COMBATING. Piya Samankatiwat Ramathibodi hospital

Transcription

1 COMBATING SEVERE COAGULOPATHY O Piya Samankatiwat y Ramathibodi hospital

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3 Haemostasis Mechanisms Endothelium and Vascular function Platelet l t amount and function Coagulation factors Fibrinolysis

4 Vascular function Endothelial response Vasoconstriction Mdit Mediators

5 Platelet function Adequate amount of platelet Platelet activation and adhesion Platelet l t aggregation Stimulation of coagulation factors through platelet factor

6 Coagulation factors Intrinsic pathway Extrinsic pathway

7 Current concept on haemostasis by coagulation factors Substrates: Vascular injury: exposure of tissue factor Contact of tissue factor and factor VIIa Activation of platelets Activation of factor VII Prothrombin Fibrinogen Thrombin burst

8 Current concept of coagulation Initiation phase Amplification phase Propagation phase

9 1. Initiation phase Injury of vessels wall leads to contact between blood and subendothelial cells Tissue factor (TF) is exposed and binds to FVIIa or FVII which is subsequently converted to FVIIa The complex between TF and FVIIa activates FIX and FX FXa binds to FVa on the cell surface

10 2. Amplification phase The FXa/FVa complex converts small amounts of prothrombin into thrombin The small amount of thrombin generated activates FVIII, FV, FXI and platelets locally. FXIa converts FIX to FIXa Activated platelets Activated platelets bind FVa, FVIIIa and FIXa

11 3. Propagation phase The FVIIIa/FIXa complex activates FX on the surfaces of activated platelets FXa in association with FVa converts large amounts of prothrombin into thrombin creating a thrombin burst. The thrombin burst leads to the formation of a stable fibrin clot.

12 Summary of haemostasis Endothelium and vascular function Platelet amount and function Stimulation of coagulation lti factors

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14 Coagulopathy Definition Clotting (coagulation) disorder Abnormality of haemostasis

15 Causes Acquired: liver failure, usage of anticoagulant, etc Autoimmune cause of acquired disorder: antiphospholipid p p syndrome Genetics: abnormal production of clotting factors e.g. haemophilia

16 Bleeding disorder d Platelet disorders Coagulation disorders Hyperfibrinolysis Medication induced coagulopathy Anaemia; severe

17 Coagulopathy Thrombocytopaenia and purpura Nonthrombocytopaenic purpura: Henoch Schönlein purpura Thrombocytopaenic purpura: ITP (Evans syndrome) TM (TTP) Heparin induced thrombocytopenia May Hegglin anomaly Platelet function adhesion (Bernard Soulier syndrome) aggregation (Glanzmann's thrombasthenia) platelet storage pool deficiency (Hermansky Pudlak syndrome, Gray platelet syndrome) Clotting factor Hemophilia (A/VIII, B/IX, C/XI) Von Willebrand disease Hypoprothrombinemia/II i XIII

18 Platelet disorders Hereditary platelet dysfunction Disorder of adhesion Bernard Soulier Syndrome: a deficiency on the surface of the platelet in an area called Glycoprotein Ib/IX Disorder of aggregation GlanzmannThrombasthenia: life threatening. a deficiency of a protein on the surface of the platelet, called Glycoprotein IIb/IIIa Disorder of secretion: Delta storage pool deficiency Gray platelet syndrome Disorder of platelet procoagulant activity Scott syndrome Combination of disorder of number and activity: May Hegglin Anomaly Alport Syndrome Wiskott Aldrich Syndrome.

19 Platelet disorders Acquired platelet disorders in number and functions: Thrombocytopaenia: immune thrombocytopaenic purpura (ITP) Platelet function can be affected by common drugs. Aspirin (ASA) and other drugs containing aspirin Non steroidal anti inflammatory drugs like indomethacin, ibuprofen and naproxen Ticlopidine Other drugs can also affect platelet function. These include: Some antibiotics Cardiovascular drugs Antidepressants Anaesthetics ti Antihistamines Platelet function returns to normal when these medications are stopped. Certain medical conditions can cause abnormal platelet function. Chronic kidney disease Cardiopulmonary bypass surgery Some forms of leukemia Rare causes: cardiac tumour

20 Coagulation factor disorders Hereditary coagulation disorders: Haemophilia A Haemophilia B Haemophilia C Von Willebrand s disease Serum prothrombin conversion accelerator (SPCA) deficiency Hypoprothrombinaemia Disseminated intravascular coagulation

