The COAGULATION CASCADE:

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1 The COAGULATION CASCADE: From Chaos to Control Blood Day 2018 Health Science Centre Winnipeg, MB Becky Rock, RN Program Coordinator: Patient Blood Management Program Alberta Health Services: Calgary Zone

2 PRESENTER DISCLOSURES Regrettably, none. 2

3 COPYRIGHT -This copy is provided exclusively for research purposes and private study. -Any use of the copy for a purpose other than research or private study may require the authorization of the copyright owner of the work in question. -Responsibility regarding questions of copyright that may arise in the use of this copy is assumed by the recipient. 3

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5 WHICH IS REALLY DANGEROUS? ANEMIA CV Surgery & IHD: in-hospital mortality, major morbidity & AKI Kidney Disease: prognosis/survival, marker ESRD, mortality & all-cause hospitalization CVA/Stroke: mortality, disability Other: Common in Hx of Parkinson s TRANSFUSION Cardiac: risk stroke, morbidity, pulmonary complication, sepsis, wound complication, LOS, intubation time, AKI, pneumonia, mediastinitis Malignancy: risk tumor recurrence, survival Vascular, Ortho, Other: risk death, morbidity, pulmonary complication, sepsis, VTE, wound complication, AKI, re-bleed, secondary infection 5 5

6 Anemia & Transfusion: Individually & synergistically contribute to worse outcomes for patients Increase incidence of the other, further worsening chronic illness & poor outcomes A Shander et al Which is Really Dangerous: Anemia or Transfusion? BJA 107 (S1): i41-i

7 Patient Blood Management is the timely application of medical & surgical concepts, designed to: Maintain Hemoglobin concentration Optimize Hematopoiesis; and, Minimize blood-loss and bleeding all in an effort to improve patient outcomes. 7

8 PREOP INTRAOP OPTIMIZE HEMATOPOIESIS MINIMIZE BLOOD LOSS and BLEEDING HARNESS and OPTIMIZE PHYSIOLOGIC TOLERANCE of ANEMIA POSTOP Multidisciplinary Team Approach

9 OUTLINE Hemostasis Primary Secondary Clot formation/stabilization Clot inhibition 9

Adenosine diphosphatase Vasodilator Prostacyclin (PG12)

10 HEALTHY ENDOTHELIUM produce substances to keep clotting in check: ANTI-PLATELET EFFECTS Nitric oxide Vasodilator Adenosine diphosphatase Vasodilator Prostacyclin (PG12) Vasodilator Collagen Endothelium Endothelium Collagen 10

11 Endothelium Collagen ANTI-COAGULATION EFFECTS Thrombomodulin Thrombin; Fibrin Heparin sulfate anti-thrombin; Xa Protein S Thrombin; Va/VIIIa Tissue Factor Pathway Inhibitor Tissue Factor; Xa, VIIa & Thrombin Collagen Endothelium 11

12 Endothelium Collagen FIBRINOLYTIC/THROMBOLYTIC EFFECTS Tissue Plasminogen Activator (tpa) Catalyzes Plasminogen Plasmin (cleaves Fibrin fibers) Collagen Endothelium 12

13 UNHEALTHY ENDOTHELIUM DYSFUNCTION: Linked to HTN, Diabetes, ^BMI INJURY: Loss of NO, ADP, PG12 protective effects of anti-plt, anti-coag, fibrinolytic substances 13

14 PRIMARY HEMOSTASIS VASOCONSTRICTION Neurogenic reflex Smooth muscle reflex Endothelin (amino acid peptide) EPI Thromboxanes & Prostaglandins 14

15 THE PLATELET (THROMBOCYTE) No nucleus 2-4 microns (RBC 7-8) 8-10 days (RBC 120) ~1/3 sequestered in spleen GPIIb/IIIa Receptor Inhibited by: NO, ADP, PG12 Alpha Granules Endothelium Collagen GPIb receptor Dense Granules 15

16 PLATELET Alpha Granules Fibrinogen vwf Platelet-Derived Growth Factor (PDGF) Dense Granules Serotonin ADP/ATP Prostaglandin Thromboxane A2 Calcium Histamine Thrombin 16

