Transfusion & Non-transfusion Approaches to Bleeding

Transcription

1 Transfusion & Non-transfusion Approaches to Bleeding Maureane Hoffman, MD, PhD Professor of Pathology, Duke University and Director, Transfusion Service and Hematology Laboratory Durham Veterans Affairs Medical Center Durham, NC

2 Disclosures I have received research funding from: Novo Nordisk CSL-Behring Momenta Pharmaceuticals Boehringer-Ingelheim I have received consulting fees/honoraria from: Novo Nordisk CSL-Behring Baxter The Medicines Company

3 Objectives Appreciate differences between the coagulation cascade (biochemistry) and cell-based (physiology) models of hemostasis Understand that lab assays provide information about coagulation factor levels, but not necessarily bleeding risk Discuss transfusion and pharmacologic approaches to restoring hemostasis

4 In the 1960 s s the coagulation factors were organized into a cascade or waterfall model. This evolved into the current cascade model Macfarlane RG. An enzyme cascade in the blood clotting mechanism, and its function as a biological amplifier. Nature. 1964;202: Davie EW, Ratnoff OD. Waterfall sequence for intrinsic blood clotting. Science. 1964;145:

5 The Coagulation Cascade aptt Intrinsic Pathway FXII/HMK/PK PT Extrinsic Pathway Factor XI Factor IX Factor XIa Factor IXa Factor VIIIa Lipid Factor VIIa Tissue Factor Lipid Factor X Prothrombin Factor Xa Factor Va Lipid Factor X Thrombin Fibrinogen Fibrin

6 The Coagulation Cascade aptt Intrinsic Pathway FXII/HMK/PK + Kaolin Factor XI Factor IX Factor XIa Factor IXa Factor VIIIa Lipid PT Extrinsic Pathway Factor VIIa Tissue Factor Lipid Factor X Prothrombin Factor Xa Factor Va Lipid Factor X Thrombin Fibrinogen Fibrin

7 The Coagulation Cascade aptt/act/teg Intrinsic Pathway FXII/HMK/PK + Kaolin Factor XI Factor IX Factor XIa Factor IXa Factor VIIIa Lipid PT Extrinsic Pathway Factor VIIa Tissue Factor Lipid Factor X Prothrombin Factor Xa Factor Va Lipid Factor X Thrombin Fibrinogen Fibrin

8 The Coagulation Cascade aptt Intrinsic Pathway FXII/HMK/PK + Kaolin Factor XI Factor IX Factor XIa Factor IXa Factor VIIIa Lipid PT Extrinsic Pathway TF/Lipid Factor VIIa Tissue Factor Lipid Factor X Prothrombin Factor Xa Factor Va Lipid Factor X Thrombin Fibrinogen Fibrin

9 The cascade was intended as a model of how coagulation proteins interact biochemically, not how hemostasis works in the body It IS a good model of what happens in the PT and aptt assays

10 aptt Does not Correlate with Bleeding Risk Factor XII/HMK/PK Prolonged aptt No bleeding Factor XI Factor XIa Prolonged aptt Variable bleeding Factor IX Factor IXa Factor VIIIa Prolonged aptt Severe bleeding Factor X Factor Xa Factor Va Prothrombin Thrombin Fibrinogen Fibrin

11 Can putting the cells back in the model explain some clinical phenomena that the protein-centered cascade model cannot?

12 Cell-based experimental model cells monocytes (TF) 1 pm TF 15/uL platelets 100,000/uL proteins prothrombin 1400 nm 100 ug/ml factor VII 10 nm 0.5 ug/ml factor IX 70 nm 4 ug/ml factor X 135 nm 8 ug/ml factor XI 30 nm 5 ug/ml factor V 20 nm 7 ug/ml factor VIII 0.3 nm 0.1 ug/ml inhibitors antithrombin 3000 nm 200 ug/ml TFPI 3 nm 0.1 ug/ml

13 Cell-based conceptual model - Hemostasis occurs on two surfaces: TF-bearing cells and platelets 1.Initiation IIa 2.Amplification 3.Propagation IIa

14 TF VIIa TF X VIIa Xa Va II Initiation IIa TF-Bearing Cell IX TF VIIa IXa Hoffman & Monroe: A Cell-Based Model of Hemostasis. Thromb Haemostas,, 85:958-65, 2001