21 Drug induced haemostatic disorders Anti platelet therapy Aspirin Clopidogrel (Plavix ) Glycoprotein (GP) IIb/IIIa inhibitors Anticoagulants a ts Heparin and LMWH Oral anticoagulant: warfarin Thrombolytic agents: streptokinase/ urokinase

22 Effects of CPB on coagulation Heparin effect Heparin rebound Heparin induced thrombocytopaenia (HIT I & II) Consumption of platelets and clotting factors Hyperfibrinolysis Hypothermia Haemodilution Systemic inflammatory response

23 Perioperative evaluation of coagulopathy History and physical examination History of medications Complete blood count Evaluation of platelet function Evaluation of coagulating factor Evaluation of fibrinolysis

24 Preoperative evaluation of coagulopathy History and physical examination Reliable and increases sensitivity and specificity of haemostasis tests Simple systematic questionnaire

25 A simple screening questionnaire have you ever bled for a long time or developed a swollen tongue or mouth after cutting or biting your tongue, cheek or lip? do you develop bruises larger than «a silver dollar» without being able to remember when or how you injured yourself? If so, how big was the largest of these bruises? how many times have you had teeth pulled and what was the longest time that you bled after an extraction? Has bleeding ever started up again the day after extraction? what operations have you had, including minor surgery such as skin biopsies? Was bleeding after surgery ever hard to stop? Have you ever developed unusual bruising in the skin around an area of surgery or injury? have you had a medical problem within the past 5 yr requiring a doctor s care? If so, what was its nature? what medications including aspirin or any other remedies for headaches, cold, menstrual cramps or other pains have you taken within ihi the past 7 9 days? has any blood relative had a problem with unusual bruising or bleeding after surgery? Were blood transfusions required to control this bleeding?

26 Preoperative evaluation of coagulopathy Complete blood count Haematocrit Evaluation of platelet number and function Platelet count Bleeding time Evaluation of coagulating factors Prothrombin time (PT) Partial thromboplastin time (PTT) Evaluation of fibrinolysis

27 Intra opertive management of bleeding

28 Intraoperative monitoring of haemostasis A large prospective trial in cardiac surgery used two bedside monitors at the same time : the Coaguchek (APTT,PT) and the T 540 (PC) to set up an algorithm for platelet concentrates and fresh frozen plasma infusion. The use of the products was guided by the instantaneous results provided by the monitors. Received significantly less intraoperative fresh frozen plasma (0.4±1.1 U vs 2.4±2.8 U) Shorter operation times and less mediastinal chest tube drainage in the early perioperative time Also received fewer platelets (1.6±5.9) vs 6.4±8.2 U) and red blood cell transfusions after the operation. Despotis GJ et al : Prospective evaluation and clinical utility of on site monitoring of coagulation in patients undergoing cardiac operations. J Thorac Cardiovasc Surg 1994; 107:

29 Intra operative management Prevention: Meticulous surgical technique and haemostasis is the most important. Pharmacologic method: aprotinin, transexamic a. Mechanical: heparin coated circuit SIRS: leucocyte reduction filter

30 Intra operative management Therapeutic: Addition doses of protamine Aprotinin Antifibrinolytics: Tranexamic acid, epsilon aminocaproic acid Recombinant factor VIIa Local haemostats: Floseal, Coseal, oxidised cellulose (Surgicel ), Gelfoam, Bio glue and fibrin glue

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32 Protamine Polycationic peptide isolated from sperm of salmon Counteract the effects of heparin and is usually given in a 1:1 ( : 1) mg/mg ratio to return the ACT to baseline. Despite complete neutralisation of heparin, the ACT may remain elevated in patients with significant thrombocytopenia or coagulopathy. Moderate thrombocytopenia has not been shown to increase ceasethe ACT in patients ts with normally functioning platelets, it does seem to increase it when associated with platelet dysfunction after bypass.

33 Aprotinin Serine proteases inhibitor Polypeptide molecule Forms complex bond with ih active serine of various protease molecules e.g. trypsin, kallikrein, plasmin The most potent antifibrinolytic agent: Aprotinin 4 µmol/l can inhibit "intrinsic" fibrinolysis of activated kallikrein and can inhibit plasmin from extrinsic" or activation of plasminogen by tissue plasminogen activator (tpa) Also exhibit anti inflammatory inflammatory effects Remark: withdrawn from FDA due to serious complications

