Bleeding and Management of Coagulopathy

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1 Bleeding and Management of Coagulopathy Jerrold H. Levy, MD, FAHA Professor of Anesthesiology Deputy Chair for Research Emory University School of Medicine Director, Cardiothoracic Anesthesiology CT Anesthesiology and Critical Care Emory Healthcare Atlanta, Georgia

3 COMPONENTS OF HEMOSTASIS Vasculature Coagulation proteins Platelets

4 Subendothelial matrix WBC Hemostasis Hemostatic plug Endothelial cell Platelets Fibrin RBC WBC

5 CLOT FORMATION Platelet Red Blood Cell Fibrin

6 VASCULAR ENDOTHELIUM Huraux C et al: Circulation 1999;99:53-59

7 DIC Triggered by TF/endothelial injury Produces fibrin deposition in microvasculature and MOS dysfunction Path: Microangiopathic hemolytic anemia Lab: platelets, fibrinogen, PT, PTT, D-dimers, ATIII

8 LIMITATIONS TO TRANSFUSIONS AND RISKS Transfusions associated with adverse outcomes Most studies evaluate RBC transfusions Transfusions are associated with both risks/costs; availability is issue too What is the efficacy of transfusions in treating surgical bleeding or reversing coagulopathy?

9 MINIMUM FACTOR LEVELS FOR HEMOSTASIS "Spontaneous" Bleeding: 5-20% Minimum Conc for Hemostasis for Major Surgery: 20-30% Fibrinogen: ~100 mg/dl (??) but normal levels mg/dl O'Shaughnessy: Guidelines for the use of FFP, cryoprecipitate and cryosupernatant. Br J Haematol (2004) 126:11-28; British Committee for Standards in Haematology, Blood Transfusion Task Force. Guidelines for the use of platelet transfusions. Br J Haematol (2003) 122: Development Task Force of the College of American Pathologists. Practice parameter for the use of fresh-frozen plasma, cryoprecipitate, and platelets. FFP, Cryoprecipitate, and Platelets Administration Practice Guidelines. JAMA (1994) 271:

10 PLATELET FUNCTION EVALUATION Platelet count Bleeding time Aggregation TEG/SonoClot Platelet function assays Experimental

11 PROHEMOSTATIC AGENTS

12 PHARMACOLOGIC PROHEMOSTATIC AGENTS Aprotinin Lysine analogs Protamine DDAVP (desmopressin) Recombinant Factor VIIa (rviia, NovoSeven) Protein concentrates, fibrinogen Fibrin glue/topical thrombin

13 LYSINE ANALOGS: Epsilon aminocaproic acid and tranexamic acid

14 EACA/Tranexamic acid Often small numbers, variable design,?tx criteria,?factor reduction Most data is TA, NOT EACA Doses of TA range from 2 g to 25 g Most EACA/TA studies with lower risk patients Meta analyses need to be cautiously interpreted EACA removed from many European markets

15 Kikura, Levy, Tanaka: A double-blind, placebocontrolled trial of epsilon-aminocaproic acid for reducing blood loss in coronary artery bypass grafting surgery. J Am Coll Surg 2006;202: pts in a D,PC,R study to receive EACA (100 mg/kg before incision, 1 g/hour infusion until chest closure, 10 g in CPB circuit) vs placebo. Postop CT drainage EACA 649 (261) vs 940 (626) ml; p=0.003). No differences RBC Tx: EACA 24% v 18% placebo, p=0.62 or units Tx (EACA 2.2 (0.8) v 1.9 (0.8 U), p=0.29. EACA did not reduce risk of RBC Tx compared with placebo (odds ratio: 1.2, 95% confidence interval; 0.4 to 3.2, p=0.63). EACA reduced postop CT drainage volume by 30% but did not reduce need for allogeneic Tx.

