Download Cardiovascular 19 – Homeostasis and Thrombosis

Cardio 19 – Homeostasis and Thrombosis
Anil Chopra
1 & 4. Describe in outline the normal homeostatic mechanisms including interaction
of vessel wall, platelets, clotting factors and the fibrinolytic system.
(1) Vessel injury.
(2) von Willebrand factor in blood plasma leaks out. vWF.
(3) Binds to GIpIb or platelet binds directly to collagen fibres without vWF using
GIpIa.
(4) - Membrane phospholipids converted to thromboxane
- ADP from platelets.
- Thrombin from coagulation cascade.
(5) Thrombin
a. Activates platelets
b. Synthesises fibrin from
fibrinogen
c. Cross-links fibrin to
aggregate platelets.
(some factors bind to phospholipid exposed on
platelet surfaces and this binding is vitamin K
dependant. This is inhibited by Warfarin)
(6) Once factors VIII and V are activated,
they accelerate the membrane
dependent reactions.
(7) The fibrin clot initiates Fibrinolysis. It
does so by activating an enzyme called
(tPA) tissue Plasminogen Activator
which converts plamsinogen to plasmin.
(8) Plasmin breaks down the fibrin clot to release fibrin degradation products
(FDP) – tissue Plasminogen Activator (tPA) used in clot busters.
N.B. Coagulation is INHIBITED as the blood coagulation cascade is an
amplification.
I. Direct inhibition by antithrombin
Antithrombin is an inhibitor of coagulation factors such as Xa, XIa, IXa and
thrombin. Its activity is enhanced by heparin sulphates. A drug Heparin enhances
antithrombin’s actions.
II. Indirect inhibition by protein C
Thrombin binds to receptor on endothelial
cell called thrombomodulin. This the
activates protein C. Protein C then binds to
protein S and together they inactivate factors
Va and VIIIa, which downregulate thrombin
production. People with factor V Leiden
cannot easily deactivate it with protein C so
they have increased thrombosis risk.
2 & 3. Describe the causes of bleeding
disorders and the different types.
Essentially bleeding disorders are caused by increases in fibrinolytic factors and
anticoagulant proteins. They can also be due to deficiency of coagulants.
e.g. Haemophilia, von Willebrand disease, liver failure, autoimmune diseases, drugs
(NSAIDs)
 Defect in collagen, von Willebrand factor or platelets (thrombocytopenia)
leads to bleeding tendancy.
 Symptoms include easy bruising, long (>20mins) nosebleeds, gum bleeding,
menorrhagia (excessive heavy periods), small red dots.
 Haemophilia is deficiency in coagulation factors.
o Haemophilia A factor VIII deficiency
o Haemophilia B  factor IX deficiency (both are sex-linked)
 Symptoms of Haemophilia include haemoarthrosis (bleeding into joints).
 In blood coagulation disorders, the platelet plug is sufficient for small vessel
injury whereas in larger vessels, the plug will fall apart.
 Superficial cuts do not bleed due to the action of platelets, however
spontaneous bleeding can occur, deep within muscles and joints.
 Liver failure can result in the deficiency of coagulation factors as they are
synthesised in the liver.
 DIC - disseminated intravascular coagulation is where coagulation and
Fibrinolysis are activated. They are associated with sepsis, major tissue
damage and inflammation so all coagulation factors are used up.
 Drugs such as Warfarin are anticoagulant.
 The immune system can produce antibodies against coagulation factors.
 Excess Fibrinolysis and anticoagulant facto production is rare except when
induced by drugs (tissue plasminogen activator – tPA and heparin).
5 & 6. Describe the manifestations for venous thrombosis and list risk factors.
Thrombosis – increase in coagulation factors and platelets.
 Venous thrombosis may obstruct blood flow or embolise to the lungs.
 3 factors contribute to thrombosis:
1) Blood  deficiency in anticoagulant (antithrombin, protein C).
 increase of coagulants (Factor VIII, II, V Leiden)
2) Vessel wall  proteins used for coagulation are on endothelial walks which
may be affected by inflammation.
3) Flow  reduced flow rate due to surgery, long flight, pregnancy.
 Risk of thrombosis increases with age.
7. Give a rough estimate of its prevalence.
In general population = 1/1000 (over 60)
= 1/10 000 (under 60)
They can embolise (migrate) to lungs and form pulmonary embolism
8. Treatment of bleeding disorders and thrombosis.
Bleeding disorders:
 Factor replacement therapy
 Drugs that can inhibit Fibrinolysis such as tranexamic acid.
 Desmopressin acetate – releases bodies store of coagulants
Thrombosis
 Warfarin inhibits vitamin K and so lowers procoagulant factors.
 Heparin increases coagulant activity
 Thrombolysis (clotbusters) tPA.