L14: Disorders Of Blood Coagulation Flashcards
Why does clotting occur?
→Blood loss is stopped by formation of a plug composed of platelets and fibrin
What does the endothelium maintain in blood vessels?
→maintains an anticoagulant surface
What are the two main processes of haemostasis?
→primary and secondary
What is primary haemostasis of clotting?
→when platelet adheres, activation
What is secondary haemostasis of clotting?
→activation of fibrin formation
Describe primary haemostasis
→Endothelial cells also store von Willebrand Factor in Weibel-Palade bodies for release when appropriately stimulated
→If collagen becomes exposed to blood 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.
Describe secondary haemostasis
→Tissue factor (TF), activates the coagulation cascade to initiate a minor burst of thrombin
→Factor FVIIa binds to Tissue Factor, which ultimately leads to conversion of prothrombin to thrombin
→Thrombin activates receptors on platelets and endothelium
→amplifies platelet aggregation and initiating release of stored von Willebrand Factor from endothelial cells.
Which cell express tissue factor?
→by nearly all sub-endothelial cells
When would collagen become exposed?
→because the endothelium is damaged
Describe the amplification process in clotting
→Thrombin activates Factor VIIIa and Factor Va
→subsequently form calcium ion-dependent complexes on the surface of platelets with Factor IXa and Factor Xa
→accelerate production of Factor Xa and thrombin, respectively
Which factors does thrombin activate?
→Factor VIIIa and Factor Va
Where are the calcium dependent complexes found?
→surface of platelets with Factor IXa
What is the tenase complex?
→Factor IXa and Factor VIIIa
→substrate is Factor X
What is the prothrombinase complex?
→Factor Xa
What does thrombin convert?
→convert fibrinogen to the fibrin mesh
Describe fibro lysis
→Plasminogen in activated to plasmin by tissue plasminogen activator, t-PA
→Plasmin degrades the fibrin mesh to fibrin degradation products which can be cleared
What is plasmin?
→proteolytic and very potent
What is antithrombin?
→a serpin
serine protease inhibitor
How is antithrombin activity enhanced?
→by binding heparan binding sites on endothelial cells
What is the role of antithrombin?
→checkpoint to inhibit coagulation (thrombin), IXa, Xa)
What does heparin mimic in heparan?
→binding domain
→increases the activity of ATIII
What are the natural anticoagulants?
→antithrombin
→protein C and S
What is Protein C activated by?
→by thrombin bound to thrombomodulin (TM) on endothelial cells
What is protein S?
→APC cofactor which helps binding to cell surfaces
Which factors degrades APC?
→degrades cofactors FVa and FVIIIa
What is haemophillia?
→- failure to clot leading to haemorrhage
What are the causes of haemophillia?
→Mutations in coagulation factors (haemophilia A and B)
→Platelet disorders (von Willebrand disease)
→Collagen abnormalities (fragile blood vessels and bruising)
What are the causes of thrombophillia?
→Inherited: mutations in coagulation factors (DVT)
→Acquired: malignancy increases clotting factors (DVT)
What is DIC?
→Disseminated intravascular coagulation
→ whole body clots
→So much coagulation that clotting factors become depleted
What are the causes of DIC?
→Infection
→Depletion of clotting factors and platelets leads to bleeding
What are examples of bleeding disorders?
→von Willebrand disease Inherited defect/deficiency in vWF →Haemophilia B (20%) Mutated FIX →Haemophilia A (80%) Mutated FVIII
What are clinical symptoms of of heamophillia?
→bleeding in the joints
What are clinical features of von Willebrand disease?
→mucous membranes bleeding
What does Factor V Leiden mutation lead to?
→Resistance to APC
→FVa is not inactivated
→Increases risk of DVT
What does antithrombin deficiency lead to?
→Thrombin, IXa and FXa are not inactivated
→Increases risk of DVT
What does protein C and S deficiency lead to?
→Protein C deficiency
→Protein S deficiency
→Increases risk of DVT
What are the three parts of Virchow’s triad?
→stasis
→vessel wall injury
→hypercoagulability
What are the symptoms of DVT?
→Pain & tenderness of veins →Limb swelling →Superficial venous distension →Increased skin temperature →Skin discoloration
What mutations/deficiency can lead to excessive clotting?
→Factor V Leiden mutation
→Antithrombin deficiency
→Protein C deficiency
→Protein S deficiency
What are the pre-treatment investigations of VTE?
→Clotting screen
→Full blood count
→Renal screen
→Liver function tests
What tests are involved in clotting screen?
→Prothrombin time
→Partial thromboplastin time
→Thrombin time
What are the treatments for DVT?
→Immediate anticoagulant effect
→Heparin or warfarin
→DOACs
Give two examples of DOACs and what they inhibit
→Rivaroxaban, apixaban (FXa inhibitors)
→Dabigatran (thrombin (FIIa) inhibitor)
What are the treatments for pulmonary embolism?
→Alteplase (tissue plasminogen activator)
→Streptokinase
→Followed by anticoagulant to prevent recurrence
What can result from excess anticoagulants?
→bleeding in the brain, arm or eyes
What are DOACs?
→direct oral anticoagulants
