Blood Coagulation Flashcards
What are the main constituents of coagulation?
- Vessel wall lined by endothelium.
- Platelets - derived from megakaryocytes in marrow.
- Coagulation factors in un-activated state.
- Inhibitors of coagulation.
- Fibrinolytic system and inhibitors.
What are coagulation factors?
- Coagulation factors = proteins which circulate in an inactive state and become activated in a cascade reaction and cause clotting.
Describe the role of endothelial cells.
- Line blood vessels and form a barrier.
- Produce thrombomodulin and heparin sulphate to inhibit thrombin production.
- Enzymes to degrade platelet granule-derived molecules.
- Prostacyclin and nitric oxide (NO) to reduce platelet adhesion.
Describe platelets.
- Fragments of megakaryocyte cytoplasm.
- Budded off into lumen of marrow sinusoids.
- Production stimulated by thrombopoietin (TPO) - liver derived.
- Cicrulate for 5-10 days with ~30% ‘stored’ in spleen.
- Form a plug when attracted by lowered prostacyclin and by collagen exposure.
- Thromboxane A2 and serotonin from platelets cause vasoconstriction.
How do platelets adhere to the vessel wall?
Platelets adhere to the vessel wall via Von Willibrand’s factor and Glycoprotein Ib.
How do platelets adhere to each other?
Platelets adhere to each other via glycoprotein IIb-IIIa and fibrinogen.
What are the functions of platelets?
- Form a plug when attracted by lowered prostacyclin and by collagen exposure.
- Granule release.
- Fibrin formation.
Describe what happens in the coagulation cascade.
- Factors present in inactive state - activated by ‘intrinsic or extrinsic’ pathway.
- Fibrin is needed to form a clot.
- Diagram:
- Black = accelerator
- Red = brakes (these try to prevent the coagulation cascade)
List the factors which inhibit coagulation.
- Protein C activated by thrombomodulin-thrombin complex.
- With co-factor - factor S - Va and VIIIa are degraded.
- Antithrombin (previously antithrombin III) inhibit Xa and IIa.
- Heparin cofactor II inhibits IIa.
- Heparin stimulated antithrombin and heparin cofactor II.
- Only a very small amount of coagulation factor is needed; its effects build faster and faster. Results in coagulation happening faster than it can be inhibited.
Describe the fibrinolytic system.
- Plasminogen activated to plasmin by tissue plasminogen activator (tPA) - from endothelial cells.
- Fibrin broken down into ‘fibrin degradation products’ including D dimers - a measurement of fibrinolysis (a measure of how well a clot has broken down).
- Inhibitors of fibrinolytic system.
- Theraputic use with eg. streptokinase to tPA for ‘clot busting’ eg acute myocardial infarction or thrombotic stroke.
What is fibrin?
Fibrin = meshwork of protein that can be brokwn down into its constituent parts.
What is the ‘gold-standard’ time frame for thrombolysis in stroke treatment?
Gold standard for stroke treatment - ideally in under 3 hours.
What is clot retrieval?
- Clot retrieval - putting a cathater in to pull the clot out.
- Arguably more effective than dissolving the clot.
How do you measure coagulation?
- Full blood count - includes platelet count / size / granules, but is a poor assessment of platelet function - specialised tests of aggregation can be done.
- Ref range 150-400 x109 /L
What is caused by an FBC <30-50 x109/L?
And <10 x109/L?
- Easy bruising and purpura when FBC <30-50 x109 /L (thrombocytopaenia).
- Risk of major bleeding if <10 x109/L.
Describe a bleeding time test.
- In vivo test of overall clotting - mainly platelet function.
- Lots of poorly controlled variables, so not often done.
Describe a prothrombin time (PT) test.
- All coagulation tests are done on citrated plasma
- Removes Ca2+
- At 37℃, thromboplastin and Ca2+ are added.
- Measure time until clot forms - extrinsic and common pathway.
- Prolonged by low levels of II, X and VII.
Describe an activated partial thromboplastin test (APTT).
