Disorders of Blood Coagulation Flashcards
Why does blood clot?
Basically: Keeps blood in, keeps pathogens out
Tightly regulated process that stops bleeding at the site of an injury
Must remain localized – why?
Because we don’t want to have systemic blood clots
Blood loss is stopped by formation of a plug composed of platelets and fibrin
What sets off haemostasis?
Endothelium in blood vessels normally maintains an anticoagulant surface
Platelets and fibrinogen circulate ready to go
Damage to vessel wall triggers clotting
Injury exposes collagen to come into contact with blood components to activate clotting
Aggregated platelets + fibrin mesh
Two main processes of haemostasis – primary and secondary
- The primary haemostasis is where we have platelet adhesion, aggregation and activation
- Secondary haemostasis is the activation of the fibrin formation through the clotting cascade
- Note that they do not occur in a linear fashion, but rather simultaneously
What happens during primary haemostasis?
- The endothelium continuously releases small amounts of von Willebrand Factor, which circulates in the blood.
Endothelial cells also store von Willebrand Factor in Weibel-Palade bodies for release when appropriately stimulated.- If collagen becomes exposed to blood (because the endothelium is damaged), von Willebrand Factor binds to it.
- Platelets express receptors for both collagen and von Willebrand Factor and become activated when these proteins bind to them.
Activated platelets express functional fibrinogen receptors, which are required for aggregation.
What happens during secondary haemostasis?
Secondary haemostasis- activation of the clotting components
❷ Tissue factor (TF), expressed by nearly all sub-endothelial cells activates the coagulation cascade to initiate a minor burst of thrombin, when there is damage to the vessel.
Factor FVIIa binds to Tissue Factor, which ultimately leads to conversion of prothrombin to thrombin ❸.
Leading to this initial trickle of thrombin
Thrombin activates receptors on platelets as well as the endothelium, amplifying platelet aggregation and initiating release of stored von Willebrand Factor from endothelial cells.
Activated platelets start to release other amplifying agents to induce more platelet actions
And we start to see activated platelets binding through their fibrinogen receptors, fibrinogen.
All the clotting reactions and fibrinogen occurs on platelets essentially.
What happens during the amplification stage of haemostasis?
Amplification: each activated factor activates more of the next
Thrombin activates two cofactors, Factor VIIIa ❶ and Factor Va ❷ which subsequently form calcium ion-dependent complexes on the surface of platelets with Factor IXa (tenase complex) and Factor Xa (the prothrombinase complex). (Yes you have to know all of the names)
These complexes greatly accelerate production of Factor Xa and thrombin, respectively.
This is the amplification stage of the coagulation cascade ❸.
The greatly increased production of thrombin via tenase and prothrombinase contributes considerably more to the process.
Thrombin will convert fibrinogen into the fibrin mesh ④ and we start to produce this network of fibrin formation that traps RBCs and platelets to plug the wound
What is fibrinolysis?
Fibrinolysis (sometimes called thrombolysis)
This is done by the fibrinolytic system
Plasminogen ❶ is activated to plasmin by tissue plasminogen activator, t-PA ❷ expressed on the surface of endothelial cells.
Plasmin, a proteolytic enzyme, degrades the fibrin mesh to fibrin degradation products which can be cleared ❸.
One of the products is called D-dimer which can be a marker for disorders of blood coagulation.
What are the natural anticoagulants?
Antithrombin (AT) is a serpin (serine protease inhibitor)
Sits on endothelial cells through heparan binding sites
Activity greatly enhanced by binding heparan binding sites on endothelial cells
Major checkpoint to inhibit coagulation (thrombin), IXa, Xa)
Its heparan binding domain is the basis of the anticoagulant activity of heparin (a med anticoagulant) which increases the activity of ATIII
Natural anticoagulants (II)
The protein C pathway which is stimulated by thrombin to keep it under control
Protein C and protein S are natural anticoagulant plasma proteins
Protein C is activated by thrombin bound to thrombomodulin (TM) on endothelial cells to form activated protein C (APC)
Protein S is an APC cofactor which helps binding to cell surfaces
APC degrades cofactors FVa and FVIIIa
What is the molecular basis of blood clotting disorders?
Defects in the key components of clotting
- Coagulation proteins
- Platelets
- Endothelium
Haemophilia - failure to clot leading to haemorrhage:
- Mutations in coagulation factors (haemophilia A and B)
- Platelet disorders (von Willebrand disease, defect in von Willebrand factor)
- Collagen abnormalities (fragile blood vessels and bruising)
Thrombophilia – excessive clotting leading to thrombosis:
- Inherited: mutations in coagulation factors (DVT)
- Acquired: malignancy increases clotting factors (DVT)
Disseminated intravascular coagulation (DIC) – whole body clots, systemic clotting:
- Infection
- Excessive clotting leads to depletion of clotting factors and platelets leads to bleeding
What are the different types of bleeding disorders?
Haemophilia A, more common, there is a mutation within Factor VIII
Haemophilia B is when there are underlying mutations in Factor IX
Von Willebrand disease occurs as a result in inherited defect/deficiency in vWF leading to decreased platelet adhesion, aggregation and activation
Haemophilia: - Bleeding into joints von Willebrand disease: - Affects mucous membranes. - Mostly mild, but bleeding can vary in severity
What are the blood disorders that result in excessive clotting?
Factor V Leiden mutation
- The mutation allows for resistance of the Protein C pathway - Resistance to APC - FVa is not inactivated - Increases risk of DVT
Antithrombin deficiency
Thrombin, IXa and FXa are not inactivated
Increases risk of DVT
Either or both:
- Protein C deficiency
- Protein S deficiency
Increases risk of DVT
What is Virchow’s triad?
Development of a venous thrombus depends on:
- Alterations in the constituents of the blood - Changes in normal blood flow - Damage to the endothelial layer
What will you see in someone with deep vein thrombosis?
- Pain & tenderness of veins
- Limb swelling
- Superficial venous distension
- Increased skin temperature
- Skin discoloration
All reflect obstruction to the venous drainage
Increased risk of pulmonary embolism especially when its above the knee
What is disseminated intravascular coagulation (DIC)?
As in sepsis (body’s response to an infection injures its own tissues and organs)
Depletion of clotting factors and platelets leads to bleeding
What is the difference between anti-coagulants and thrombolytics?
Anti-coagulants prevent
- E.g. warfarin, heparin,
- More recently direct oral anticoagulants (DOACs) which target
Thrombolytics/Fibrinolytics reverse
- E.g. plasminogen activators: tPA, streptokinase
How do you screen for venous thromboembolism (VTE)?
Investigations pre-treatment Clotting screen - Prothrombin time - Partial thromboplastin time - Thrombin time Full blood count Renal screen Liver function tests - If clinical suspicion of liver disease
