Disorders of blood coagulations Flashcards
Why is it important blood clots?
→ To keep blood in and pathogens out
→ Tightly regulated process that stops bleeding at the site of an injury
→ Must remain localized –
→ Blood loss is stopped by formation of a plug composed of platelets and fibrin
→ Endothelium in blood vessels normally maintains an anticoagulant surface
→ Injury exposes collagen to come into contact with blood components to activate clotting (activates primary and secondary haemostasis)
→ Two main processes of haemostasis – primary and secondary
→ Platelets and fibrinogen, circulate in the blood ready to go
What does primary haemostasis and secondary haemostasis involve (briefly)?
→ Primary- platelet adhesion, aggregation, activation
→ Secondary- activation of fibrin formation through the clotting cascade
both occur at the same time- ie not separate processes
Describe some details of primary haemostasis
→ You have an endothelial cell sitting on a bed of collagen
→ The endothelial cells release Von Willebrand factor continuously
→ Endothelial cells also store von Willebrand factor in Weibel-palade bodies for release upon appropriate stimulation
→ If the endothelium becomes damaged (and collagen becomes exposed to blood) then the von willebrand factor binds to the collagen
→ 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 some details of secondary haemostasis
→ Secondary haemostasis is where we have activation of clotting proteins
→ 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. (Factor VIIa activates Factor Xa which produces the initial trickle of thrombin- which needs amplification to lead to activation of fibrin (which comes from fibrinogen).
→ Amplification comes from thrombin activating 2 factors- VIIIa and Va which are both calcium ion dependent, also co factors with factors IXa and VIIa on the surface of platelets.
→ These complexes essentially lead to more activation of thrombin which converts the fibrinogen to fibrin)
→ 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 very important for activating fibrin. (positive feedback loop)
conversion/activation of fibrinogen to fibrin occurs on the platelets
→ 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.
What is the difference between fibrinolysis and hemostasis?
The difference between fibrinolysis and hemostasis is that fibrinolysis is the process wherein a fibrin clot, the product of coagulation, is broken down
While hemostasis is the process of keeping blood inside a damaged vessel to stop bleeding
What is the difference between primary and secondary haemostasis?
→ During primary hemostasis, platelets in the blood aggregate at the injury site and form a platelet plug to block the hole
→ Primary hemostasis is followed by secondary hemostasis
→ During secondary hemostasis, platelet plug is further reinforced by a fibrin mesh produced through proteolytic coagulation cascade
→ Therefore, the key difference between primary and secondary hemostasis is that primary hemostasis makes a weak platelet plug at the injury site while secondary hemostasis makes it strong by generating a fibrin mesh on it.
Outline the cell based model of coagulation
→ A tear in the endothelium exposes tissue factor (TF) and von Willebrand factor (vWF).
→ vWF binds to platelets through the GP1b receptor, anchoring them to the area of injury. The platelet membrane provides a phospholipid surface on which coagulation factors are active.
→ Coagulation is initiated when tissue factor binds to circulating factor VII, activating it and catalysing the conversion of FIX and FX to FIXa and FXa respectively.
→ This complex is known as the extrinsic tenase complex.
→ However, the FXa produced by the extrinsic tenase is very rapidly inactivated by tissue factor pathway inhibitor (TFPI).
→ Hence, it can only catalyse the formation of small amounts of thrombin (IIa) from prothrombin (II).
→ Thrombin binds to the GP1b receptors on the platelet surface, activating FXI, FVIII and FV. This results in the amplification phase.
→ FXIa helps to amplify the conversion of FIX to FIXa by the extrinsic tenase.
→ The degree of amplification is variable, explaining the variable clinical phenotype of FIX deficiency.
→ In the propagation phase, FVIIIa binds to FIXa, acting as a cofactor and resulting in the generation of the intrinsic tenase complex.
→ This results in the generation of large amounts of FXa from FX.
→ The FXa combines with FVa to form the prothrombinase complex.
→ The prothrombinase complex catalyses the conversion of prothrombin (II) to thrombin (IIa) in large amounts.
→ The resultant thrombin converts fibrinogen (I) to fibrin (Ia), which cross-links platelets via the GPIIa/IIIb receptor.
→ This results in the formation of a platelet plug, stabilised by a fibrin mesh at the site of vessel injury.
→ Coagulation is terminated by two mechanisms other than TFPI.
→ Firstly, endothelial injury results in heparan sulphate (HS) being exposed to the blood
→ This induces a conformational change in circulating antithrombin (AT), which then binds thrombin (IIa) and Xa, inactivating them.
→ Secondly, thrombin (II) binds to thrombomodulin (TM), which is expressed on endothelial cell surfaces
→ This induces a conformational change in TM, which allows it to bind to protein C (PC) and activate it (aPC). aPC then binds to FVa, inactivating it
→ Protein S (not depicted) is a co-factor for protein C.
Once you’ve formed that fibrin ‘plug’/ clot, it cannot remain there so how is it resolved?
→ Thrombolysis and Fibrinolysis - used interchangeably
→ You need to break down the fibrin.
→ Plasminogen in activated to plasmin by tissue plasminogen activator, t-PA (expressed on the surface of endothelial cells
→ Plasmin degrades the fibrin mesh to fibrin degradation products (eg E-dimer is the name of one) which can be cleared
What keeps coagulation in check? (main anticoagulant natural (in vivo) pathway)
→ Antithrombin (AT) is a serpin (serine protease inhibitor)
→ Activity greatly enhanced by binding heparan binding sites on endothelial cells
→ Antithrombin acts as a Major checkpoint to inhibit coagulation (thrombin), IXa, Xa)
→ Its heparan binding domain is the basis of the anticoagulant activity of heparin which increases the activity of ATIII
Heparan- the natural binding site
Heparin- anticoagulants we use for treatment
What is protein C and protein S? (second natural (in vivo) anticoagulant pathway)
→ 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
→ Activated Protein C degrades cofactors FVa and FVIIIa
What is antithrombin?
→ Antithrombin is the major inhibitor of thrombin, factor IXa, and factor Xa in plasma, but it also inactivates the other serine proteases of the intrinsic coagulation pathway, factors XIa and XIIa, as well as some noncoagulation serine proteases, such as plasmin, kallikrein and the complement enzyme C1.
→ Antithrombin is a protein in our blood stream, which functions as a naturally occurring mild blood thinner. It is like a police protein that prevents us from clotting too much.
→ It blocks our blood clotting mechanism by inactivating the major clotting protein “thrombin.
List some diseases/disorders linked to blot clotting and what groups of disorders they come under
→ 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 mutated in haemophilia A and B, which one is more common?
→ Haemophilia A is more common (80%) and this is where there are Mutations in FVIII
→ Haemophilia B (20%) which is less common and where we see underlying mutations in factor FIX
→ We also see von Willebrand disease
→ Inherited defect/deficiency in vWF
→ These all lead to bleeding as a lack of some factors within the clotting cascade means blood doesn’t clot
What is a mutation that causes an increase in the risk of DVT? (Deep vein thrombosis)
What happens with Factor V in this mutation is it allows for resistance to inhibition of this pathway (called resistance to activated protein C)
What other mutations/deficiencies can lead to excessive clotting?
→ Antithrombin deficiency
→ Thrombin, IXa and FXa are not inactivated
→ Increases risk of DVT
→ Protein C deficiency
→ Protein S deficiency
→ Both also Increase the risk of DVT
