coagulation disorders-ms1.ppt
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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
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