Hemostasis, Bleeding, and Vascular Disorders. PD Dr. med. Michel Adamina, MSc, EMBA HSG Klinik für Viszeral- und Thoraxchirurgie

Transkript

1 Hemostasis, Bleeding, and Vascular Disorders PD Dr. med. Michel Adamina, MSc, EMBA HSG Klinik für Viszeral- und Thoraxchirurgie

2 Outline Hemostasis Coagulation and functional tests Bleeding disorders Anticoagulant drugs Thromboembolie 2

3 Phases of the hemostatic process Initiation and formation of the platelet plug Propagation of the clotting process by the coagulation process Termination of clotting by antithrombotic control mechanisms Clot removal by fibrinolysis 3

4 Hemostasis is a dynamic process Fine balance between Thrombus formation Intrinsic / extrinsic / common pathways Thrombus inhibition avoids abnormal thrombus propagation: protein C, protein S, heparin co-factor II, antithrombines, antithromboplastines Thrombus dissolution 4

5 Coagulation process Tissue injury: liberation of tissue factor, aka thromboplastin extrinsic pathway Injury of vascular endothelium: contact activation intrinsic pathway Platelet phase: platelet adhesion (vw) platelet aggregation (serotonin) platelet activation (collagen, thrombin) thrombus Vascular phase: vasoconstriction (serotonin) blood flow slowed down 5

6 Coagulation factors & coagulation cascade I Fibrinogen banked blood II Prothrombin banked blood III Thromboplastin tissue IV Calcium V Proaccelerin fresh blood VI activated factor V VII Proconvertin banked blood VIII Antihemophilic A fresh blood IX Antihemophilic B banked blood X Stuart power banked blood XI PTA * banked blood XII Hageman factor banked blood XIII Fibrin stab. factor banked blood * plasmothromboplastin antecedant 6

7 Coagulation factors Vitamin K dependent factors factors II, VII, lx, X protein C and protein S 7

8 Role of the liver Loss of liver parenchym decreases: - all coagulation factors except f Vlll and von Willebrand co-f. - physiologic inhibitors of the coagulation (ATlll, prot C, prot S) - components of the fibrinolytic system (mainly plasminogen and α2 antiplasmines) Liver dysfunction induces: - platelet dysfunction - dysfibrinogenemia - accelerated fibrinolysis (impaired clearance of tissue plasminogen activators t-pa) 8

9 Mechanisms of platelet activation Loss of the antithrombotic continuum of endothelial cells causes platelet adhesion Shear forces induces aggregation through the binding of v.w Factor to GP-lb receptor. Transformation of archidonic acid into thromboxane A2 which exerts a strong feed-back amplification Platelet activation is mediated by various agonists such as thrombin, ADP, thromboxane A2, platelet activating fact., serotonin, epinephrin. It induces a conformational change in the structure of GP llb/llla receptors which increases their activity for fibrinogen and v.w factor 9

10 Coagulation cascade Intrinsic system Extrinsic system Platelet thrombus platelet activation tissue thromboplastin VII + Ca XII XII a XI a + Ca IX a VIIl + Ca V V a + Ca X X a Prothrombin (II) Thrombin XIII XIII a Fibrinogen (I) Fibrin s + Ca Fibrin i 10

11 Coagulation cascade Intrinsic system Extrinsic system Platelet thrombus platelet activation tissue thromboplastin VII + Ca XII XII a XI a + Ca IX a VIIl + Ca X X a V V a + Ca Prothrombin (II) Thrombin XIII XIII a Fibrinogen (I) Fibrin s + Ca Fibrin i 11

12 Extrinsic pathway: clotting initiation Activation of fact X by tissue factor-vll a complex is 50 times weaker than by the intrinsic pathway. The tissue factor-vlla complex also activates factor lx & X, thus strongly interacting within the intrinsic pathway, ie amplification process. This mechanism is useful to maintain the clotting process because tissue factor-vlla complex is rapidly inhibited by the endogeneous TFPI (tissue factor pathway inhibitor) 12