34 Aprotinin (1) High dose: 2 million KIU prior to heparinisation 2 million KIU in pump prime 0.5 million KIU/h (2) Low dose: half of above (3) Weight adjusted: 3.5 mg/kg IV bolus 70 mg pump prime load 3.5 mg/kg/h for 1 hour 1 mg/kg/h /h continuous infusion i

35 Tranexamic acid and epsilon aminocaproic acid (EACA) The appropriate it dosing of tranexamic acid is not well defined. 10 mg/kg over 20 minutes followed by a 1 mg/kg/h Infusion 1 g bolus followed by an infusion of 400 mg/h with 500 mg in the pump prime. Another study showed that one dose of 100 mg/kg given before CPB was very effective in reducing bleeding. For EACA 5 g after the induction of anesthesia, 5 g on pump, and 1 g/h during the procedure. Giving a 5 10 g dose only at the time of heparinization for bypass also reduces blood loss.

36 Postopertive management of bleeding

37 Causes of excessive bleeding after cardiac surgery Inadequate surgical haemostasis Prolonged bypass time Platelet dysfunction or consumption (dilutional thrombocytopenia) Excessive e hemostatic ostatcactivationat Exposure to long acting antiplatelet or antithrombotic agents.

38 Levy JH, Tanaka KA, Steiner ME. Evaluation and management of bleeding during cardiac surgery. Curr Hematol Rep Sep;4(5): Excessive bleeding after cardiac surgery occurs because of alterations in the hemostatic system pertaining to dilutional thrombocytopenia, excessive hemostatic activation, and exposure to long acting antiplatelet t l t or antithrombotic agents.

39 Recognition of bleeding disorder: Tests Platelet function: bleeding time, platelet function analyser (PFA) Coagulogram: PT, aptt Blood level of coagulation factors Fibrinolytic oy cactivity tests s

40 Post operative operative assessment Clinical evaluation Conventional haemostatic assessment Complete blood count with platelet count Coagulogram: PT, PTT, TT and INR Additional tests(if required): D dimer, FDP, fibrinogen level Pit Point of care Activated clotting time (ACT) Hepcon PFA 100 Thromboelastography (TEG)

41 Thromboelastography

42 THROMBOELATOGRAPHY Qualitative analysis

43 Thromboelastography in practice p Low MA Platelet dysfunction

44 Thromboelastography in practice Fibrinolysis

45 Advantages of TEG over conventional coagulation monitoring It is dynamic, giving information on entire coagulation process, rather than on isolated part It gives information on areas which it is normally difficult to study easily fibrinolysis and platelet function in particular Near patient testing means results are rapid facilitating appropriate intervention It is cost effective compared to conventional tests

46 Platelet function analyser (PFA)

47 Comparison of structured use of routine laboratory tests or near patient assessment with clinical judgement in the management of bleeding after cardiac surgery 210 patients allocated in one of 3 groups Laboratory guide algorithm (LGA, n=51) Point of care (POC, n=51) Clinician discretion (n=108) Blood loss, transfusion of blood and blood components Avidan MS, Alcock EL, Da Fonseca J et al. BJA 2004, 92(2):

48 Comparison of structured use of routine laboratory tests or near patient assessment with clinical judgement in the management of bleeding after cardiac surgery 210 patients allocated in one of 3 groups In clinician discretion group had unnecessary transfusion although degree of blood loss was not different among groups. In LAG and POC groups, algorithm was equally effective. In contrast, POC group had significantly less blood component use in previous studies. Avidan MS, Alcock EL, Da Fonseca J et al. BJA 2004, 92(2):

49 Point of care of tests Targeting blood component therapy according to identified abnormalities in coagulation system Identifying patients who could benefit from pharmacologic interventions Identifying patients who have a surgical source of bleeding can be expedited if coagulation tests reveal relatively normal results in the setting of excessive bleeding.

50 Current therapeutic strategy Fluid replacement to maintain adequate cardiac output Avoid idhypothermia Adequate haematocrit concentration Coagulation factors and platelets ltlt Pharmacological agents e.g. aprotinin, tranexamic acid (Transamin ) ), epsilon aminocaproic acid (EACA, amicar ) Recombinant activated factor VII (rfviia, NovoSeven )

51 Hypothermia Reversible reduction in platelet count and function Altered coagulation Enhanced fibrinolysis At C, patients ts developed e more oe extensive bleeding than at normothermia. Prolonged bleeding time, PT andptt