16 SAFETY DATA WITH LYSINE ANALOGUES

17 SEIZURES/TRANEXAMIC ACID Mohseni K: Polymyoclonus seizure resulting from accidental injection of TA in spinal anesthesia. Anesth Analg 2009; 108: Breuer T: The blood sparing effect and the safety of aprotinin compared to TA in paediatric cardiac surgery. Eur J Cardiothorac Surg 2009; 35: ; Martin K: The risks of aprotinin and TA in cardiac surgery: a one-year follow-up of 1188 consecutive patients. Anesth Analg 2008; 107: Yeh HM: Convulsions and refractory ventricular fibrillation after intrathecal injection of a massive dose of TA. Anesthesiology 2003; 98: Furtmuller R: TA, a widely used antifibrinolytic agent, causes convulsions by a GABA antagonistic effect. J Pharmacol Exp Ther 2002; 301: Schlag MG: Epileptic seizures following cortical application of fibrin sealants containing TA in rats. Acta Neurochir (Wien) 2002; 144: 63-9 Fodstad H: Convulsive seizures following subdural application of fibrin sealant containing TA in a rat model. Neurosurgery 2001; 49: Hasan D: Epileptic seizures after subarachnoid hemorrhage. Ann Neurol 1993; 33: Yamaura A: Cerebral complication of antifibrinolytic therapy in the treatment of ruptured intracranial aneurysm. Eur Neurol 1980; 19: 77-84

18 GABA Tranexamic Acid EACA-Amicar

19 PROTAMINE

20 PROTAMINE Basic polypeptide isolated from salmon sperm 70% arginine, reverses unfractionated heparin not LMWH Heparin rebound can occur Produces ADRs No alternatives available

21 ACT (sec) Excess protamine causes hemostatic dysfunction * * * PROTAMINE (mcg/ml) Mochizuki: Protamine reversal of heparin affects platelet aggregation and ACT after CPB. Anesth Analg 1998; 87: * *

22 ANAPHYLAXIS TO PROTAMINE All patients: 0.06% (1/1500) NPH diabetics: 0.6-2% (1/50-1/160) Levy JH: Anesth Analg 1986; 65:739 Levy JH: JTCS1989; 98:200

23 PROTAMINE REACTIONS PATHOPHYSIOLOGY IgE antibodies IgG antibodies Complement activation Direct/indirect effects

24 Desmopressin (DDAVP)

25 Summary: DDAVP Rx on surgical bleeding with inherited coagulation disorders Data includes small numbers, mostly retrospective analyses Data includes multimodal approaches Antifibrinolytics are used concomitantly and other factor concentrates Bleeding depends on types of surgical procedure; superficial vs major vascular/cardiac/neuro Monitoring effects, especially with platelet function tests, is limited

26 Levi: Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints. Lancet 1999;354(9194):1940. Meta-analysis of all randomized, controlled trials of aprotinin, lysine analogues and desmopressin). 72 trials (8409 pts) were included. Aprotinin decreased mortality almost two-fold Both decreased the frequency of surgical reexploration and allogeneic blood Tx. Desmopressin resulted in a 2.4-fold increase in the risk of MI, a small decrease in periop blood loss, but NO beneficial effects on other clinical outcomes.

27 Recombinant Factor VIIa (rfviia)

28 rviia (NovoSeven ) Mechanism of Action NovoSeven is human rfviia rfviia increases TF occupancy rfviia in pharmacological doses binds to activated platelets rfviia provides FX activation independent of Tissue Factor (TF) Improves platelet function

29 REPORTS OF rviia: Cardiac Surgery Tanaka KA et al: Treatment of excessive bleeding in Jehovah s Witnesses following cardiac surgery rfviia. Anesthesiology 2003;98:1513 Stratmann G: Use of rfviia as a rescue treatment for intractable bleeding following repeat aortic arch repair. Ann Thorac Surg : 2094 Halkos ME et al: Early experience with activated rfvii for intractable hemorrhage after cardiovascular surgery. Ann Thorac Surg 2005;79(4): Diprose P: Activated rfvii after CPB reduces allogeneic Tx in complex non-coronary cardiac surgery: randomized double-blind placebo-controlled pilot study. Br J Anaesth 2005;95: Gill R: Safety and efficacy of rfviia: a randomized placebo controlled trial after cardiac surgery. Circulation 2009;120:21-7.

30 Levy, Fingerhut, Thomas et al: Recombinant factor VIIa in patients with coagulopathy secondary to anticoagulant therapy, cirrhosis, or severe traumatic injury: review of safety profile. Transfusion 2006;46: Critical safety data obtained from 13 Novo sponsored clinical trials of rfviia in patients with coagulopathy due to anticoagulant therapy, cirrhosis, or severe traumatic injury. Thrombotic AEs were reported for 5.3% (23/430) of placebo and 6.0% (45/748) of active treatment. No significant differences was found between placebo-treated and rfviia-treated patients for thrombotic AEs, either on an individual trial basis or for these trial populations combined (p = 0.57).