13 Coagulation cascade Intrinsic system Extrinsic system Platelet thrombus platelet activation tissue thromboplastin XII XII a XI a + Ca IX a VIIl + Ca VII + Ca X X a V V a + Ca Prothrombin (II) Thrombin XIII XIII a Fibrinogen (I) Fibrin s + Ca Fibrin i 13

14 Endogeneous anticoagulants Intrinsic activation of clotting process inhibited by smoothness of the vascular endothelium (Negatively charged proteins in the vascular endothelium continuously repell clotting factors and platelets + NO /TFPI / thrombomodulin, prostacycline, release of fibrinolytic mediators). endogeneous anticoagulants, mainly - AT lll (binds to thrombin and prevents fibrinogen-fibrin) - Heparin co-factor II (homologous with ATlll) - Prot C (inhibits activity of factors V and Vll) - Prot S (enhances the effect of protein C). - TFPI tissue factor pathway inhibitor (inhibits tissue factor-vlla complex) 14

15 15 15 Klinik für

16 Blutgerinnung so wie ich sie verstehe 16

17 Ausgangslage Thbc Endothel Subendothel 17

18 Endothelschaden Thbc Endothel: Subendothel Von Willebrand Faktor Kollagen TF 18

19 Adhäsion Endothel Subendothel Thbc vwf 19

20 Aktivierung ADP Thromboxan A 2 Endothel Thbc Subendothel 20

21 Aggregation Fibrinogen GP IIb/IIIa Rec Endothel Thbc Subendothel 21

22 Endothel Subendothel Thbc Primäre Hämostase Plättchenreicher Thrombus 22

23 Extrinsic Thrombin XIa XIIa Subendothel Prothrombin Ca 2+ + Va + Xa Prothrombinase- Komplex VII X TF 23

24 Extrinsic Thrombin XIa XIIa Subendothel Prothrombin Ca 2+ + Va + Xa Prothrombinase- Komplex VII + X TF 24

25 Intrinsic Thrombin Ca 2+ + VIIIa + IXa XIa XIIa Subendothel Prothrombin Ca 2+ + Va + Xa Prothrombinase- Komplex VII + X TF 25

26 Intrinsic Thrombin Ca 2+ + VIIIa + IXa X Prothrombin Ca 2+ + Va + Xa Prothrombinase- Komplex X XIa XIIa Subendothel VII + TF 26

27 Thrombin Burst THROMBIN Ca 2+ + VIIIa + IXa X Prothrombin Ca 2+ + Va + Xa Prothrombinase- Komplex X XIa XIIa Subendothel VII + TF 27

28 Thrombin Fibrinmonomere Protofibrillen Fibrinogen F XIIIa Fibrin- Thrombus Fibrin-Netzwerk 28

29 Endothel Subendothel Thbc Sekundäre Hämostase Fibrinbildung 29

30 Fibrinolyse Plasminogen Plasminogenaktivator Fibrinogen-Spalprodukte Endothel Subendothel 30

31 Thbc Endothel Subendothel 31

32 Summary XIIIa mod. nach Corti R, et al. Kardiovaskuläre Medizin 2004; 7:

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34 34 Coagulation and functional tests

35 Coagulation tests Prothrombin time Global test for extrinsic + common pathways Global test for factors l, ll, V, Vll, X measures level of anticoagulant therapy (Quick: 100 %,INR: 1.0) a PTT* Global test for intrinsic + common pathways Global test for factors l, ll, V, VIII, Xll * activated partial thromboplastin time 35

36 Coagulation tests Thrombin time time for plasma to clot after adding exogeneous thrombin (N=13-17 ) Increased in cases of hypo-dys- or afibrinogenemia and of DIC Activated clotting time alternative measure of level of heparinization (N 120 ) Ethanol test measures circulating fibrin monomers (reflects thrombin activity) 36

37 Platelet function tests Peripheral platelet count 150k 400k Platelet function analyzer (PFA-100) Evaluates platelet number and function, replaced the Bleeding Time test Rotational thrombelastometry Evaluates speed and strength of clot formation Can accomodate physiologic condition as well as real-life conditions, e.g. hypothermia 37

