SBE were highest on day 1 • 56% were procedure related • 12 non-procedure related events occurred • 9 had platelets < 30 x109/L • 3 had an INR > 2

40. Bernard et al. Critical Care 2003 • Most serious ADR is bleeding • NNH=66 in PROWESS (3.5% SBE with therapy vs. 2% with placebo) • Bernard et al. found SBE rate to be 5.3% overall in the 7 trials assessed

41. Bernard et al. Critical Care 2003 Conclusion • Bleeding occurs most often on day 1 of infusion • Occurs most often with procedures • ICH during infusion is associated with severe thrombocytopenia or meningitis • Therapy should be stopped if platelets < < 30 x109/L

42. Who was the culprit • Xigris was started April 6th at 23:15 and platelets declined April 7th by 08:30 • SBE occurred most often on 1st day of infusion-associated with thrombocytopenia • Timing seems appropriate • Patient is also at risk of sepsis induced thrombocytopenia & DIC • Naranjo ADR scale= 3, possible What do you think?

43. Goals of Therapy Patients Goals • Full code Team Goals • Cure urosepsis • Improve renal function • Wean patient from ventilator • Prevent Bleeding • Prevent Clotting • Decrease morbidity & mortality • Minimize adverse drug events

44. Therapeutic Options • Continue Drotrecogen Alfa • Discontinue Drotrecogen Alfa • Continue Heparin • Discontinue Heparin • Start Sequential compression devices • Give Platelets

45. Monitoring

46. Monitoring

47. Questions?

48. References • Bernard GR, Macias WL, Joyce DE et al. Safety assessment of drotrecogen alfa (activated) in the treatment of adult patients with severe sepsis. Critical Care 2003;7:155-63. • Bernard GR, Vincent JL, Laterre PF et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. NEJM 2001; 344 (10): 699-709. • Lee KH, Hui KP, Tan WC. Thrombocytopenia in sepsis: a predictor of mortality in the intensive care unit. Singapore Med J 1993;34:245-46. • Marino PL. The ICU Book 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2007. page 684-7. • Naranjo CA, Busto U, Sellers EM et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; 30(2): 239-45.