Haemostasis and coagulation problems

HEMOSTASIS

VESSEL WALL PLATELETS COAGULATION FACTORS Primary purpose is to arrest hemorrhage but is linked to INFLAMMATION FIBRINOLYSIS WOUND HEALING

Hemostasis is Unique !

It takes place in flowing blood The stimulus starts a cascade of enzymes which amplifies itself The system is fine tuned with perfect positive and negative feed back

HEMOSTASIS

Blood vessel

Platelet

Fibrin clot

The Endothelial cell in Hemostasis

PROCAOGULANT FUNCTIONS

ANTICOAGULANT FUNCTIONS

Tissue Factor von Willebrands factor Collagen

Prostacyclin Thrombomodulin Protein C Protein S Tissue Plasminogen Activator Heparan

Ultra structure of a platelet

Platelet role in hemostasis

1.adhesion through vWF

2. Release of ADP, etc

3. Aggregation, vWF

4, Clot retraction

Damaged endothelium

RESTING PLATELET

ADHERING PLATELET

PLATELET PLUG AND FIBRIN CLOT

Coagulation the formation of a fibrin plug

Coagulation factors

All 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 surface contact XII PK / HMWK XIIa

EXTRINSIC PATHWAY TISSUE FACTOR + VII + PL + Ca

XI XIa IX IXa + VIIIa + Ca + PL COMMON PATHWAY X Xa + Va + Ca + PL

PROTHROMBIN FIBRINOGEN

THROMBIN FIBRIN + XIII STABLE POLYMER

Problems in classical coagulation 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 coagulation cascade

THE INITIATION PHASE

INITIATION PHASE FX Prothrombin FVII

FVIIa

TF

FXa Thrombin

THE PROPAGATION PHASE

PROPAGATION PHASE FIX FXIa FIXa FVIIIa FX FXa FVa FV FVIII FXI

Prothrombin

Thrombin

THE STABILIZATION PHASE

Thrombin
Cross-linked fibrin Fibrin FXIIIa Fibrinogen FXIII

Monroe et al. Arterioscler Thromb Vasc Biol 22:1381,2002

THE CENTRAL ROLE OF THROMBIN

INITIATION PHASE PROPAGATION PHASE FVII TF FIX FXIa FXI thrombomodulin

FVIIa

FIXa
FVIIIa FX FXa FVa FV FVIII

Heparincofactor II

Prothrombin Cross-linked fibrin Fibrin FXIIIa

Thrombin
Fibrinogen FXIII

Antithrombin

STABILIZATION PHASE

ENDOTHELIAL CELL

Elimination of thrombin

Contact Phase of Coagulation

CONTACT XII XIIa XI IX XIa PREKALLIKREIN KALLIKREIN IXa

HMWK

BRADYKININ
PROUROKINASE UROKINASE

PLASMINOGEN
INFLAMMATION

PLASMIN
FIBRINOLYSIS COAGULATION

Contact Phase of Coagulation

Not important in vivo for haemostasis Factor XII deficiency not associated with bleeding Factor XI deficiency associated with a mild bleeding disorder However it is linked to inflammation and fibrinolysis

Structure of Fibrinogen
FPA
s ss s s s ss

FPB

ss ss ss

ss

g
Aa

Bb

Normal Fibrinolysis within a Thrombus

THROMBUS
ENDOGENOUS + BOUND PLASMIN ACTIVATOR PLASMINOGEN THROMBOLYSIS

FDP

ACTIVATOR INHIBITOR

ANTI PLASMIN BLOOD

Regulation of coagulation pathways

Tissue factor pathway inhibitor (TFPI) Antithrombin III Protein C and S system Heparin cofactor II alpha2 macroglobulin Activated protein C inhibitor alpha1 antitrypsin

Positive Feed back

XI IX VIII XIa IXa VIIIa TF + VII TF-VII TF-VIIa

Xa

V
THROMBIN

Va
PRO THROMBIN

Negative Feedback
XI IX VIII XIa IXa VIIIa TF + VII TF-VII TF-VIIa TFPI

X PROTEIN C, S ANTI THROMBIN THROMBIN

Xa

Va

PRO THROMBIN

Synthesis of Coagulation factors

Synthesis of Coagulation Factors

GENE mRNA POLYPEPTIDE POST TRANSLATIONAL MODIFICATION
GAMMA CARBOXYLATION VIT K DEPENDANT FACTORS BETA HYDROXYLATION AMINO END OF EGF DOMAIN OF C, S, VIII, IX, X [METAL BINDING]

MULTIMERIZA OF VON WILLE FACTOR

The purpose of coagulation is to arrest hemorrhage by rapidly laying down a stable fibrin clot which is just enough to seal the rent in the vessel: bleeding or thrombosis results if there is an imbalance in the system.

Diagnosis of coagulation disorders

Clinical history is the strongest predictor of bleeding risk with any procedure. Screening tests: 1. Prothrombin time: Extrinsic and common pathway 2. APPT: Intrinsic and common pathways 3. Thrombin time: common pathway 4. FDP: fibrinolytic pathway

Laboratory tests for coagulation disorders

Platelet count Blood picture APPT Prothrombin Time Thrombin Time Fibrin Degradation Products

Bleeding problems in a surgical patient

Requires immediate evaluation Rapid approach to diagnosis Institution of treatment

Causes

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 tests

Hb & PCV Platelet count PT APTT Fibrinogen assay Bleeding time: Platelet function defect FDP: DIC Peripheral blood film

Causes

Preexisting haemostatic failure DIC due to:

mismatched transfusion
prolong surgery fat embolism amniotic fluid embolism

Massive transfusion Cardio pulmonary by pass:

platelet functional defect heparin