38 Gerinnungstests im Labor Prothrombin-Zeit Thromboplastin-Zeit Quick/INR Aktivierte partielle Thromboplastinzeit aptt XIIIa Fibrinogen Faktor XIII Primäre Hämostase mod. nach Corti R, et al. Kardiovaskuläre Medizin 2004; 7:

39 39 Rotem Prinzip

40 Rotem Normalbefund 40 Gerinnung AA-Chirurgie/ Leh 10/2011

41 Rotem Reagenzien (Cytochalasin) 41

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43 Fall 1 38 jährige Patientin Polytrauma nach Motorradunfall Beatmungsprobleme Hypoton 88/61mmHg, Puls 115/min. Becken instabil E-FAST unauffällig: keine Blutung in abdomine keine Pleuraergüsse, kein Perikarderguss Kein ventraler Pneumothorax bds. Thorax ap.: V.a. Lungenkontusion bds. keine Hinweise für Pneumo- oder Hämatothorax Welche Gerinnungsabklärungen sind indiziert? 43 Gerinnung AA-Chirurgie/ Leh 10/2011

44 Fall 1 Blutbild / Thrombozyten, Testblut (Schnell) INR (Bedside innert 2-3 Minuten) jedoch: normale INR und normale aptt schliessen Gerinnungsstörung keinesfalls aus! Rotem Fibrinogen Faktor XIII 44 Gerinnung AA-Chirurgie/ Leh 10/2011

45 Fall 1 45 Gerinnung AA-Chirurgie/ Leh 10/2011

46 Fall 1 Patientin Normalbefund 46

47 Fall 1 A10 (Amplitude 10 min. nach CT): pathol. < 7 mm MCF (max. Gerinnselfestigkeit): pathol. < 10 mm 47

48 Fall 1 INR normal vbga: BE -7. Hb 96 g/l Thrombozyten folgen Faktor XIII und Fibrinogen noch ausstehend Nach Volumengabe (2 Liter RL) Patient mit BD 102/65 mmhg, Puls 107/min. ( Responder ) Was würden Sie tun? 48 Gerinnung AA-Chirurgie/ Leh 10/2011

49 Fall 1 Poly-/ Angio-CT mit ev. Coiling bei V.a. Blutung im Rahmen Beckenfraktur Gerinnungsstabilisierung: Gabe von Fibrinogen (Haemocomplettan P) & ev. Gabe von Faktor XIII (Fibrogammin P) ev. Ec-Gabe immer zusammen mit FFP 1:1 (Hämorrhagie Klasse II-III;; falls Transient Response ) Gabe von Gerinnungsprodukten immer i.r. Teamleader und Anästhesie Nach Korrektur unmittelbar erneute Gerinnungskontrolle Dynamischer Prozess! 49

50 Fall 1 Ziel-Blutdruck Permissive Hypotonie: RR Syst mmhg (ausser: SHT, Querschnittläsion) Todesursache bei Trauma Pat % Schädelhirntrauma & Hämorrhagie Bei Hämorrhagie 90 % der Todesfälle innert der ersten 24 Stunden und 50% davon trotz erfolgreicher OP an persistierender Gerinnungsstörung! 50

51 Fall 2 68 jähriger Patient Schmerzen abdominal, in den Rücken ausstrahlend nach Verhebetrauma, blass BD 85/67mmHg, Puls 127/min., absolut unregelmässig bekannte arterielle Hypertonie OAK bei permanentem Vorhofflimmern Sono: V.a. rupturiertes Bauchaortenanurysma Thorax ap.: keine Zeit gehabt Welche Gerinnungsabklärungen sind indiziert? 51

52 Fall 2 Blutbild/ Thrombozyten, Testblut ( Schockblut bereits vor Ort) mind. 6 Ec-Konzentrate austesten, 2 FFP (Schnell) INR INR 2,4 (Quick 29%) Hb 103 g/l Was würden Sie tun? 52

53 Fall 2 Volumengabe, Ec-Transfusion Ec immer mit FFP im Verhältnis 1:1 i.r. Gefässchirurge / je nach KL-Stabilität entweder: direkt ad OP ev. vorgängig Angio-CT Abdomen Parallel Gerinnungsstabilisierung / Aufhebung OAK aber wie? 53

