1. Hematology in the ICU Jonathan Bleeker, M.D. Sanford Health 12 January 2015

2. Objectives Discuss etiology/management of thrombocytopenias in ICU Discuss etiology/management of coagulapathies in ICU Discuss blood product administration in the ICU

3. Thrombocytopenia in the ICU Approximately 40% of ICU patients are admitted with or develop thrombocytopenia – 10-20% develop severe thrombocytopenia (<50K) Causes of thrombocytopenia in the ICU

4. Thrombocytopenia in the ICU Pseudothrombocytopenia – Clotting in the tube, EDTA-associated platelet clumping

5. Thrombocytopenia in the ICU Pseudothrombocytopenia Hemodilution – IVF and PRBC 10 units PRBC can decrease platelets by 50%

6. Thrombocytopenia in the ICU Pseudothrombocytopenia Hemodilution Increased consumption – Bleeding – Sepsis – Disseminated intravascular coagulation (DIC) – Thrombotic thrombocytopenic purpura (TTP/HUS) – Intravascular devices (balloon pump, VAD, etc.) – Large thrombotic burden

7. Thrombocytopenia in the ICU Pseudothrombocytopenia Hemodilution Increased consumption Increased destruction – Heparin induced thrombocytopenia (HIT) – Immune thrombocytopenic purpura (ITP) – Some drug-dependent thrombocytopenias

8. Thrombocytopenia in the ICU Pseudothrombocytopenia Hemodilution Increased consumption Increased destruction Decreased production – Drug impact on bone marrow (chemotherapy, alcohol, etc) – Severe infection – Malignancy (both hematologic and solid tumor) – Nutritional deficiencies

9. Thrombocytopenia in the ICU Pseudothrombocytopenia Hemodilution Increased consumption Increased destruction Decreased production Platelet sequestration – Hypersplenism

10. Thrombocytopenia in the ICU Management – For most—treat the underlying cause Infection, cancer, thrombosis Withdrawal of offending agents – Specific causes ITP TTP/HUS DIC HIT

11. ITP Mechanism Not completely understood—often postviral in children Cines, et al. NEJM. 2002;346(13):995-1008

12. ITP Clinical presentation – Thrombocytopenia (often severe--<10K) – Petechiae/purpura – Mucosal bleeding (nose, oral cavity, vaginal, GI, CNS) Only 1.5% of patients present with significant bleeding 1 Diagnosis – Diagnosis of exclusion – Rule out TTP/HUS, DIC, medications (HIT), HIV/Hep C – Do NOT need a bone marrow biopsy to make initial diagnosis 1 Moulis, et al. Blood. 2014;124(22):3308-3315

13. ITP Treatment – Decrease clearance of platelets Steroids, IVIG, splenectomy – Decrease antibody production Rituxmab, steroids, immunosuppressives – Increase platelet production Thrombopoietin agonists (romiplastim, eltrombopag) Cines, et al. NEJM. 2002;346(13):995-1008

14. Thrombocytopenia in the ICU Management – For most—treat the underlying cause Infection, cancer, thrombosis Withdrawal of offending agents – Specific causes ITP TTP/HUS DIC HIT

15. Thrombocytopenia in the ICU TTP – Mechanism Interaction between von Willebrands factor, platelets and vessel wall

16. Mechanism of TTP Tsai, et al. Kidney International (2006) 70, 16–23

17. Mechanism of TTP TTP – Mechanism Interaction between von Willebrands factor, platelets and vessel wall Leads to microangiopathic hemolytic anemia http://www.immunopaedia.org.za/index.php?id=685

18. Mechanism of TTP ASH image bank. Accessed at http://imagebank.hematology.org/AssetDetail.aspx?AssetID=4049

19. TTP Clinical presentation – Fever Rare – Anemia (microangiopathic hemolytic anemia) Schistocytes crucial to diagnosis – Thrombocytopenia Usually severe (mean 25,000 in one series) 1 – Renal dysfunction 70-80% with some evidence of renal dysfunction 2 – Neurologic dysfunction Ranges from mild headaches to obtundation 1 Rock, et al. Br J Haematol. 1998;103(4):1031. 2 Eknoyan, et al. Am J Nephrol. 1986;6(2):117-31.

20. TTP Diagnosis – Working diagnosis MAHA and thrombocytopenia without other cause (DIC) – Confirmation ADAMTS13 testing – Typically less than <10% in antibody mediated TTP – Greater than >50%--need to evaluate as to potential other causes

21. TTP Treatment – Plasmapheresis Removes anti-ADAMTS13 antibodies Replacement plasma contains ADAMTS13 – Plasma infusion Does not remove antibodies, but does provide ADAMTS13 – Steroids/rituximab Decrease antibody production http://www.immunopaedia.org.za/index.php?id=685

22. TTP Initial treatment – PLEX +/- steroids Continue daily PLEX until platelets and LDH are normal x 2 days Steroid taper starts 1-2 weeks after normalization Monitor closely for recurrence

23. Thrombocytopenia in the ICU DIC – Mechanism

24. Excessive activation of coagulation cascade Eventual consumption of clotting factors Fibrin forms Decreased fibrinogen MAHA Microvascular thrombi Platelet consumption Fibrinolysis Increased FDP

25. DIC Clinical presentation 1 – Bleeding (64%) – Renal dysfunction (25%) – Liver dysfunction (19%) – Respiratory dysfunction (16%) – Shock (14%) – Thromboembolism (7%) – Central nervous system involvement (2%) 1 Siegal, et al. Thromb Haemost. 1978;39(1):122.

