Haemostasis and coagulation Haemostasis and coagulation problemsproblems

HEMOSTASISHEMOSTASIS

VESSEL WALL PLATELETS COAGULATION FACTORS

Primary purpose is to arrest hemorrhage but is linked to

INFLAMMATION FIBRINOLYSIS WOUND HEALING

Hemostasis is Unique !Hemostasis is Unique !

It takes place in flowing bloodThe stimulus starts a cascade of enzymes

which amplifies itselfThe system is fine tuned with perfect

positive and negative feed back

HEMOSTASIS

Blood vessel

Platelet

Fibrin clot

The Endothelial cell in The Endothelial cell in HemostasisHemostasis

PROCAOGULANTFUNCTIONS

ANTICOAGULANT FUNCTIONS

Tissue Factorvon Willebrand’s factorCollagen

ProstacyclinThrombomodulinProtein CProtein STissue Plasminogen ActivatorHeparan

Ultra structure of a platelet

Damaged endothelium

Platelet role in hemostasis

vWF

1.adhesion through vWF

2. Release of ADP, etc

3. Aggregation,

4, Clot retraction

RESTING PLATELET

ADHERING PLATELET

PLATELET PLUG AND FIBRIN CLOT

Coagulation – the formation of Coagulation – the formation of a fibrin pluga fibrin plug

Coagulation factorsCoagulation factorsAll the coagulation factors except F VIII are

produced by the liver hepatocyte. FVIII is produced by the vascular endothelial cells.

Some of the coagulation factors are Vit K dependent. II, VII, IX and X.

In obstructive jaundice, Vit K absorption is defective leading to a coagulopathy.

Factor VII has the shortest half life (7 hrs).

FUNCTIONS OF VWF

1.vWF mediates platelet adhesion at site of injury 2.Stabilizes FVIII in circulation

CLASSICAL COAGULATION CASCADE

INTRINSIC PATHWAY EXTRINSIC PATHWAY

surface contact TISSUE FACTORXII XIIa + PK / HMWK VIIXI XIa +IX IXa PL + Ca + VIIIa + Ca + PL

COMMON PATHWAYX Xa + Va + Ca + PL

PROTHROMBIN THROMBINFIBRINOGEN FIBRIN + XIII STABLE POLYMER

Problems in classical Problems in classical coagulation pathwaycoagulation pathway

Individuals with F XII deficiency do not bleed (Hageman died of pulmonary embolism )

Intrinsic and extrinsic pathways are not independent of each other (Patients with factor VIII deficiency have severe bleeding )

Therefore in the body blood does not clot in the same way as it does in the tube

Modern concept of the Modern concept of the coagulation cascade coagulation cascade