52 Adequacy of haematocrit Keep Hct at the level of 35 % (Hb 11 gm/dl) An adequate haematocrit is required for optimum haemostasis. Red blood cells (RBC) have an established role in arterial thrombosis formation. Escolar et al. studied the effect of RBC and platelet count on the interaction of platelets with the subendothelium, using the Baumgartner perfusion technique. Platelet aggregation was impaired when haematocrit was decreased d to 20% and this was independent of platelet count. Escolar G, Garrido M, Mazzara R, Castillo R, Ordinas A : Experimental basis for the use of red cell transfusion in the management of anemic thrombocytopenic patients. Transfusion 1988; 28 :

53 Roles of red blood cell in clot formation Rheologic role: in living blood circulation, red blood cells circulate in the central flow while platelets l t in the periphery. Elevating haematocrit promotes the transport of platelets towards the vessel wall. Source of adenosine diphosphate (ADP) enhance platelet degranulation Contain multiple cryptic adhesion receptors Catalyse phosphatidylserine p exposure needed for activation of coagulation cascade May express antithrombotic properties

54 Coagulation factors and platelets Platelet concentrate 0.2 Unit/Kg FFP 10 ml/kg Cryoprecipitate 0.2 Unit/Kg

55 Pharmacologic agents Protamine Aprotinin (Trasylol ) Tranexamic acid Epsilon aminocaproic acid

56 Protamine Additional dose will be given in case of prolonged ACT or PTT 1 mg/kg/dose intravenously

57 Tranexamic acid and epsilonaminocaproic acid In first time coronary revascularisation EACA and tranexamic acid decreased total exposure to allogenic blood products Justifying the routine use of synthetic antifibrinolytics Dose: 1 4 mg/kg/dose Hardy JF, Belisle S, Dupont C et al. Prophylactic tranexamic acid and epsilonaminocaproic acid for primary myocardial revascularization. Ann Thorac Surg 1998;

58 Mode of Action Recombinant factor VIIa Tissue factor (TF)/FVIIa, or TF/rFVIIa interaction, is necessary to initiatiate haemostasis At pharmacological concentrations rfviia directly activates FX on the surface of locally activated t platelets. l t This activation will initiate the thrombin burst independently of FVIII and FIX. This step is independent of TF. The thrombin burst leads to the formation of a stable clot

59 Consider re opening if: bleeding >200 ml/hr for 3 4 hours or more than 5 % of blood volume per hour bleeding >400 ml/hr in 1 hour total loss > ml

60 Excessive mediastinal bleeding after CPB Heparinase ACT protamine Normalise temperature Hct < 27 % PRC Immediate reoperation if > ml/hr x 2 hr, > 150 ml/hr thereafter tamponade Bleeding is controlled Bleeding persists: Platelet count PT, aptt, fibrinogen TEG? HemoSTATUS? Sonoclot? PFA 100? Normal coagulation test Fibrinogen < 1 g/l: fibrinogen concentrates < 100 x 10 9 /L platelets Bleeding persists > 100 x 10 9 /L PT > 1.5 normal, aptt > 1.5 normal PT > 1.5 normal, aptt > 1.5 normal Yes FFP No Platelets Yes FFP No Platelets Bleeding persists despite blood products IV antifibrinolysis Reoperation? Clot removal +/ local antifibrinolysis

61 Complications of blood transfusion Immune mediated transfusion reactions Acute Haemolysis Febrile nonhaemolytic transfusion reaction (FNHTR) Acute lung injury (TRALI) leads to ARDS Urticaria Anaphylaxis Delayed eayed Alloimmune Haemolysis Graft versus host disease (GVHD) Platelet refractory Prevention is the most crucial way in order to minimise transfusion complications.

62 Complications of blood transfusion Non immune mediated transfusion reactions Acute Haemolysis Embolic Metabolic disorder: citrate toxicity, coagulopathy, hypothermia, hyperkalaemia, hypocalcaemia Circulatory overload Delayed Metabolic iron overload Infection: viral, bacteria, parasite Preventionis is the mostcrucial way inorder to minimise transfusion complications.

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64 Conclusion Simplemethods methods, for example historytaking taking and systematic questionnaire, are crucial in preoperative evaluation of coagulopathy. Thorough surgical haemostasis remains the most important measure to reduce postoperative bleeding in cardiac surgery Application of a structured approach has been reported in terms of reduction in unnecessary blood transfusion. Aggressive postoperative haemostasis management is significant in prevention of transfusion complications

65 Conclusion Properly manage the bleeding problem. Reduce unnecessary blood and blood component transfusion. Minimise transfusion reactions and transfusion related complications. Identify patients at risk and high risk operations Surgical bleeding must be excluded. d Use of the right test, right component (medicine) at the right time