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55 Fall 2 PPSB (Beriplex P/N 500) = Konzentrat der humanen Gerinnungsfaktoren II, VII, IX, X (PPSB: Prothrombin, Prokonvertin, Stuart-Prower-Faktor, antihämophiler Faktor B) und Protein C und S (alle Vit. K abhängig), enthält Heparin! PPSB 20 E/kg KG i.v. (meist E i.v.) Rücksprache mit TL und/oder Anästhesie Vitamin K (Konakion ) in der Regel 2 mg i.v./ p.o. weshalb? HWZ der Ger.-Faktoren: HWZ F. II: h HWZ F. VII: 3-6 h HWZ F. IX h HWZ F. X h 55

56 Fall 2 Nach Gabe von Beriplex: unmittelbar erneuter Bedside INR & ROTEM (& Fibrinogen/ Faktor XIII) Laufendes Gerinnungs-Monitoring durch Anästhesie während OP sowie nach Gabe weiterer Gerinnungsprodukte 56

57 Take Home Message Gutes Gerinnungs- Management kann die Mortalität beim Trauma/ hämorrhagischen Schock senken Multidisziplinär: Anästhesie, TL, ev. Hämatologe Dynamischer Prozess (prä-, peri- und postoperativ) 57

58 Besten Dank für die Aufmerksamkeit! 58

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65 65 Bleeding disorders

66 Anamnese 1. Thromboembolie-Anamese 2. Epistaxis 3. Menometrorrhagie 4. Verlängerte Blutung nach Zahnziehen 5. Hämatome und Ecchymose 6. Verlängerte Blutung aus Wunden 7. Zahnfleischbluten 8. Postoperative Blutung (allgemein) 9. Postpartale Blutung 10. Gastrointestinale Blutung 11. Gelenkblutungen 12. Hämaturie 66 Pfanner G, et al. Anästhesist 2007; 56: Koscielny J, et al. Clin Appl Thromb Hemost 2004; 10:

67 Anamnese 67 Koscielny J, et al. Clin Appl Thromb Hemost 2004; 10:

68 Anamnese 68 Koscielny J, et al. Clin Appl Thromb Hemost 2004; 10:

69 Anamnese 69 Koscielny J, et al. Clin Appl Thromb Hemost 2004; 10:

70 Gerinnungsstörungen externe Faktoren Acidose Hypothermie Anämie Ca mod. nach Corti R, et al. Kardiovaskuläre Medizin 2004; 7:

71 Disseminated intravascular coagulation Overproduction of thrombin in circulation Induces life-threatening thrombosis + bleeding Clinical signs: - Hypotension activation of the kallikrein/bradykinin system - Hypoxemia bleeding and thrombosis in the lung - Renal failure fibrin deposits in the glomerula - Mental disorders fibrin deposits in cerebral microvessels 71

72 Disseminated intravascular coagulation Triggering conditions: Infection: endothelial injury intrinsic pathway Obstetrical complications extrinsic pathway Neoplasms extrinsic pathway Massive trauma extrinsic pathway Transfusion liberation of phospholipids Severe shock and acidosis miscellaneous. Hypotension due to liberation of kallikrein/bradykinin is only induced by the activation of the intrinsic system 72

73 Disseminated intravascular coagulation Laboratory diagnosis -Lowered platelet count and plasma fibrinogen level -Elevated fibrin split products levels -Prolonged prothrombin time factor consumption + lowered fibrinogen level -Prolonged thrombin time lowered fibrinogen level -Prolonged reptilase time >22 sec, heparin independent -Decreased AT lll consumed by ongoing inhibition of thrombin -Decreased euglobulin time global test for fibrinolytic activity: normal >2 hours, decreases to several minutes 73

74 Disseminated intravascular coagulation Treatment Correct the triggering mechanism: (Uterus emptying / Drainage of abcesses and antibiotics / Chemotherapy / Hormontherapy (Prostata CA) etc). Catheter removal Coagulation support: - heparin alone in patients solely thrombotic - heparin + coagulation factors in thrombotic + hemorrhagic patients 74