17 ADHESION Activated Platelet GPIIb/IIIa receptor ND GPIb receptor Endothelium INJURY SITE: Collagen vwf Endothelium 17

18 ADHESION Release of Granule Substances: von Willebrand factor Plts stick to collagen via Glycoprotein Ib/IX (GPIb/IX) receptor Plts stick directly to collagen via other receptors DDAVP (Desmopressin ) -stimulates vwf release rfviia (Novoseven ) -potentially enhances Plt receptors 18

19 AGGREGATION P2Y12 receptor P2Y1 receptor PAR-1 receptor vwf/fibrinogen GPIb receptor GPIIb/IIIa Receptor Collagen exposure 19

20 AGGREGATION Granule Substances: Fibrinogen Binds to GP IIb/IIIa receptor Aggregates: provide phospholipid surface needed for factor activation Fibrinogen concentrate (Riastap ) -improves Platelet ability to aggregate 20

21 AGGREGATION Cyclooxygenase (COX) Enzyme for synthesis of prostaglandins prostacyclin (PG12) and Thromboxane (TxA2) Stimulates aggregation Sparks release ADP Vasoconstricts Aspirin NSAIDs -COX Inhibitor drugs -inhibit TxA2 21

22 COAGULATION CASCADE 22

23 SECONDARY HEMOSTASIS: ACTIVATION (Factors) GENERATION (Thrombin) Intrinsic XII XI IX VIII Common X V II Extrinsic Pathway VII Pathway TISSUE FACTOR FIBRINOGEN FIBRIN CLOT 23

24 1+ 2 Fibrinogen Prothrombin V Prothrombin V Thrombin Thrombin Fibrin Va Xa Va Xa VII X VIIa X IX vwf Fibrinogen IXa VIIIa XIa VIII XI Plasminogen tpa upa Plasmin XIII XIIIa Fibrin Clot Tissue Factor FDP D-dimer 24 vonwillebrand factor ADP Serotonin Collagen exposure

25 INITIATION PHASE Tissue Factor (FIII, Thromboplastin): Plasma protein found in monocytes, activated Plts, epithelium Cell surface receptor: FVII (With Ca++) FVII FVIIa 25

26 AMPLIFICATION PHASE TF/FVIIa Complex & Ca++ (FIV) Activate EXTRINSIC Path FX FXa; with FVa Catalyzes Prothrombin (FII) Thrombin (FIIa) 26

27 AMPLIFICATION CONTINUES: Thrombin: FV FVa FVIII FVIIIa results in more activated Plts FXI FXIa V FV Leiden Inherited clotting disorder hypercoagulability ~1/3 DVT/PEs XI Deficiencies rare; can Hemophilia 27C

28 PROPAGATION PHASE: FVIIIa & FIXa Tenase Complex: FXa FXa, FVa, Ca++ & activated Plts: Prothrombinase complex = Prothrombin & Thrombin VIII Deficiency in Hemophilia A IX (Christmas Factor) Deficiency in Hemophilia B 28

29 CLOT FORMATION & STABILIZATION Thrombin: Fibrinogen Fibrin monomers polymerize to make soluble fibrin clot FXIII FXIIIa cross-links fibrin & stabilizes clot 29

30 INHIBITION OF COAGULATION Slowing formation: Thrombomodulin Thrombin binds to thrombomodulin= INACTIVE Activates Protein C; with co-factor Protein S FVa & FVIIIa Anti-thrombin (endogenous anti-coagulant): Thrombin FX & other factors Prostacyclin (PG12): Plt adhesion/aggregation 30

31 INHIBITION, CONTINUED Clot destruction (fibrinolysis): t-pa & u-pa: Converts Plasminogen Plasmin PLASMIN: Breaks down x-linked fibrin into fibrin degradation products Smallest: D-dimer 31

32 PATHWAY MODEL PTT Intrinsic Common Intrinsic XII XI Extrinsic Pathway VII PT Extrinsic Common IX VIII Common X V II FIBRINOGEN Pathway TISSUE FACTOR FIBRIN CLOT 32

33 PTT Intrinsic Common PT Extrinsic Common X $10 Common V II $5 $2 Pathway FIBRINOGEN $1 33

34 PTT Intrinsic Common PT Extrinsic Common Extrinsic Pathway VII Lucky 7 Common X V II Pathway TISSUE FACTOR FIBRINOGEN 34

35 PTT Intrinsic Common PT Extrinsic Common Intrinsic XII XI Twelve Eleven Nine IX Eight VIII Ten Common X V II FIBRINOGEN Pathway 35

