Coagulation - Normal and Abnormal Flashcards
Describe the term haemostasis
Haemostasis is the mechanism that leads to cessation of bleeding from a blood vessel.
Describe the ideal coagulation system
Allows blood to flow through vessels
Cope with leaks, big and small, whilst allowing the rest to flow.
Repair mechanisms to dissolve clots
Main constituents of coagulation
Vessel wall lined by endothelium
Platelets derived from megakaryocytes in marrow.
Coagulation factors in pre-activated state
Inhibitors of coagulation
Fibrinolytic system and inhibitors
Function of endothelial cells
Line blood vessels and form a barrier
What do endothelial cels produce ?
Produce thrombomodulin and heparin sulphate to inhibit thrombin production.
Enzymes to degrade platelet granule-derived moleucles
Prostacyclin and nitric oxide to reduce platelet adhesion.
Describe the production of platelets
Fragments of megakaryocytic
Budded off into lumen of marrow sinusoids
Production stimulated by thrombopoetin (TPO) which is liver derived.
Describe the function of platelets
Form a plug when attracted by lowered prostacyclin and by collagen exposure.
Thromboxane A2 and serotonin from platelets cause vasoconstriction.
State the lifespan of platelets
Circulate for 5-10 days with around 30% stored in spleen
Location of platelets
Adhere to vessel wall via Von Willibrand’s factor and Glycoprotein Ib.
Adhere to each other via Glycoprotein IIb-IIa and fibrinogen
State the 2 pathways of the coagulation cascade
Intrinsic Pathway - endothelial collagen
Extrinsic Pathway - Trans-membrane protein in connective tissue around vessels named tissue factor
Outline the main elements of the coagulation cascade
Fibrin is the final product of the clotting cascade.
Fibrinogen is the precursor for fibrin, and is activated by thrombin (IIa).
Thrombin is activated in 2 ways :
- Intrinsic
- Extrinsic
What does the common pathway to produce thrombin involve ?
Involves Factor 5 (Va) and Factor 10 (Xa), which generate thrombin
What slows down the coagulation cascade ?
TFPI
Antithrombin
Active Protein C
Describe protein C
Activated by thrombomodulin thrombin complex
Describe antithrombin
Inhibits Xa and IIa
Function of heparin
Heparin stimulates antithrombin and heparin cofactor II
Heparin cofactor II inhibits IIa
Co-factor (factor S)
Va and VIIIa are degraded
How is plasminogen activated ?
Activated to plasmin by tissue plasminogen activator - from endothelial cells
What is a measurement of fibrinolysis ?
Fibrin broken down into fibrin degradation products - including D dimers
Therapeutic use of the fibrinolytic system
Use with streptokinase or tPA for clot busting
e.g. Acute myocardial infarction to thrombotic stroke.
Measurement of coagulation
Full blood count
Bleeding time
Prothrombin time
Reference range for FBC
150-400 x 10^9/L
Easy bruising and purport <30-50
Risk of major bleeding <10
Describe bleeding time
In vivo test of overall clotting - mainly platelet function
Lots of poorly controlled variables so not often done.
Prothrombin Time
(measures extrinsic pathway)
Done on citrated plasma which removes Ca2+
At 37C thromboplastin and Ca2+ are added
Measure the time until clot forms
Prolonged by levels of II, X, VII
Function of citrated plasma
Removed Ca2+
Ionised calcium makes things clot
Describe the activated partial thromboplastin test
Ca2+, kaolin and phospholipids are added to citrated plasma.
Measure of the intrinsic and common pathway
Prolonged in haemophilia and by heparin
PT time
APPT
Extrinsic pathway
Intrinsic / Common pathway
How can prolonged PT or APTT be tested ?
50:50 mix with normal plasma to see if prolongation corrects.
How can fibrinogen be measured ?
BY measuring clot density
OR
Thrombin time - thrombin and calico added to citrated plasma
Inherited blood disorder
Haemophilia - X linked defect in VIII or IX gene
Haemophilia stats
Approx 1:5000 of males
Female carriers not affected
can be mild - chance finding or issue from surgery
Severe haemophilia
<1% VIII level
Frequent bleed into joints and soft tissues
Treatment of haemophilia
Prophylaxis or Treatment
Clotting factors
Gene Therapy - factor 9 deficiency
Be aware of examples of congenital and acquired coagulation disorders
Von Willebrand disease
Haemophilia
Acquired coagulation disease :
- liver
- disseminated intra-vascular coagulation (DIC)
Von Willebrand
Usually autosomal dominant
Defect in platelet adhesion and binding of VIII
Up to 1% of pop
Acquired coagulation disease - liver
Liver disease - alcohol, autoimmune, viral hepatitis
PT and fibrinogen abnormal
Bleeding due to abnormal clotting, low platelets
Portal hypertension causing oesophageal varices ad uper GI bleeding
Where are coagulation factors produced ?
Liver
Acquired coagulation disease - DIC
Activation of clotting cascade
Causes depletion of clotting factors and damage due to clot.
Treat the cause and replace clotting factors
Describe factors which increase risk of clotting
Trauma
Malignancy e.g. prostate cancer
Sepsis
Amniotic fluid embolism
Thrombocytopenia
Low platelets
Could be due to :
- under production
- increased use
- abnormal distribution
Causes of low platelet count
Abnormal marrow function
Drug adverse effete
Cytotoxic chemotherapy
Immune thrombocytopenia
Splenomegally
Large haemangioma
Increased risk of clotting
Abnormal :
- vessel wall
- flow
- blood component
Thrombophilia
Increased risk of clotting
- inherited defect in coagulation inhibitors
Abnormal vessel wall
Atheroma
Plaque
Varicose veins
Aneurysm
Abnormal flow
Atrial fibrillation
Immobile - plane flight, surgery
Varicose veins
Abnormal blood components
Increased haemoglobin/ RBC count
Increased platelet / WBC count
Increased viscosity of plasma
Reduced coagulation factor inhibitors