26. DIC Diagnosis – Working diagnosis MAHA and coagulopathy (unlike TTP) Management – TREAT THE UNDERLYING PROCESS – Bleeding Maintain platelets >20K (50K with bleeding) Maintain fibrinogen >100 FFP as needed if aPTT prolonged and bleeding – Thrombosis ? Role of heparin ? Role of antithrombin

27. HIT Mechanism Kelton, et al. Blood. 2008; 113(17):2607-2615

28. HIT Risk factors – Type of heparin used UFH: 2.6% v LMWH: 0.2% in surgical population 1 – Dose of heparin used Therapeutic: 0.76% v prophylactic <0.1% 2 – Gender Women > Men – Surgical v. Medical patient Surgical > Medical 1 Martel, et al. Blood. 2005;106(8):2710. 2 Smythe, et al. Chest. 2007;131(6):1644.

29. HIT Relatively rare cause of thrombocytopenia in ICU – 9.4% of 524 ICU patients had significant thrombocytopenia while on heparin – Only 2 of these patients (0.4%) actually had HIT – How can we sort this out? – When should we suspect HIT? Crowther, et al. J Crit Care (2010) 25, 287–293.

30. HIT Clinical manifestations – Thrombocytopenia >50% drop in platelets Typically not below 20,000 (thus, bleeding is unusual) – Timing Typically 5-10 days after heparin exposure – Thrombosis 25-50% of patients with HIT have thrombosis

31. HIT 67 year old female with prosthetic aortic valve admitted with fever 3 weeks after hip replacement – Platelet counts 3 weeks ago: 145,000 Admission: 154,000 Day after admission: 56,000 – Medication review Aspirin, heparin gtt, TMP/SMX, omeprazole, Pipercillin/Tazobactam, lamotrigine, phenytoin – Exam: Unremarkable Lo, et al. J Thromb Haemost. 2006;4(4):759.

32. Could this be HIT? Low prob (0-3): 1% risk of HIT Int prob (4-5): 11.4% risk of HIT High prob (6-8): 34% risk of HIT Lo, et al. J Thromb Haemost. 2006;4(4):759.

33. HIT Clinical diagnosis – 4T score—does is work in the ICU? 1 50 patients investigated for HIT 39/50 had a low (0-3) 4T score – None were confirmed to have HIT 11/50 had moderate or high 4T score – 2/11 had HIT – OK, so a patient has a mod/high 4T score…. 1 Crowther, et al. J Crit Care (2010) 25, 287–293.

34. OK…what test(s) do we order now? Heparin-PF4 antibody Pros: Quick, cheap, high sensitivity (>90%) Cons: Low specificity (75-85%) Seratonin release assay Pros: High sensitivity and specificity (95+%) Cons: Expense, availability, timing Practical summary – Start with Hep-PF4 ab: If negative, believe it. If positive and high risk, believe it. If questionable clinical scenario, send SRA to confirm.

35. Treatment of HIT Immediate discontinuation of ALL heparin products Start alternative anticoagulant – Argatroban (do not choose in liver dysfunction) – Bivalirudin (do not choose in renal dysfunction) – Fondiparinux Pentasaccharide which binds to heparin’s binding site on antithrombin Does not appear to stimulate Hep-PF4 ab production

36. Treatment of HIT Continue alternative anticoagulant alone until… – Platelets reach normal range – Then, warfarin can be started and combined therapy continued until INR therapeutic Starting earlier increases risk of warfarin skin necrosis

37. Deciperhing thrombocytopenias PltsHgbSchistosPT/aPTT ITP HIT TTP DIC Nl Nl/ No Yes Nl

38. Objectives Discuss etiology/management of thrombocytopenias in ICU Discuss etiology/management of coagulapathies in ICU Discuss blood product administration in the ICU

39. Coagulopathy in the ICU

40. Prolonged PT Warfarin effect Other anticoagulants FVII deficiency/inhibitor Mild vit K deficiency Liver disease

41. Coagulopathy in the ICU Prolonged aPTT FVIII deficiency/inhibitor FIX deficiency inhibitor Factor XI deficiency Heparin Argatroban/dabigatran Lupus inhibitor

42. Coagulopathy in the ICU Both prolonged Deficiencies of II, V, X, fibrinogen Xa inhibitors (rivaroxban) DIC Supratherapeutic anticoagulation Heparin + Warfarin Liver disease

