The COAGULATION CASCADE:From Chaos to ControlBlood Day 2018Health Science Centre Winnipeg, MB

Becky Rock, RNProgram Coordinator: Patient Blood Management ProgramAlberta Health Services: Calgary Zone

PRESENTER DISCLOSURESRegrettably, none.

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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.

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WHICH IS REALLY DANGEROUS?

ANEMIACV Surgery & IHD: in-hospital mortality, major

morbidity & AKIKidney Disease: prognosis/survival, marker

ESRD, mortality & all-cause hospitalization

CVA/Stroke: mortality, disabilityOther: Common in Hx of Parkinson’s

TRANSFUSIONCardiac: risk stroke, morbidity,

pulmonary complication, sepsis, wound complication, LOS, intubation time, AKI, pneumonia, mediastinitis

Malignancy: risk tumor recurrence, survivalVascular, Ortho, Other: risk death, morbidity,

pulmonary complication, sepsis, VTE, wound complication, AKI, re-bleed, secondary infection 5

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-i59 2011

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Patient Blood Management is the timely application of medical & surgical concepts, designed to:Maintain Hemoglobin concentrationOptimize Hematopoiesis; and,Minimize blood-loss and bleeding

…all in an effort to improve patient outcomes.

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OPTIMIZEHEMATOPOIESIS

MINIMIZEBLOOD LOSS

and BLEEDING

HARNESS and OPTIMIZE

PHYSIOLOGIC TOLERANCE of

ANEMIA

Multidisciplinary Team Approach

PREOP

INTRAOP

POSTOP

OUTLINE

Hemostasis• Primary• Secondary• Clot formation/stabilization• Clot inhibition

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CollagenEndothelium

EndotheliumCollagen

produce substances to keep clotting in check:

ANTI-PLATELET EFFECTS• Nitric oxide Vasodilator• Adenosine diphosphatase Vasodilator• Prostacyclin (PG12) Vasodilator

HEALTHY ENDOTHELIUM

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CollagenEndothelium

EndotheliumCollagen

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

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CollagenEndothelium

EndotheliumCollagen

FIBRINOLYTIC/THROMBOLYTIC EFFECTS

Tissue Plasminogen Activator (tPA) Catalyzes Plasminogen Plasmin

(cleaves Fibrin fibers)

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UNHEALTHY ENDOTHELIUM

DYSFUNCTION: • Linked to HTN, Diabetes, ^BMI

INJURY:• Loss of NO, ADP, PG12 protective effects of anti-plt, anti-coag, fibrinolytic

substances

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PRIMARY HEMOSTASIS

VASOCONSTRICTION• Neurogenic reflex• Smooth muscle reflex• Endothelin (amino acid peptide)• EPI• Thromboxanes & Prostaglandins

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←GPIb receptor

←GPIIb/IIIaReceptor

EndotheliumCollagen

Alpha Granules

Dense Granules

No nucleus• 2-4 microns (RBC 7-8)• 8-10 days (RBC 120)• ~1/3 sequestered in

spleen

Inhibited by: NO, ADP, PG12

THE PLATELET (THROMBOCYTE)

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Alpha Granules Dense Granules• Fibrinogen• vWF• Platelet-Derived

Growth Factor (PDGF)

• Serotonin• ADP/ATP• Prostaglandin• Thromboxane A2• Calcium• Histamine• Thrombin

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PLATELET

ND

←GPIb receptor

← GPIIb/IIIa receptor

←vWF

Activated Platelet

EndotheliumCollagen

INJURY SITE:

Endothelium

ADHESION

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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

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DDAVP(Desmopressin®)-stimulates vWF

release

rFVIIa(Novoseven®)-potentially

enhances Pltreceptors

GPIbreceptor→ ←GPIIb/IIIa Receptor

P2Y1 receptor

P2Y12 receptor

PAR-1 receptor

Collagen exposure

←vWF/Fibrinogen

AGGREGATION

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AGGREGATION

Granule Substances: Fibrinogen• Binds to GP IIb/IIIa receptor

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Fibrinogen concentrate (Riastap®)

-improves Platelet ability to

aggregateAggregates: provide phospholipid surface needed for factor activation

AGGREGATION

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Cyclooxygenase (COX)• Enzyme for synthesis of

prostaglandins—prostacyclin (PG12) and…

Thromboxane (TxA2)• Stimulates aggregation• Sparks release ADP• Vasoconstricts

AspirinNSAIDs

-COX Inhibitor drugs

-inhibit TxA2

COAGULATION CASCADE

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SECONDARY HEMOSTASIS:

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ACTIVATION (Factors) GENERATION (Thrombin)

