Disorders of blood coagulation Flashcards
What is clotting?
Essential for survival, tightly regulated process that stops bleeding at the site of injury + keeps pathogens out
- Plug composed of platelets and fibrin. Net of fibrin will trap platelets, RBCs, erthryocytes to close wound
What type of surface does blood vessels and endothelial cells maintain?
What else is also circulating in the blood?
What triggers clotting?
Anti-coagulant surface, due to proteins with anti-coagulant properties expressed on endothelial cells.
Platelets and fibrinogen (precursor of fibrin) circulate in inactive conformation.
Damage to vessel wall triggers clotting, primary and secondary haemostasis.
What is primary haemostasis?
Platelet adhesion, activation and aggregation.
Primary haemostasis
- What are endothelial cells sat upon? What do they release?
- Where is VWF stored?
- What is released upon stimulation? What does VWF bind to?
- What receptors do platelets express?
- Sitting on a bed of collagen, releasing von Willebrand factor upon stimulation and continuously
- Stored in granules within endothelial cells, Weibel-Palade bodies
- More VWF released. Trauma to the vessel, endothelium damaged, exposes collagen, VWF binds to collagen
- Receptors to collagen and VWF, binds to exposed collagen and VWF. Becomes activated, expresses fibrinogen receptors needed for aggregation.
What is secondary haemostasis?
Activation of fibrin formation through clotting cascade.
Occurs in concert with primary haemostasis.
Secondary haemostasis
What causes tissue factor release?
What does thrombin activate?
- Trauma to vessel causes tissue factor to be expressed by sub-endothelial cells. Tissue factor binds + activates coagulation protein factor 7A/VIIa and 10/Xa. 10A produces thrombin from prothrombin.
- Thrombin activates endothelial cells and platelets
Secondary haemostasis 2
- What do activated platelets release?
- What does thrombin activate?
- What do these cofactors form?
- What do these complexes cause?
- Amplifying agents and mediators, induces more platelet activation e.g thromboxane’s, adenosine disphosphate. Activated platelets bind to fibrinogen via receptors.
- Cofactors 8A/VIIIa and 5A/Va.
- Calcium ion-dependent complexes on surface of platelets with factor IXa/9a (tenase complex) and factor Xa/10a (prothrombinase complex)
- Accelerates production of factor Xa and thrombin. Amplification of coagulation pathway to produce more thrombin.
Secondary haemostasis 3
What does thrombin convert?
Fibrinogen to fibrin mesh. Forms network of fibrin formation which traps RBC and platelets, forms a network that plugs the wound in the vessel.
- What is fibrinolysis?
- Where is tissue plasminogen activator expressed?
- What is plasmin?
- What is D-dimer?
- Breakdown of fibrin mesh, wound ultimately resolved.
- t-PA expressed on surface of endothelial cells, activates plasminogen (precursor proteinc circulating in blood) into plasmin
- Proteolyic enzyme, chops up fibrin mesh - fibrin degradation products.
- A fibrin degradation product, marker in disorders looking for ongoing fibrinolysis
- What regulates and keeps in check thrombin formation?
- What is antithrombin?
- Where does antithrombin sit?
- Natural anticoagulant pathways. Too much coagulation is detrimental.
- Antithrombin is a thrombin inhibitor and serpin. Serpin is a serine protease inhibitor. So thrombin and proteases, factor XA and factor Va.
- Sits on endothelial cells, binding heparin binding sites.
Why is anti-thrombin important?
It is a major checkpoint to inhibit coagulation - thrombin, 10a/Xa and 9A/IXa
Binding to heparin enhances activity of anti-thrombin. Heparin affinity is basis of anti-coagulants in use.
- What is the protein C pathway?
- What activates protein C pathway
- What does protein is allow?
- Negative regulation of thrombin to keep it under control. Protein C and S are natural anticoagulant plasma proteins.
- Activated by thrombin bound to thrombomodulin (TM) on endothelial cells to form activated protein C (APC)
- Protein S is an APC cofactor, enables complex to bind to cells, platelets and APC then degrade cofactors FVa and FVIIIa ( that are part of tenase and prothrombinase complex)
This gives natural inhibition of coagulation.
What is the molecular basis of haemophilia ?
Failure to clot, leading to haemorrhage
- Mutations in coagulation factors (haemophilia A and B)
- Platelet disorders (von Willebrand disease), VWF is essential for activating platelets in primary haemostasis, can lead to bleeding if there’s deficiency
- Collagen abnormalities (fragile blood vessels and bruising), issue with strength of blood vessels, if they’re weakened they’re fragile
What is the molecular basis of thrombophila?