36 PATHWAY MODEL Intrinsic XII XI IX VIII Common X V II Extrinsic Pathway Pathway VII TISSUE FACTOR FIBRINOGEN FIBRIN CLOT 36

37 CELL-BASED MODEL In-vivo activity on cell surfaces TF bearing cells Platelets 3 overlapping phases Coag cascades remain, but are cell-based: Extrinsic: TF cells Intrinsic: Platelets IIa TF-bearing cells Activated Platelets Platelets 1. Initiation 2. Amplification 3. Propagation IIa 37

38 1. Initiation TF bearing cell TF VIIa IXa 2. Amplification Va Va Xa VIIIa Thrombin XIa Prothrombin Prothrombin Thrombin Xa Va IXa VIIIa 3. Propagation XIa Activated Platelet 38

39 MODEL COMPARISON PATHWAYS Does NOT explain individual factor deficiencies Represented by routine Coag tests CELLS Better explains clotting localization to site of injury Represented by POC viscoelastic testing 39

COAGULATION TESTING Standard Laboratory Tests PLASMA (no platelet or cellular components) Initiation of clot only (no info on clot consistency or tensile strength)

40 COAGULATION TESTING Standard Laboratory Tests PLASMA (no platelet or cellular components) Initiation of clot only (no info on clot consistency or tensile strength) Results usually mins (25 if you re lucky?) Central lab Viscoelastic Tests WHOLE BLOOD Initiation, clot strength & clot lysis Initial results 5 mins Point-of-Care 40 40

41 COAGULATION DRUGS Anti-coagulants directly or indirectly interrupt factors Route: IV, SC or PO Anti-platelets interrupt platelet adhesion/aggregation Route: IV or PO Anti-fibrinolytics interrupt clot breakdown; stabilize clot Route: IV, PO, nasal spray, topical 41

42 RIVAROXABAN (XARELTO ) APIXABAN (ELIQUIS ) DIRECT-ACTING: Inhibits Xa TEST: anti-xa assay Reversal: Stop 3 days pre-op or longer (e.g.: CKD) Antidote: andexanet alfa (AndexXa ) 42

43 DABIGATRAN (PRADAXA ) ARGATROBAN (ACOVA ) DIRECT-ACTING: Inhibits IIa (Thrombin) TEST: Thrombin Time Reversal: Stop 3 days preop or longer (e.g.: CKD) Antidote: idarucizumab (Praxbind ) 43

44 UNFRACTIONATED HEPARIN INDIRECT-ACTING: Combines with anti-thrombin Inhibits: II, X, IX, XI, XII TEST: PTT or anti-xa Reversal: Stop 4h pre-op Protamine 44

45 LOW MOLECULAR WEIGHT HEPARIN DALTEPARIN (FRAGMIN ) ENOXAPARIN (LOVENOX ) TINZAPARIN (INNOHEP ) INDIRECT: Combines with anti-thrombin Inhibits: II & X TEST: anti-xa Reversal: Stop 12-24h pre-op No antidote (Protamine may reverse IIa effects, not X) 45

46 WARFARIN (COUMADIN ) INDIRECT: Vitamin K antagonist Vit K is needed by II, VII, IX, X & Proteins C&S to activate TEST: PT/INR Reversal: STOP; give Vit K or 4 factor PCC + Vit K 46

47 PROTHROMBIN COMPLEX CONCENTRATE (OCTAPLEX, BERIPLEX ) RAPID reversal of high INR due to warfarin DIRECT: Adds 4 Factors (II, VII, IX, X) & Proteins C&S Vit K needed to activate factors 47

48 ANTI-PLATELETS GPIIb/IIIa receptor antagonists abciximab (Reopro ) eptifbatide(integrillin ) ADP receptor antagonists clopidogrel (Plavix ) plasurgrel (Effient ) ticagrelor (Brilinta ) COX-1 inhibitors ASA (Aspirin ) P2Y12 receptor GPIIb/IIIa receptor PAR-1 receptor COX GPIb/IX receptor 48

49 ANTI-FIBRINOLYTICS TRANEXAMIC ACID (CYCLOKAPRON ) AMINOCAPROIC ACID (AMICAR ) INDIRECT: Inhibits activation of Plasminogen to Plasmin 49