Intrinsic Extrinsic Pathway

Common Pathway

XII

XI

IX

VIII

VII

TISSUE FACTOR

II

V

X

FIBRINOGEN FIBRIN CLOT

Collagen exposure

vonWillebrandfactor ADP Serotonin

vWFFibrinogen

Tissue Factor

VII VIIa

XaVaV

X

VaXa

IX

IXa VIIIa

XIaVIII

XI

V

1+ 2

Prothrombin

Thrombin

Prothrombin

Thrombin

tPA

uPA

Plasminogen

Plasmin

XIII XIIIa

Fibrinogen

Fibrin

Fibrin Clot

FDPD-dimer

X

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INITIATION PHASE

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Tissue Factor (FIII, Thromboplastin):

• Plasma protein—found in monocytes, activated Plts, epithelium

• Cell surface receptor: FVII

• (With Ca++) FVII FVIIa

AMPLIFICATION PHASE

TF/FVIIa Complex & Ca++ (FIV)Activate EXTRINSIC Path

• FXFXa; with FVa…• Catalyzes Prothrombin (FII) Thrombin (FIIa)

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Thrombin:• FVFVa• FVIIIFVIIIa…results in moreactivated Plts• FXIFXIa

VFV LeidenInherited

clotting disorderhyper-

coagulability~1/3 DVT/PEs

AMPLIFICATION CONTINUES:

XIDeficiencies rare; can →

Hemophilia C

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FVIIIa & FIXaTenase Complex: • FXaFXa, FVa, Ca++ & activated Plts:Prothrombinasecomplex = Prothrombin & Thrombin

PROPAGATION PHASE:

VIIIDeficiency in Hemophilia A

IX(Christmas

Factor)Deficiency in Hemophilia B

CLOT FORMATION & STABILIZATION

Thrombin:FibrinogenFibrin monomers

…polymerize to make soluble fibrin clot

FXIIIFXIIIa…cross-links fibrin & stabilizesclot

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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

INHIBITION OF COAGULATION

Slowing formation:

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t-PA & u-PA:• Converts PlasminogenPlasminPLASMIN:• Breaks down x-linked fibrin into

fibrin degradation products…Smallest: D-dimer

INHIBITION, CONTINUED

Clot destruction (fibrinolysis):

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PATHWAY MODEL

Intrinsic Extrinsic Pathway

Common Pathway

XIIXI

IX

VIII

VII

TISSUE FACTOR

II

V

X

FIBRINOGEN FIBRIN CLOT

Common

IntrinsicPTT

Common

ExtrinsicPT

Common PathwayII

V

X

FIBRINOGEN

Common

IntrinsicPTT

CommonExtrinsic

PT

$10$5$2

$133

Extrinsic Pathway

Common Pathway

VII

TISSUE FACTOR

II

V

X

FIBRINOGEN

Common

IntrinsicPTT

Common

ExtrinsicPT

Lucky ‘7’

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Intrinsic

Common Pathway

XII

XI

IX

VIII

II

V

X

FIBRINOGEN

Common

IntrinsicPTT

Common

ExtrinsicPT

TwelveEleven

NineEight

Ten

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PATHWAY MODEL

Intrinsic Extrinsic Pathway

Common Pathway

XII

XI

IX

VIII

VII

TISSUE FACTOR

II

V

X

FIBRINOGEN FIBRIN CLOT

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In-vivo activity…on cell surfaces• TF bearing cells• Platelets• 3 overlapping phases

Coag cascades remain, but arecell-based:• Extrinsic: TF cells• Intrinsic: Platelets

CELL-BASED MODEL TF-bearing cells

Platelets

Activated Platelets

1. Initiation

2. Amplification

3. Propagation

IIa

IIa

TFbearing

cell

1. Initiation

2. Amplification3. Propagation

TFVIIa

IXa

VaXa

Prothrombin

Thrombin

VIIIa XIa

XaVa

IXaVIIIa XIaProthrombin

Thrombin

Activated Platelet

Va

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MODEL COMPARISON

PATHWAYS• Does NOT explain

individual factor deficiencies

• Represented by “routine” Coag tests

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CELLS• Better explains clotting

localization to ‘site of injury’

• Represented by POC viscoelastic testing

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COAGULATION TESTINGStandard LaboratoryTests PLASMA (no platelet

or cellular components) Initiation of clot only (no

info on clot consistency or tensile strength)

Results usually 30-45 mins (25 if you’re lucky?)