15 Endothelial cells don t have TF TF is in cells outside the vessel

16 Platelets Adhere & Are Partially Activated at Sites of Injury

17 Hoffman & Monroe: A Cell-Based Model of Hemostasis. Thromb Haemostas, 85:958-65, 2001 Amplification TF VIIa TF X VIIa Xa Va II VIII/vWF IIa VIIIa + vwf XI TF TF-Bearing Cell VIIa V Priming Amount of Thrombin Platelet V Va XIa XIa VIIIa Va Activated Platelet

18 Propagation Xa TFPI VIIa TF TF VIIa Xa Va VIII/vWF IIa VIIIa + vwf XI TF-Bearing Cell V Platelet V Va XIa TF IX IX VIIa X II IXa Xa IIa XIa VIIIa Va Activated Platelet Large amount of thrombin Hoffman & Monroe: A Cell-Based Model of Hemostasis. Thromb Haemostas,, 85:958-65, 2001

19 A Cell-Based Model of Hemostasis TF X VIIa Xa Va TF-Bearing Cell II IIa VIII/vWF VIIIa IXa XIa TF IXa VIIa X IX Xa II V VIIIa Va Activated Platelet Va Platelet IIa XI XIa IX Hoffman M, et al. Blood Coagul Fibrinolysis. 1998;9(suppl 1):S61-S65. S65.

20 There Really Are Intrinsic and Extrinsic Pathways They are not redundant - they operate on different cellular surfaces to fill different roles The extrinsic or TF pathway works on the initiating cells The intrinsic pathway works on platelets to produce the thrombin burst

21 All of our coagulation lab tests are oversimplifications of hemostasis in vivo!! Lab tests are useful, but remember that all of them have limitations YES - even those done on whole blood like TEG/ROTEM

22 Now on to Pathophysiology

23 Why do previously normal patients bleed? Anatomic defects - surgical bleeding Microvascular (coagulopathic) bleeding Dilution or depletion of coag factors and platelets Hyperfibrinolysis Hypothermia Acidosis?

24 Good News! The common tests are useful for evaluating the cause of bleeding The PT and aptt are useful if we have a bleeding patient and we want to figure out if a factor deficiency is responsible TEG & ROTEM are also useful, but need more than just the basic test

25 The tests we have are fine for directing transfusion therapy Prolonged PT or aptt = plasma Low fibrinogen = cryoprecipitate Low platelet count or defect on platelet function testing = platelet concentrates

26 Blood component therapy does not always stop the bleeding The goal of transfusion is to restore the patient to normal Replacement doesn t always work FFP is always somewhat diluted Platelets have a storage defect Consumption may outstrip replacement May need more volume than patient can tolerate Even if we restore apparently normal levels, bleeding may not stop

27 To maintain hemostasis a sufficiently stable clot must be formed Primary hemostasis via platelet plug Stabilized by a meshwork of fibrin due to platelet surface thrombin generation Final clot must resist mechanical and enzymatic disruption until healing occurs

28 Fibrin assembly can be a race against plasmin degradation

29 Do any of our lab tests tell us when local fibrinolysis is winning the race? No - we probably have to guess Our lab tests only tell us about the conditions of the blood components

30 What else can we do for microvascular bleeding, when transfusion hasn t done the trick? Anti-fibrinolytics Coagulation factor concentrates - can achieve supra-normal levels of factors FVIIa Fibrinogen concentrate Prothrombin complex concentrates

31 The whole idea is to get a stable platelet/fibrin clot IIa Fibrinogen

32 Fibrin clot structure & stability depend on the amount/rate of thrombin generated and the amount of fibrinogen incorporated Higher levels of each give more structurally stable clots

33 More thrombin gives a more tightly packed clot

34 We can enhance thrombin generation by: Replacing deficient factors or platelets Should return thrombin generation to normal Might not be enough Administration of rfviia Note that this is an off-label use Can get thrombin generation higher than normal in non-hemophilic patients This could be both good and bad

35 The Best Dose of FVIIa for Surgical Patients is Less than Hemophilia Between , 40 patients received low- dose rfviia (ave 18 μg/kg) for coagulopathy after cardiac surgery. Compared to propensity score-matched controls, FVIIa group had less 24-hr bleeding, shorter time on ventilator and shorter stay in the ICU. No thromboembolic events were noted Gelsomino et al:treatment of refractory bleeding after cardiac operations with low-dose recombinant activated factor VII (NovoSeven): a propensity score analysis. Eur J Cardiothorac Surg Jan;33(1):64-71