THE INITIATION PHASE

INIT

IAT

ION

PH

AS

E FVII

FVIIa

TF

FX FXa

ThrombinProthrombin

THE PROPAGATION PHASE

FX FXa

ThrombinProthrombin

PR

OP

AG

AT

ION

PH

AS

E

FIXa

FVa FV

FVIIIa FVIII

FXIa FXI

FIX

THE STABILIZATION PHASE

Thrombin

Fibrin Fibrinogen FXIIIa FXIII

Cross-linked fibrin

Monroe et al.Arterioscler Thromb Vasc Biol22:1381,2002

INIT

IAT

ION

PH

AS

ETHE CENTRAL ROLE OF THROMBIN

FX FXa

FVII

FVIIa

TF

ThrombinProthrombin

Fibrin Fibrinogen FXIIIa FXIII

Cross-linked fibrin

STABILIZATION PHASE

PR

OP

AG

AT

ION

PH

AS

E

FIXa

FVa FV

FVIIIa FVIII

FXIa FXI

FIX

Elim

inat

ion

of th

rom

bin

Anti-thrombin

Heparin-cofactor II

thrombo-modulin

EN

DO

TH

EL

IAL

CE

LL

Contact Phase of Contact Phase of CoagulationCoagulation

XII XIIa XI

XIa

IX

IXa

CONTACT

PREKALLIKREIN KALLIKREIN

HMWK BRADYKININ

PROUROKINASE UROKINASE

PLASMINOGEN PLASMIN

INFLAMMATION FIBRINOLYSIS COAGULATION

Contact Phase of CoagulationContact Phase of Coagulation

Not important ‘in vivo’ for haemostasisFactor XII deficiency not associated with

bleedingFactor XI deficiency associated with a mild

bleeding disorderHowever it is linked to inflammation and

fibrinolysis

Structure of FibrinogenStructure of Fibrinogen

s s

s s

ss ss

ss ssss ss

A B

FPA

FPB

Normal Fibrinolysis within a Normal Fibrinolysis within a ThrombusThrombus

ENDOGENOUS + BOUND PLASMIN THROMBOLYSISACTIVATOR PLASMINOGEN

THROMBUS

BLOOD

ANTI PLASMINACTIVATOR INHIBITOR

FDP

Regulation of coagulation Regulation of coagulation pathwayspathways

Tissue factor pathway inhibitor (TFPI)Antithrombin IIIProtein C and S systemHeparin cofactor IIalpha2 macroglobulin

Activated protein C inhibitoralpha1 antitrypsin

Positive Feed backPositive Feed back

TF + VII

TF-VII

TF-VIIa

Xa X V Va

THROMBIN PRO THROMBIN

XI XIa

IX IXa

VIII VIIIa

Negative FeedbackNegative Feedback

TF + VII

TF-VII

TF-VIIa TFPI

Xa X V Va

THROMBIN PRO THROMBIN

XI XIa

IX IXa

VIII VIIIa

ANTI THROMBIN

PROTEIN C, S

Synthesis of Coagulation Synthesis of Coagulation factorsfactors

Synthesis of Coagulation Synthesis of Coagulation FactorsFactors

GENE

mRNA

POLYPEPTIDE

POST TRANSLATIONALMODIFICATION

GAMMA BETA HYDROXYLATION MULTIMERIZATIONCARBOXYLATION AMINO END OF EGF OF VON WILLEBRANDVIT K DEPENDANT DOMAIN OF C, S, VIII, IX, FACTORFACTORS X [METAL BINDING]

The purpose of coagulation is The purpose of coagulation is to arrest hemorrhage by to arrest hemorrhage by

rapidly laying down a stable rapidly laying down a stable fibrin clot which is just fibrin clot which is just

enough to seal the rent in enough to seal the rent in the vessel: bleeding or the vessel: bleeding or

thrombosis results if there is thrombosis results if there is an imbalance in the system.an imbalance in the system.

Diagnosis of coagulation Diagnosis of coagulation disordersdisorders

Clinical history is the strongest predictor of bleeding risk with any procedure.

Screening tests: 1. Prothrombin time: Extrinsic and common

pathway2. APPT: Intrinsic and common pathways3. Thrombin time: common pathway4. FDP: fibrinolytic pathway

Laboratory tests for Laboratory tests for coagulation disorderscoagulation disorders

Platelet countBlood pictureAPPTProthrombin TimeThrombin TimeFibrin Degradation Products

Bleeding problems in a Bleeding problems in a surgical patientsurgical patient

Requires immediate evaluationRapid approach to diagnosisInstitution of treatment

CausesCauses

Local causes: requires surgical correction– Slipped ligatures– Limited to the site of surgery

Haemostatic defects– Evidence of bleeding outside surgical field– Petechiae & purpura– Oozing from venepuncture sites

Coagulation testsCoagulation testsHb & PCVPlatelet countPTAPTTFibrinogen assayBleeding time: Platelet function defectFDP: DICPeripheral blood film

CausesCausesPreexisting haemostatic failureDIC due to:

– mismatched transfusion– prolong surgery– fat embolism– amniotic fluid embolism

Massive transfusionCardio pulmonary by pass:

– platelet functional defect– heparin