Disorders of blood co-agulation Flashcards
Why do we need blood clots?
- Needed for survival, to keep blood in
* To keep pathogens out
What forms the blood clot and is it a regulated process?
Why does it occur in a localized fashion?
- It is a tightly regulated process, involves various proteins and enzymes, and pathways that need to be coordinated to form the fibrin formation and platelet plug. Blood loss is stopped by formation of a plug composed of platelets and fibrin
- Blood clotting occurs in a localised fashion because we don’t want systemic blood clots as this is an issue in disease.
Describe the anticoagulant surface and what happens when we injury ourselves
- The endothelium in blood vessels normally maintains an anticoagulant surface.
- Injury exposes collagen to come into contact with blood components to activate clotting
What are the two pathways of clotting?
• Two main processes of haemostasis – primary (platelet adhesion, aggregation and activation) and secondary (activation of fibrin formation through the clotting cascade).
Describe the process of primary hemostasis
- The endothelium sits on top of a bed of collagen
- The endothelial cells release Von Willebrand factor upon stimulation, it is stored within granules within endothelial granules called Weibel palade bodies.
- The VWB factor will bind to the collagen
- The platelets circulating in the blood, they are also a source of VWB factor as they express receptors for collagen and VWB factor. They bind to both the exposed collagen through its receptors and VWB via the VWB factor receptor. Once they have bound the platelets become activated which then express other receptors such as the fibrinogen receptor needed for aggregation
Describe the process of secondary haemostasis
Primary and secondary haemostasis do not occur in a linear fashion, they occur together. These are not separate processes.
- Tissue factor (TF), expressed by nearly all sub-endothelial cells 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 as well as the endothelium, amplifying platelet aggregation and initiating release of stored von Willebrand Factor from endothelial cells.
- Thrombin activates two cofactors, Factor VIIIa and Factor Va which subsequently form calcium ion-dependent complexes on the surface of platelets with Factor IXa (tenase 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 coagulation cascade
- The greatly increased production of thrombin via tenase and prothrombinase contributes considerably more to the process. Thrombin will convert fibrinogen to the fibrin mesh ④
Describe the process of Fibrinolysis/ thrombolysis (breakdown of the fibrin into smaller pieces)
What system is responsible for this?
- The plasminogen system is responsible for this reaction.
- Plasminogen is activated to plasmin (a proteolytic enzyme which means that is makes quick work of fibrin mesh into fragments into fibrin degradation products such as d-dimer – a marker in disorders) by tissue plasminogen activator, t-PA.
- Plasmin degrades the fibrin mesh to fibrin degradation products which can be cleared.
Describe the first natural coagulant pathway
• These keep the coagulation pathway in check because thrombin has an amplification process, so it increases gradually, which further activates platelets and endothelial cells to release more VWB factor.
• To much coagulation is bad so it is vital there are pathways that regulate the coagulation pathway.
1. Antithrombin (AT) – a thrombin inhibitor, it is a serpin (serine protease inhibitor). AT inhibits thrombin and factor IXa and factor Xa.
2. AT is found on endothelial cells at heparan binding sites on the surface of endothelial cells. this greatly enhances the activity of antithrombin.
3. Heparin is anticoagulants that can be administered for treatments. Heparin increases the activity of AT.
Describe the first second coagulant pathway
- This is the protein C pathway
- Thrombin also stimulates a pathway that keep coagulation in check. It activates a negative regulation of itself.
- Thrombomodulin is a protein expressed on endothelial cells, that binds to thrombin. This then activates an anticoagulant protein, that is present in the blood called protein C.
- Protein C becomes activates to form activated protein C by the action of thrombin-thrombomodulin complex.
- Activated protein C has a binding partner called protein S. This enables this complex to bind to cell platelets, which then degrades co-factors cofactors FVa and FVIIIa
Which part of the clotting cascade can defects occur?
- Coagulation proteins
- Platelets
- Endothelium
What is haemophilia, thrombophilia and Disseminated intravascular coagulation (DIC)
Haemophilia - failure to clot leading to haemorrhage
• Mutations in coagulation factors (haemophilia A and B)
• Platelet disorders (von Willebrand disease)
• 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
• Infection
• Depletion of clotting factors and platelets leads to bleeding
What is hemophilia A and B caused by?
What is VWB disease casued by?
On image
What is excessive clotting caused by?
- Factor V Leiden mutation
- Resistance to APC
- FVa is not inactivated
- Increases risk of DVT
- Antithrombin deficiency
- Thrombin, IXa and FXa are not inactivated
- Increases risk of DVT
- Protein C deficiency
- Protein S deficiency
- Increases risk of DVT
What makes up the triad of thrombosis?
stasis
vessel wall injury
hypercoagulability
What does the development of venous thrombosis depend on?
- Alterations in the constituents of the blood
- Changes in normal blood flow
- Damage to the endothelial layer
- 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