Excessive clotting leading to thrombosis
- Inherited: mutations on coagulation factors (DVT), important for increasing risk of DVT
- Acquired: malignancy increases clotting factors (DVT) like tissue factor, thrombin, FXA, cancer patients therefore at risk of DVT
What is the molecular basis of disseminated intravascular coagulation?
DIC - whole body clots, clotting in vasculature systemically
- Can be due to infection, coagulation and bleeding happening simultaneously
- Depletion of clotting factors and platelets leads to bleeding
What causes haemophilia A and B?
Why do these mutations cause haemophilia?
A more common than B, 80% of cases.
- A is caused by mutations in factor 8/VIII
- B caused by mutations in factor 9/IX
Significant increase in bleeding without functional FVIIa and FIXa due to insufficient thrombin being formed to activate fibrin mesh.
See bleeding into joints mostly.
What is VW disease?
Bleeding disorder. Deficiencies in VWF. Without VWF we don’t have platelet adhesion, aggregation and activation. Increased risk of bleeding.
- Affects mucous membranes
- Mostly mild, but bleeding can vary in severity
- Managed with lifestyle and being careful
Explain the Factor V Leiden mutation and how it causes excessive clotting
Factor V Leiden mutation, most common mutation, increases risk of DVT in inpatients.
Mutation allows for resistance to inhibit APC pathway.
APC no longer works on FVA, doens’t degrade it, FVA is resistance.
FVA amplifies clotting cascade even in present of natrual anti-coagulant pathway.
Explain how anti-thrombin deficiency causes excessive clotting
Can protein C and S deficiency cause clotting?
- Deficiency in antithrombin, inhibition of FIXa and FXa diminished, not inactivated. Clotting continues, increasing risk of DVT.
but you will still have one or the other pathway working e.g APC pathway
- Yes deficiency in C and S can cause excessive clotting, mutations in these proteins increases risk of DVT
What are the clinical findings of DVT?
- Pain and tenderness of veins
- Limb swelling
- Superficial venous distension
- Increased skin temperature
- Skin decolouration
increased risk of pulmonary embolism if fragment of clot breaks off and moves to lungs.
What is Virchow’s triad for DVT?
Hypercoagulability, changes on the constituents of blood – factor V Leiden mutation, anti-thrombin deficiency, protein S and C deficiencies all increased hypercoagulability.
Vessel wall injury, trauma can lead to thrombosis.
Stasis, where you have reduced venous flow through immobility, e.g long haul flights, laying in hospital, anything that increases the risk of immobility. Increases risk of DVT.
What does development of a venous thrombus depend on?
Alterations in the constituents of the blood
Changes in normal blood flow
Damage to the endothelial layer
How is thrombosis managed?
- Anti-coagulants, prevent more coagulation occuring
- Warfarin (needs to be monitored) and heparin (injectable)
- More targeted anti-coagulants, target specific components of coagulation cascade e.g direct oral anticoagulants (DOACs)
- thrombolytics and fibrinolytics used in some cases, degrade clot
- recombinant forms of tPA to break clots - used in patients with embolism
- bacterial plasminogen activator, streptokinase
What investigations are done pre-treatment of venous thromboembolism?
clotting screen, need to know integrity of clotting factors before treatment
- Prothrombin time
- partial thromboplastin time
- Thrombin time
Full blood count
Renal screen - need to see if kidneys function normally as drugs excreted renally
Liver function tests - if suspicion of liver disease
What is the treatment of venous thromboembolism?
DVT: anti-coagulate – prevents more clotting
- Immediate anticoagulant effect
- Heparin or warfarin
- DOACs
- Rivaroxaban, apixaban (FXa inhibitors)
- Dabigatran (thrombin FIIa) inhibitor
PE: thrombolysis, patient is at risk, need to break up clot in lungs
- Alteplase (tissue plasminogen activator)
- Streptokinase
- Followed by anticoagulant to prevent recurrence
What is a side effect of using too many anti-coagulants?
It’s common to end up with bleeding from using too much of an anticoagulant
Bleeding can be minor or severe
- Nose bleeds
- Haemorrhages
- Bruising
- Ultimately significant bleeds will occur in the brain which can be fatal, intracerebral bleeds that can cause haemorrhagic strokes
Important to monitor patients and use anticoagulants judiciously