50 ANTIFIBRINOLYTIC MECHANISM OF ACTION Enables stabilization of clot Blocks Plasmin s ability to break down clot prematurely Science Direct Cor et Vasa Volume 55, Issue 2, April 2013, Pages e184-e189 50

OPTIMIZE HEMATOPOIESIS MINIMIZE BLOOD LOSS & BLEEDING HARNESS and OPTIMIZE ANEMIA TOLERANCE PREOP As EARLY as possible: -DETECT & TREAT ANEMIA -OPTIMIZE HEMOGLOBIN PO or IV iron EPO Other vitamins

51 OPTIMIZE HEMATOPOIESIS MINIMIZE BLOOD LOSS & BLEEDING HARNESS and OPTIMIZE ANEMIA TOLERANCE PREOP As EARLY as possible: -DETECT & TREAT ANEMIA -OPTIMIZE HEMOGLOBIN PO or IV iron EPO Other vitamins -IDENTIFY BLEEDING AND/OR RISK -Manage & treat bleeding -OPTIMIZE anti-coagulants -Address supplement use: vitamin, herbal, Homeopathic & Naturopathic -Estimate patient s tolerance for blood loss INTRAOP POSTOP -COORDINATE TIMING of surgery or procedure with Optimization -Utilize IV Iron & EPO to treat anemia -Cell salvage -Surgery: METICULOUS hemostasis & technique -Anesthesia: consider spinal, regional, patient positioning & warming -Pharmacologic Agents: e.g.: Tranexamic Acid -Monitor/manage bleeding -DVT prophylaxis -Manage temperature/pain -MINIMIZE PHLEBOTOMY -Treat infections promptly -Optimize ventilation & oxygenation -MAXIMIZE O2 DELIVERY; consider supplementary O2, bedrest, raise HOB 30 -REDUCE 02 DEMAND; treat infections, optimize cardiac o/p with beta-blockers, etc. -Nutritional support; prevent GI stress Multidisciplinary Team Approach

52 PBM PILLAR #2: MINIMIZING BLOOD-LOSS & BLEEDING PRE-OP IDENTIFY BLEEDING and/or RISK MANAGE/TREAT bleeding OPTIMIZE anti-coagulants Address supplement use: vitamin, herbal, Homeopathic & Naturopathic 52 52

53 PBM PILLAR #2: MINIMIZING BLOOD-LOSS & BLEEDING Cell salvage INTRA-OP Surgery: METICULOUS hemostasis & technique Anesthesia: consider spinal/regional over General; patient positioning & warming Pharmacologic Agents: e.g.: TXA 53 53

54 PBM PILLAR #2: MINIMIZING BLOOD-LOSS & BLEEDING Monitor/manage bleeding POST-OP DVT prophylaxis Manage temperature/pain MINIMIZE PHLEBOTOMY TREAT INFECTIONS promptly 54 54

55 PBM Results: RBC transfusion THA, TKA, Revision Female vs Male NO CHANGE DVT/PE rate 01/09Anemia Management Plan 08/12 TXA Protocol for Arthroplasty Surgery 55

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57 SUMMARY Hemostasis: a complex process which controls bleeding by utilizing multiple components of blood clotting system Coagulation drugs impact clotting system in various ways, either Directly or Indirectly Laboratory coagulation testing helps determine source of coagulopathy and potential management of same PBM improves outcomes using an evidencebased, cost-effective approach to care 57

58 REFERENCES Bloody Easy: Coagulation Simplified, March 2013; Ontario Regional Blood Coordinating Network Dailey JF. Blood, 2001; 2 nd ed. Medical Consulting Group, Ipswich, MA Daily JF. Daily s Notes on Blood, 2002; 4 th ed. Cache River Press, St Louis, MO Luchtman-Jones L, Broze GJ. The current status of coagulation. Ann Med 1995;27:47-52 McCarron K. Stop that clot! Anticoagulant medications 101. Nursing Made Incredibly Easy! 2010;8:40-1 Seeber P, Shander A. Basics of Blood Management, 2013; 2 nd ed. Wiley & Sons Ltd, Oxford, UK Smith SA. A New Cell-Based Model of Coagulation, 2008; ACVIM 2008-VIN Hoffman M. Remodeling the Blood Coagulation Cascade. J. Thromb Thrombol 2003; 16:

Using TEG in the ED, OR, and ICU. Don H. Van Boerum, MD, FACS

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