75 Bleeding disorders Inherited or acquired: Lack of coagulation factors. Platelet disorders Vasculopathies 75

76 Bleeding disorders Inherited lack of coagulation factors von Willebrand disease prevalence up to 1% bridges PLT to subendothelium, carrier for f VIII hemophilia A (factor VIII) and B (factor lx) F V (Morbus Owren), F Vll, F X, F XI (Jewish), F XII, F XIII Afibrinogenemia (F I) 76

77 Bleeding disorders Acquired lack of coagulation factors oral anticoagulation heparin fibrinolysis liver disease lack of vitamin K (fact ll, Vll, lx, X) disseminated intravascular coagulation (consumption of coagulation factors) severe hemodilution 77

78 Bleeding disorders Inherited platelet disorders Thrombocytopenia Thrombasthenia - von Willebrand s disease - Glanzmann - Naegeli =lack of GP llb/llla complexes Giant platelets - Bernard Soulier syndrome = lack of GP-lb 78

79 Bleeding disorders Acquired platelet disorders Thrombocytopenia (splenomegaly, bone marrow diseases) Lupus, APL syndrome (autoantibodies/steroid treatment), Werlhof (idiopathic thrombopenic purpura) Uremia, Alcoholismus, Viruses (Pfeiffer, HIV, EBV, CMV, rubella, etc) Drugs - antiplatelet drugs - heparin (HIT) - phenylbutazon (antiinflammatory drug) - sulfinpyrazon (antihyperuricemic drug) - others (chemotherapy) 79

80 Bleeding disorders Inherited vasculopathies Teleangiectasia Osler - Rendu - Weber (mult. teleangiectasiae skin +mucosa) Ehlers - Danlos (abnormal collagen in the vessel wall) Cavernous hemangioma 80

81 Bleeding disorders Acquired vasculopathies Toxic (meningococci) Metabolic disease (Cushing) Medication induced (steroids) Avitaminosis (scorbut) Autoimmune disease (purpura Schönlein- Henoch) 81

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83 Antithrombotic / Anticoagulant drugs 83

84 Antithrombotic / Anticoagulant drugs Natural (ATlll, heparin co-factor 2, prot C, prot S Xigris = recombinant activated human proteinc) Antiplatelet (Salicylates, Tirofibran, Clopidogrel, Dextran) Vitamin K antagonists (Marcoumar, Sintrom) Thrombin & F Xa inhibitors (NF heparin, LMWH,Orgaran) Specific F Xa inhibitors (Fondaparinux) Direct thrombin inhibitors (Argatroban, Ximelagatran, Hirudines) F Vlla inhibitors (r-nap c2, recombinant of an ankylostoma saliva) Fibrinolytic agent (urokinase, streptokinase, rt-pa) Defibrinogenating agent (Snake venoms, ancrod, crotalase) 84

85 Anticoagulants Heparin suppresses function Oral anticoagulants suppress synthesis of clotting factors 85

86 Antiplatelet agents Salicylate inhibit the synthesis of thromboxane A2 in platelet Clopidogrel (Plavix ) blocks the binding of ADP with its receptor and, thus, the activation of the GPlla/lllb complex Tirofibran (Aggrastat ) Abciximab (Reo-Pro ) Eptifabatidum (Integrilin ) block the GP llb/llla receptor and /or the binding of fibrinogen and vw. factor Dipyridamole (inhibits phosphodiesterase) and Dextrans exert a less potent and less specific antiplatelet activity 86

87 Anticoagulants: coumarin o main action as vitamin K antagonist o inactivates factors II, VII, IX, X o long half live (days) o antagonist is vitamin K o rapid reversal through Beriplex, FFP or whole blood 87

88 Heparin Negatively charged muccopolysaccharide. Short half-life (hours) Present endogeneously in high concentrations in the liver and granula of the mast cells Binds with AT lll and causes an 1000x increase in its activity as an inhibitor of thrombin (f lla) = blocks the coagulation cascade Inactivates also factors IXa, Xa No oral form / reversal through protamin 88

89 Heparin induced thrombocytopenia Decrease of circulating thrombocytes to < 40 % of baseline value and/or less than thrombocytes/ml under heparin treatment Appears within 1-21 days of ttt. Reversal 1-10 days Possible with all routes of administration and at any dosage Increased anti-platelet factor 4 plasma level: 50%-60% specific and sensitive Bleeding is rarely an issue Major clinical problem is thrombosis 89 Probable platelet defect => white thrombi!!

