disorders of blood coagulation Flashcards
Why is a blood clot important?
- keeps blood in
- keeps pathogens out
- tightly regulated process that stops bleeding at the site of an injury
- must remain localised - if blood clot gets transported to the brain = stroke
what is hemostasis?
- platelets and fibrinogen circulate ready to go
- damage in vessel wall triggers clotting
- aggregated platelets + fibrin mesh
- blood loss is stopped by formation of a plug composed of platelets and fibrin.
- fibrinolysis breaks down blood clots preventing clots from growing and detaching.
- the balance between these two processes is called hemostasis.
How is clotting normally prevented when there is no trauma/injury?
=> endothelium in blood vessels normally maintains anticoagulant surface
=> injury exposes sub endothelial surface collagen to come into contact with blood component to activate clotting
outline the process of primary haemostasis
Primary hemostasis involves adhesion, aggregation and activation.
- The endothelium continuously releases small amounts of von williebrand Factor in weibel-palade bodies for release when approximately 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 fibrogen receptors , which are required for aggregation.
Outline secondary haemostasis.
Secondary hemostasis causes activation of fibrin formation through clotting cascade.
- activated platelets
- tissue factor (TF) , expressed by nearly all subendothelial cells activates the coagulation cascade to initiate minor burst of thrombin. Factor FVIIa binds to Tissue Factor, which ultimately leads to conversion of prothrombin to thrombin.
- Thrombin activates receptors on platelets as well as endothelium, amplifying platelets aggregation and initiating release of stored von Willebrand Factor from endothelial cells.
- thrombin will activate 2 cofactors : factor Va and Factor VIIIa which subsequently form calcium ion- dependent complexes on the surface of platelets with factor IX a ((tense complex) and Factor Xa (the prothrombinase complex). These complexes greatly accelerate production of Factor Xa and thrombin, respectively.
This is the amplification stage of the coaggulation cascade. - The greatly increased production of thrombin via tenase and prothrombinase contribute considerably more to the process. Thrombin will convert fibrinogen to fibrin mesh.
Define antithrombin.
- thrombin inhibitor
- its a serpin (serine protease inhibitor)
- activity of antothrombin in greatly enhanced by binding sites on endothelial cells
- major checkpoint to inhibit coaggulation(thrombin, IXa and Xa)
What is another fibrinolytic system/plasminogen activation system?
- plasminogen (circulating in blood) => plasmin (proteolytic enzyme)
- it breaks fibrin into fragments called fibrin degradation products, one of these products is called D-dimer.
Why is D- dimer significant?
-D - dimer can be used to identify the stages of clotting cascade.
What is the difference between heparan and heparin?
- Heparan = natural binding site on endothelial cell
2. heparin = anticoaggulant, mimics effects of antithrombin.
How do protein C and protein S function to inhibit coaggulation?
- protein C and protein S are natural anticoaggultant plasma protein.
- protein C is activated when thrombin binds to thrombomodulin (TM) on endothelial cell.
- Protein C is converted to active protein C (APC)
- protein S is an APC co factor which helps binding to cell surfaces Protein S degrades co factors FVa and FVIIIa( mutation in this co factor leads to hemophilia)
Define haemophilia
-failure to clot leading to haemorrhage
What defects lead to haemophilia A and B?
- mutations in coagulation factors
- platelet abnormalities
- collagen abnormalities
A = mutation in factor 8 (80%) B= mutation on co factor 9 (20%)
What is Von willebrand disease?
- inherited defect/deficiency in vWF
- without vWF platelets can’t bind to endothelial cells so no clotting.
- platelet disorders
- type of haemophilia
what is thrombophilia?
- excessive clotting leading to thrombosis
1. inherited : mutations in coagulation factors (DVT)
2. acquired: malignancy increases clotting factor (DVT)
What is disseminated intravascular coagulation (DIC) - whole body clots?
- infection
- depletion of clotting factors and platelets leads to bleeding.
What cofactor mutation occurs in heamophilia A?
- FVIII (factor 8)
- 80% of mutations
What cofactor mutation occurs in haemophilia B?
- FIXa (facto 9)
- 20% mutation
Where is bleeding in hemophilia and von willebrand disease localised to?
- hemophilia = bleeding into joints
2. Von willebrand disease: affects mucous membranes, mostly mild but bleeding can vary in severity
Explain resistance to activated protein C and how it leads to increased risk of DVT.
- factor V leiden mutation causes FVa to be resistance to APC so FVa is not inactivated so clot gets bigger and increases risk of DVT.
Explain how antithrombin deficiency leads to excessive clotting.
- antithrombin deficiency means inhibition of FXa and FIXa and thrombin doesn’t occur.
- clotting continues, leading to excessive clotting
- increased risk of DVT
What is the Virchow’s triad of thrombosis made up of?
- hypercoagulability
- Vessel wall injury
- stasis
What does development of a venous thrombus depend on?
- alterations in the constituents of blood
- changes in normal blood flow
- damage to the endothelial layer
What are symptoms of deep vein thrombosis?
- swelling
-pain and tenderness of veins
-superficial venous distension
-increased skin temperature - skin discolouration
All reflect obstruction to the venous drainage increased risk of pulmonary embolism.
What is disseminated intravascular coagulation (DIC)?
- As sepsis (body’s response to an infection injures its own tissues and organs.
- depletion of clotting factors and platelets leads to bleeding.
What are examples of anti-coagulants?
- eg: Warfarin, heparin, direct oral anticoagulants (DOACs)
- prevent clotting
What are examples of direct oral anticoaggulants?
- Rivaroxaban, apixaban (FXa inhibitors)
- Dabigatran (thrombin, FIIa inhibitor)
What do thrombolytic/fibrinolytics do?
- break down clots
- eg: plaminogen activators, tPA, streptokinase(bacterial)
What are investigation for venous thrombin embolism (VTE)?
- clotting screen :
- prothrombin time
- partial thromboplastin time
- thrombin time - full blood count
- Renal screen
- Liver function tests
- if clinical suspicion of liver disease.
What are treatments of venous thrombin embolism (VTE)?
- DVT: anticoagulate
- immediate anticoagulant effect
-heparin or warfarin
-DOACs = rivaroxaban, apixaban (FXa inhibitor)
Dabigatran (thrombin FIIa inhibitor) - PE : thrombolysis
- alteplase (tissue plasminogen activator
- streptokinase
- followed by anticoagulant to prevent recurrence.
What are bleeding complications from anticoagulants?
- intracerbral bleed