- Ca2+ kaolin and phospholipids added to citrated plasma.
- Measure of intrinsic and common pathway.
- Prolonged in haemophilia and by heparin.
What is fibrinogen?
How is it measured?
- Fibrinogen is the final substrate for making fibrin.
- It can be measured by:
- Clot density
- Thrombin time - thrombin and Ca2+ added to citrated plasma
Describe the further tests which can be carried out on prolonged PT or APTT.
- Correction tests and factor assays
- A prolonged PT or APTT can be tested further:
- 50:50 mix with normal plasma to see if the prolongation corrects.
- Factor assays to look for specific deficiencies.
Describe the genetic causes of haemophilia A and B?
- Haemophilia A and B:
- X-linked defect in VIII or IX gene.
- Commonly a new mutation so no family history.
- Female heterozygotes (carriers) are not affected.
What is the prevalence of Haemophilia A&B?
~1:5000 males
Describe the variation in severity of haemophilia A&B.
- Can be very mild - chance finding or issue for surgery.
- Severe (<1% VIII level) - frequent bleeds into joints and soft tissues.
Describe Von Willebrand disease.
- Usually autosomal dominant.
- Defect in platelet adhesion and binding of VIII.
- Up to 1% population.
- Mild disease - easy bruisingm heavy periods.
- Severe disease - similar to haemophilia.
Describe acquired coagulation disease of the liver.
- Liver disease - alcohol / autoimmune / hepatitis.
- All coagulation factors are produced in the liver.
- PT and fibrinogen abnormal, later APPT abnormal.
- Bleeding due to abnormal clotting, low platelets.
- Portal hypertension causing oesophageal varices and upper GI bleeding.
Describe acquired coagulation disease - disseminated intra-vascular coagulation (DIC).
How do you treat it?
- Activation of clotting cascade due to:
- Trauma
- Malignancy eg. prostate cancer
- Sepsis
- Amniotic fluid embolism
- Causes depletion of clotting factors and damage due to the clot.
- Treat the cause and replace the clotting factors.
What is thrombocytopaenia?
Low platelets
What could thrombocytopaenia be due to?
- Could be due to:
- Under-production
- Increased use
- Abnormal distribution
Describe thrombocytopaenia due to under production of platelets.
- Abnormal marrow function - acute leukaemia, metastatic tumour, aplastic anaemia.
- Expected side effect of cytotoxic chemotherapy.
- Idiosyncratic and unexpected drug adverse effect eg. co-trimoxazole, anti-inflammatories.
Describe thrombocytopaenia due to increased use.
- Immune thrombocytopaenia (ITP)
- Autoimmune disease of children or adults.
- May be triggered by infection or drug.
- Auto antibodies to platelets.
- Treated by:
- Watch and wait
- Steroids
- Immunoglobulins
- Splenectomy
- Drugs to mimic thrombopoetin
Describe thrombocytopaenia due to abnormal distribution.
- Splenomegally (abnormal enlargement of the spleen).
- Examples:
- Portal hypertension
- Leukaemia
- Examples:
- Can have large haemangioma.
Describe thrombophilia
- Increased risk of clotting.
- Caused by:
- Inherited defects in coagulation inhibitors, eg. protein C, S, antithrombin.
- Inherited defect in factor V - Factor V Leiden (causes increased clotting).
- Acquired problems - Virchow’s triad:
- Abnormal vessel wall
- Abnormal flow
- Abnormal blood component
What can cause an abnormal vessel wall?
- Atheroma and plaque
- Varicose veins
- Aneurysm
What can cause abnormal flow through a vessel?
- Atrial fibrilation
- Immobility (eg. long distance flight, plaster cast, surgery)
- Varicose veins
What can cause an abnormal blood component?
- Increased haemoglobin / red cell count - polycythaemia.
- Increased WBC or platelet count - stasis and increased clotting.
- Increased viscosity of plasma.
- Reduced coagulation factor inhibitors.
What is polycythaemia?
An abnormally increased concentration of Hb in the blood, either through reduction of plasma volume or increased red cell numbers.