90 Low molecular weight heparins Dalteparine/Enoxaparine/Nadroparine Inhibit Xa much more than thrombin (ca 4:1) Bind to ATlll and heparin co-factor ll (thrombin inhibition) Only parenteral form / standard dosage / no monitoring necessary Do not significantly modify aptt Are partially antagonized by protamin sulfate 20% cross-reactions with heparin (HIT) 90

91 Thrombocytenaggregationshemmer Clopidogrel (Plavix ) Prasugrel (Efient ) Abciximab (ReoPro ) Tirofiban (Aggrastat ) XIIIa Acetylsalicylic acid (Aspirin ) mod. nach Corti R, et al. Kardiovaskuläre Medizin 2004; 7:

92 Vitamin K-Antagonisten Vitamin-K- Antagonisten Vitamin-K- Antagonisten XIIIa mod. nach Corti R, et al. Kardiovaskuläre Medizin 2004; 7:

93 Heparin (unfraktioniert) Heparin + Antithrombin XIIIa mod. nach Corti R, et al. Kardiovaskuläre Medizin 2004; 7:

94 Heparin (niedermolekular) Heparin + Antithrombin Niedermolekulare Heparine (+ Antithrombin) XIIIa mod. nach Corti R, et al. Kardiovaskuläre Medizin 2004; 7:

95 Heparin (niedermolekular): Niereninsuffizienz In patients with a CrCl<30ml/min, LMWH accumulates >> individual dose-adjustment according to anti-xa recommended Schmid P, et al. J Thromb Haemost 2009; 7:

96 Faktor Xa - Inhibitoren Danaparoid (Orgaran ) [i.v./s.c.] Fondaparinux (Arixtra ) [s.c.] Rivaroxaban (Xarelto ) [p.o.] XIIIa mod. nach Corti R, et al. Kardiovaskuläre Medizin 2004; 7:

97 Direkte Thrombin-Inhibitoren Lepirudin (Refludan ) [i.v.] Bivalirudin (Angiox ) [i.v.] Dabigatran (CH:-) [p.o.] XIIIa mod. nach Corti R, et al. Kardiovaskuläre Medizin 2004; 7:

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99 99 Thromboembolie

100 Thromboembolie Ausmass des Risikos Ungefähres Risiko für thromboembolische Komplikation bei unbehandelten Patienten Geerts WH; et al. Chest 2008; 133 (6 Suppl): 381S-453S. 100

101 Thromboembolie Ausmass des Risikos Ungefähres Risiko für thromboembolische Komplikation bei unbehandelten Patienten 101 Geerts WH; et al. Chest 2008; 133 (6 Suppl): 381S-453S. Clagett GP, Reisch JS. Ann Surg 1988; 208:

102 Thromboembolie Ausmass des Risikos Datenbankuntersuchung an Frauen mittleren Alters in Grossbritannien; Beobachtungsperiode Sweetland S, et al. BMJ 2009; 339: b4583

103 Thromboembolie Ausmass des Risikos Sweetland S; et al. BMJ 2009; 339: b

104 Venous thrombosis caused by Virchow s triad stasis, endothelial lesions, increased coagulability Anesthesia by itself increases coagulability >> 20-50% risk of DVT under anesthesia deep venous thrombosis as source of pulmonary embolism prevention: heparin, dextran, coumarin surgery: thrombectomy, caval filter,vein restoration fibrinolysis 104

105 Venous thrombosis: risk factors Immobilization Previous event Malignancy Thrombocytosis Obesity Varicosis Hormonal treatments Rxtherapy of the lower abdomen 105

106 Arterial thrombosis Search for source of peripheral arterial embolization Prevention by means of antiplatelet agents Surgery: thrombectomy, thrombendarterectomy (carotid) or resection (aneurysms) Fibrinolysis 106

107 Thrombophilia Deficiency in - AT lll - Heparin co-factor ll - TFPI - Protein C - Protein S Thrombocytosis apl syndrome High serum viscosity Polycythemia 107

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