36 The Best Dose of FVIIa for Surgical Patients is Less than Hemophilia Between , 425 patients underwent thoracic aortic operations with CPB; 77 received intraoperative rfviia ( 60 μg/kg) for coagulopathy. Propensity matching identified controls for comparison. FVIIa group received less postop blood (2.5 vs 5.0 units; p=0.05). No patient receiving FVIIa required postop rfviia or reexploration for bleeding. Rates of stroke, thromboembolism, myocardial infarction, and other adverse events were equivalent Andersen et al: Intraoperative use of low-dose recombinant activated factor VII during thoracic aortic operations. Ann Thorac Surg. 2012; 93(6):1921-8

37 Maureane s Recommendations on Use of rfviia in CV Surgical Patients Optimize platelets and coag factors as much as possible with transfusion Consider patient s temp and ph Administer antifibrinolytic If still significant bleeding, consider FVIIa Don t either go for FVIIa first or wait til patient is in truly dire straits Use <60 µg/kg - convenient to use 2 mg vial (= 28 µg/kg for a 70 kg patient)

38 Maureane s Recommendations cont d Also consider FVIIa when provision of blood products is difficult or impossible Supply issues such as RBC antibodies, availability of platelet products Acceptance issues such as Jehovah s witness

39 Fibrinogen Concentrate

40 Higher levels of fibrinogen produce more tightly packed and stable fibrin clots in vitro and increase fibrin content of clots and resistance to lysis in vivo Machlus et al. Blood 2011, 117:

41 Higher pre-op fibrinogen associated with less bleeding after CPB and Fibrinogen concentrate reduced bleeding compared to historical controls Ucar et al. Preoperative fibrinogen levels as a predictor of postoperative bleeding after open heart surgery. Heart SurgForum. 2007;10(5):E Rahe-Meyer et al. Bleeding management with fibrinogen concentrate targeting a high-normal plasma fibrinogen level: a pilot study. Br J Anaesth.2009;102(6):

42 We can increase fibrinogen with: Cryoprecipitate Concentrated form of fibrinogen as well as FVIII/vWF Might enhance platelet adhesion as well as increase fibrinogen Administration of fibrinogen concentrate (note that this is an off-label use) Infectious disease risk probably less than cryo Can give a known dose of fibrinogen

43 How much is enough fibrinogen?..or too much? We don t know.

44 Early Administration of Fibrinogen Might Reduce the Need for Blood Transfusion Fibrinogen level was targeted to 360 mg% ( high normal )

45 Could extra fibrinogen make up for a coagulation or platelet defect? 38 patients with decreased preop platelet function by Multiplate aggregometry. Those with bleeding after CPB (29 patients) received either fibrinogen concentrate or blood components Outcomes were no different between fibrinogen and transfusion groups. Of course, fibrinogen group received fewer blood products. This result suggests that increased fibrinogen might make up for another defect in coagulation (namely poor platelet function). Solomon C, et al. Haemostatic therapy in coronary artery bypass graft patients with decreased platelet function: comparison of fibrinogen concentrate with allogeneic blood products. Scand J Clin Lab Invest. 2012;72(2):121-8.

46 What is the best thing to do for your bleeding patient? (more things we don t know) Blood components/fviia/fibrinogen? What strategy is most effective? What tests can we use to guide therapy? What should our targets be? What are the risks of thrombosis? Immediately? Several days post-op?

47 Take-home messages The cascade model helps us interpret the PT and aptt tests A cell-based model gives us insight into hemostatic mechanisms in vivo It is not clear which tests are the best guides for hemostatic therapy Clot stability can be enhanced by increasing thrombin generation or increasing the fibrin in the clot

48 Questions

49 The extrinsic pathway acts in vivo to initiate coagulation PT Assay in vivo Adapted from: Monroe DM and Hoffman, M: What does it take to make the perfect clot? Arterio Thromb Vasc Biol 26:41-48, 2006

50 The intrinsic pathway acts on platelet surfaces to generate large amounts of thrombin aptt in vivo Adapted from: Monroe DM and Hoffman, M: What does it take to make the perfect clot? Arterio Thromb Vasc Biol 26:41-48, 2006