Central lab

ViscoelasticTests WHOLE BLOOD Initiation, clot strength &

clot lysis Initial results 5 minsPoint-of-Care

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COAGULATION DRUGS• Anti-coagulants

→directly or indirectly interrupt factorsRoute: IV, SC or PO

• Anti-platelets→interrupt platelet adhesion/aggregation

Route: IV or PO• Anti-fibrinolytics

→interrupt clot breakdown; stabilize clotRoute: IV, PO, nasal spray, topical

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DIRECT-ACTING:• Inhibits XaTEST: anti-Xa assayReversal: Stop 3 days pre-op or longer (e.g.: CKD)

Antidote: andexanet alfa (AndexXa®)

RIVAROXABAN (XARELTO®) APIXABAN (ELIQUIS®)

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DIRECT-ACTING:• Inhibits IIa (Thrombin)TEST: Thrombin TimeReversal: Stop 3 days pre-op or longer (e.g.: CKD)

Antidote: idarucizumab(Praxbind®)

DABIGATRAN (PRADAXA®) ARGATROBAN (ACOVA®)

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INDIRECT-ACTING:• Combines with anti-thrombin• Inhibits: II, X, IX, XI, XIITEST: PTT or anti-Xa

Reversal: Stop 4h pre-opProtamine

UNFRACTIONATED HEPARIN

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INDIRECT:• Combines with anti-thrombin• Inhibits: II & XTEST: anti-Xa

Reversal: Stop 12-24h pre-op No antidote (Protamine may

reverse IIa effects, not X)

LOW MOLECULAR WEIGHT HEPARINDALTEPARIN (FRAGMIN®) ENOXAPARIN (LOVENOX®) TINZAPARIN(INNOHEP®)

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INDIRECT:• Vitamin K antagonist• Vit K is needed by II, VII, IX,

X & Proteins C&S to activateTEST: PT/INR

Reversal: STOP; give Vit K or 4 factor PCC + Vit K

WARFARIN (COUMADIN®)

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RAPID reversal of high INR due to warfarinDIRECT:• Adds 4 Factors (II, VII, IX,

X) & Proteins C&S• Vit K needed to activate

factors

PROTHROMBIN COMPLEX CONCENTRATE (OCTAPLEX®, BERIPLEX®)

COX

GPIb/IX receptor→

GPIIb/IIIa receptor→

P2Y12 receptor→

← PAR-1 receptor

COX-1 inhibitorsASA (Aspirin®)

ADP receptor antagonistsclopidogrel (Plavix®) plasurgrel (Effient®) ticagrelor (Brilinta®)

GPIIb/IIIa receptor antagonistsabciximab (Reopro®) eptifbatide(Integrillin®)

ANTI-PLATELETS

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INDIRECT:Inhibits activation of Plasminogen to Plasmin

ANTI-FIBRINOLYTICS

TRANEXAMIC ACID (CYCLOKAPRON®) AMINOCAPROIC ACID (AMICAR®)

ANTIFIBRINOLYTIC MECHANISM OF ACTION

Enables stabilization of clotBlocks Plasmin’s ability to break down clot prematurely…

50Science Direct Cor et Vasa Volume 55, Issue 2, April 2013, Pages e184-e189

OPTIMIZE HEMATOPOIESIS

MINIMIZE BLOOD LOSS &BLEEDING

HARNESS and OPTIMIZE ANEMIA TOLERANCE

Multidisciplinary Team Approach

PREOP

INTRAOP

POSTOP

As EARLY as possible: -DETECT & TREAT ANEMIA-OPTIMIZE HEMOGLOBIN• PO or IV iron• EPO• Other vitamins

-COORDINATE TIMING of surgery or procedure with Optimization

-Utilize IV Iron & EPO to treat anemia

-IDENTIFY BLEEDING AND/OR RISK-Manage & treat bleeding-OPTIMIZE anti-coagulants-Address supplement use: vitamin, herbal, Homeopathic & Naturopathic

-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

-Estimate patient’s tolerance for blood loss

-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

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PBM PILLAR #2: MINIMIZING BLOOD-LOSS & BLEEDING

PRE-OP

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IDENTIFY BLEEDING and/or RISKMANAGE/TREAT bleedingOPTIMIZE anti-coagulantsAddress supplement use: vitamin,

herbal, Homeopathic & Naturopathic

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PBM PILLAR #2: MINIMIZING BLOOD-LOSS & BLEEDING

INTRA-OP

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Cell salvage Surgery: METICULOUS hemostasis &

techniqueAnesthesia: consider spinal/regional

over General; patient positioning & warming

Pharmacologic Agents: e.g.: TXA

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PBM PILLAR #2: MINIMIZING BLOOD-LOSS & BLEEDING

POST-OP

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Monitor/manage bleedingDVT prophylaxisManage temperature/painMINIMIZE PHLEBOTOMYTREAT INFECTIONS promptly

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01/09Anemia Management Plan

08/12 TXA Protocol forArthroplasty Surgery

PBM Results:

RBC transfusion

• THA, TKA, Revision

• Female vs Male

NO CHANGE DVT/PE rate

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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 evidence-based, cost-effective approach to care

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REFERENCESBloody Easy: Coagulation Simplified, March 2013; Ontario Regional Blood Coordinating Network

Dailey JF. Blood, 2001; 2nd ed. Medical Consulting Group, Ipswich, MA

Daily JF. Daily’s Notes on Blood, 2002; 4th 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; 2nd 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; 16:17-20

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