31 Rescue Therapy with rviia in the Perioperative Setting: Off label Severe (1 L/hr) or life-threatening (CNS) bleeding without surgical source of bleeding Marginal response to routine hemostatic therapy (i.e., platelets, FFP, cryo, DDAVP) Judicious use with CV disease, DIC or ongoing activation (CPB) Consider lower dose (30 mcg/kg) Patients with multiple antibodies and platelets/factors not available Goodnough LT: Transfusion 2004;44(9):

32 Fibrinogen

33 Hypofibrinogenemia Fibrinogen is an acute phase reactant; levels increase as an inflammatory response. Normal fibrinogen levels= mg/dl; however most algorithms recommend 100 mg/dl. Fibrinogen corrects TEG, RoTEM abnormalities, and increase clot strength In US, cryoprecipitate is used: CRYO contains also vwf and FXIII. Elsewhere fibrinogen concentrates are used

34 Cryoprecipitate: proteins per bag FVIII, IU/bag: vwf, IU/bag: Fibrinogen mg/bag: FXIII, IU/bag: Fibronectin, mg/bag: 50-60

35 Factor XIII

36 FXIII FXIII belongs to the family of transglutaminases, thiol enzymes that catalyze covalent crosslinking of proteins in tissues and involved in hemostasis. FXIII acts as the final enzyme in coagulation cascade; catalyzes cross-linking of fibrin molecules converting the primary blood clot into a stable form. FXIII crosslinks other substrates such as alpha-2- antiplasmin, thus controlling the rate of fibrinolysis, and some extracellular matrix proteins such as fibronectin and collagen, thus anchoring the clot into the site of injury.

37 FXIII activity (%) LL Screen Pre-Ind post-cpb Placebo (N=6) 11,9 IU/kg (N=8) 25 IU/kg (N=5) 35 IU/kg (N=7) 50 IU/kg (N=6) lower ref Pre-rFXIII 30 min 1 hr 4 hr 8 hr 24 hr 48 hr 72 hr 7 days 5-7 wks Levy JH: Thromb Haemost 2009;102(4):765.

38 TOPICAL HEMOSTATIC AGENTS Gelatin sponge: Gelfoam, purified pork skin gelatin (Jello) Oxidized regenerated cellulose: Surgicel or Oxycel, from alpha-cellulose (plant-based)- in knit or microfibrillar form Microfibrillar collagen: Avitene - collagen derived from bovine skin Topical thrombin: bovine derived, human, and human recombinant (RECOTHROM ) Fibrin sealants: Tisseal/Crosseal (human fibrinogen, thrombin, aprotinin)

39 Treating Bleeding (1) Check ACT after protamine; AVOID excess protamine- Inc ACT may be low platelets Send fibrinogen and platelet count If PTT elevated, protamine < 25 mg If still bleeding, consider platelets but check fibrinogen-fibrinogen (cryo) corrects platelet dysfunction?ddavp; but ~Vasopressin?

40 Treating Bleeding (2) Treat anemia; may contribute to bleeding If marginal response to routine hemostatic therapy (i.e., platelets, FFP, cryo, DDAVP) consider OFF LABEL use of rfviia Restart antifibrinolytics With massive bleeding, initiate massive transfusion protocol

41 Massive Transfusion Protocol for Cardiac Surgery Patients Pack RBCs FFP PLTs Cryo rfviia 1 4U 4U 1 AP 10U 2 2 mg 3 4U 4U 1 AP 10U 4 4U 4U 1 AP 10U 5 2 mg

42 Thromboelastography recordings obtained with the ROTEM(R) device after the addition of rfviia and/or fibrinogen in the presence of tissue type plasminogen activator in volunteer plasma Tanaka, K. A. et al. Anesth Analg 2008;106: Copyright restrictions apply.

43 Increasing use of non reversible hemostatic inhibitors = bleeding in surgical/trauma patients IV antithrombins Platelet inhibitors (Clopidogrel, Prasugrel) LMWHs, pentasaccharide (Fondaparinux), other Xa inhibitors, and new agents All of the above

44 NOVEL ANTICOAGULANTS Direct thrombin inhibitors: r-hirudin (Refludan, Desirudin) Oral Xa inhibitors (rivaroxaban, apixiban) Oral thrombin inhibitors: dabegatran. Levy JH: Novel anticoagulants: implications in the perioperative setting. Anesthesiology, In Press

45 BleedingWeb.com

Recombinant Activated Factor VII: Useful. Department of Surgery Grand Rounds 11/8/10 David Mauchley MD

Recombinant Activated Factor VII: Useful Department of Surgery Grand Rounds 11/8/10 David Mauchley MD Hemostasis and Coagulation Traditional cascade model Two convergent pathways Series of proteolytic