43. Coagulopathy in the ICU Liver disease Anticoagulant reversal – Warfarin – Direct thrombin inhibitors (dabigatran) – Xa inhibitors (rivaroxaban)

44. Coagulopathy in the ICU Liver disease – Coagulation tests are not an accurate predictor of bleeding risk in patients with liver disease – Procoagulant proteins made in liver Factors II, V, VII, IX, X, XI, XII Reflected in PT, aPTT, etc – Anticoagulant proteins made in liver Protein C, protein S, antithrombin, plasminogen Not terribly well reflected in any of our standard testing

45. Coagulopathy in the ICU Don’t chase abnormal coags with FFP in a cirrhotic pt – Coags are not an accurate measure of actual bleeding risk – “Chasing” coags with FFP does not work 1 80 patients—got 2-6 units of FFP Only 12.5% got PT to within 3 seconds of normal – Enormous volumes of FFP would be required Recommended FFP dose to correct PT is 10-15 ml/kg Average pt=1200 mL FFP (6 units) – FFP won’t last that long anyway… Half life of factor VII FFP is 4-8 hours 1 Youssef, et al. Am J Gastroenterol. 2003;98(6):1391.

46. Coagulopathy in the ICU Liver disease Anticoagulant reversal – Warfarin – Direct thrombin inhibitors (dabigatran) – Xa inhibitors (rivaroxaban)

47. Anticoagulant reversal Warfarin – Inhibits vitamin K dependent “activation” of multiple clotting factors (II, VII, IX, X) – Reversal Factor replacement – FFP » Effective, but a lot of volume and relatively low factor concentrations – Unactivated prothrombin complex concentrates (PCC) » Contain factors II, VII (some), IX, X » Lower volume than FFP, given much faster Vitamin K—allows for re-“activation” of these clotting factors – Non-life threatening bleeding—Oral=IV >SQ routes – Life threatening bleeding—recommend IV route

48. Anticoagulant reversal Warfarin – No bleeding INR <5—hold warfarin and change dose INR 5-10—hold warfarin, change dose and consider low dose vit K INR >10—hold warfarin, vit K and change dose – Major bleeding PCC +/- FFP or rFVIIa – PCC dosing: 30-50 IU/kg – FFP: 1-2 units to ensure FVII administered (rFVIIa an alternative) Vit K: 10 mg IV

49. Anticoagulant reversal Direct thrombin inhibitors (dabigatran) Hankey G J, et al. Circulation. 2011;123:1436-1450

50. Anticoagulant reversal Direct thrombin inhibitors (dabigatran) – No specific antidote – Activated PCC (FEIBA) Rapid onset hemostasis, short duration of action, high clot risk – Unactivated PCC – Antifibrinolytics to prevent clot breakdown – Activated charcoal to prevent absorption – Drug is dialyzable

51. Anticoagulant reversal Xa inhibitors (Rivaroxaban) Hankey G J, et al. Circulation. 2011;123:1436-1450

52. Anticoagulant reversal Xa inhibitors (Rivaroxaban) – No specific antidote – Unactivated PCC – Antifibrinolytics to prevent clot breakdown – Activated charcoal to prevent further absorption – Drug is not dialyzable

53. Objectives Discuss etiology/management of thrombocytopenias in ICU Discuss etiology/management of coagulapathies in ICU Discuss blood product administration in the ICU

54. Blood products in the ICU PRBC Platelets FFP Cryoprecipitate

55. Blood products in the ICU Indications for PRBC – Hemorrhagic shock – Bleeding with evidence of hypoperfusion – Hemoglobin <7 g/dl Response – 1 unit PRBC should raise HCT 3% and Hgb 1 g/dL

56. Blood products in the ICU Indications for platelets – Any clinically significant active bleeding – Plts <10,000 if no bleeding or procedures – Plts <50,000 if procedure planned – Plts <100,000 if neurosurgical procedure planned Platelet preparations – “6 pack”—pooled from 6 different donors – “Apheresis”—single donor platelets

57. Blood products in the ICU Expected response – Platelets should increase 10-30K with a 6 pack of plts or apheresis unit – Why won’t the platelets go up? Consumption due to illness vs. alloantibodies Draw a 1 hour post infusion platelet level and if… – Platelets bump and then drop, they are being consumed (sepsis, DIC, etc) – Platelets do not bump, due to alloantibodies Consider single donor platelets or ABO matched platelets if concerned for alloantibodies

58. Blood products in the ICU Indications for FFP – Reversal of factor deficiencies Including those due to anticoagulants – Degree of impact based on severity of factor deficiency Indications for cryoprecipitate – Replace fibrinogen Goal fibrinogen often >100 in DIC, etc. – Given in “10 packs” 10 pack of cryoprecipitate should raise fibrinogen 60-80 mg/dL

59. Hematology in the ICU QUESTIONS?