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Molecular Basis of Disease > 13- Disorders of Blood Coagulation > Flashcards

13- Disorders of Blood Coagulation Flashcards

1
Q

what is clotting?

A

a tightly regulated localised process

stops bleeding at the site of injury and keeps pathogens from entering the wound

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2
Q

what is a clot?

A

a localised plug formed from a mesh of cross-linked fibrin and aggregated platelets to prevent blood loss

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3
Q

what is primary haemostasis?

A

process for the formation of the platelet plug

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4
Q

what is secondary haemostasis?

A

formation of the fibrin clot

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5
Q

what is VWF?

A

von-Willebrand factor - released by blood vessel endothelium
- important in platelet adhesion by binding to exposed collagen

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6
Q

where is VWF stored?

A

in specialised structures called Weibel-Palade bodies in vessel endothelial cells

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7
Q

what is the coagulation cascade?

A

a series of enzymatic reactions that lead to thrombin formation - activates fibrin and the formation of the fibrin mesh

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8
Q

describe primary haemostasis

A

damage/ injury to vessel exposes subendothelial collagen - endothelial cells release VWF

VWF binds to exposed collagen - platelets have both VWF and collagen receptors = platelets bind to both and become activated (platelet activation)

activate platelets attract more platelets to site of injury (platelet aggregation) - form platelet plug

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9
Q

describe secondary haemostasis

A

tissue factor is expressed on subendothelial vessel cells - exposed upon damage/ injury

tissue factor binds to factor VIIa - becomes a complex, activates coagulation cascade

TF-VIIa complex activate more factors
- factor X converted to factor Xa by tenase enzyme
- factor II/ prothrombin converted to factor IIa/ thrombin

thrombin converts fibrinogen to fibrin - fibrin forms cross-linked mesh with platelets and RBCs = forms a stable clot

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10
Q

describe the amplified production of thrombin

A

thrombin activates platelets - platelets release factors VIIa and Va

factor Va, Ca2+ ions and thrombin together form a Ca2+ dependent prothrombinase

prothrombinase catalyses prothrombin to thrombin conversion = more thrombin produced/ amplified to convert fibrinogen to fibrin

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11
Q

what is fibrinolysis?

A

dissolving/resolving a clot from the site of injury

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12
Q

describe the process of fibrinolysis

A

inactive plasminogen in the clot is converted into active plasmin by tissue plasminogen activator (tPA) in vessel endothelial cells

plasminogen to active plasmin - plasmin breaks down clot into smaller fragments called D-dimers

D-dimers cleared by circulation

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13
Q

list two natural antcoagulants

A

antithrombin
protein C & protein S

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14
Q

what is antithrombin?

A

a serine protease inhibitor that inhibits key factors of the coagulation cascade and turns off thrombin amplification

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15
Q

how does antithrombin act as a natural anticoagulant?

A

inhibits key factors of the coagulation cascade - e.g. factors IXa, Xa and IIa (thrombin)

activity is enhanced by heparin binding to its binding site on endothelial cells - heparin is a therapeutic anticoagulant that prevents coagulation by inhibiting thrombin

turns off thrombin activation and positive feedforward amplification loop = regulates clotting factors and prevents excessive coagulation

(inhibits key factors of the coagulation cascade - especially thrombin, prevents thrombin activation/ amplification, prevent excessive coagulation, activity enhanced heparin binding to heparin binding site and inhibiting thrombin)

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16
Q

what are proteins C and S?

A

natural anticoagulant plasma proteins, regulate thrombin levels

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17
Q

how do proteins C & S act as natural anticoagulants?

A

thrombin is amplified by positive feedback - too much thrombin activates its own anticoagulant pathway

thrombin binds to thrombomodulin endothelial cell surface receptor - protein C is activated by thrombin-thrombomodulin

protein C becomes activated protein C/ APC - protein S is an activation cofactor, helps APC bind to cell surfaces and degrade factors Va and VIIa = inhibits coagulation cascade

18
Q

what does protein C do?

A

when excess thrombin is produced - it activates its own anticoagulant pathway

thrombin binds to thrombomodulin endothelial cell surface receptor = activates protein C

protein C converted to activated protein C/ APC

APC degrades key cofactors in the coagulation cascade like factor Va and VIIa

19
Q

what does protein S do?

A

co-factor involved in protein C to activated protein C/ APC conversion

20
Q

what does antithrombin do?

A

inhibits key factors of clotting cascade - thrombin, factors IXa and Xa

regulates factors of the clotting cascade, prevents thrombin production and amplification - heparan binding to its binding site on endothelial cells enhances antithrombin activity

21
Q

examples of blood clotting disorders

A

haemophilia - haemophilia A, B and von Willebrand disease = bleeding disorders

thrombophilia - excessive clotting leading to thrombosis

disseminated intravascular coagulation/ DIC

22
Q

what is haemophilia? what subtype diseases fall under it?

A

failure to clot leading to haemorrhage

haemophilia A and B
von Willebrand disease/ platelet disorders
collagen abnormalities

23
Q

symptoms of haemophilia?

A

bleeding into joints - causes pain, swelling and tenderness
many large/ deep bruises

24
Q

what is haemophilia A?

A

failure to clot leading to haemorrhage due to a mutation in factor VII

25
Q

what is haemophilia B?

A

failure to clot leading to haemorrhage due to a mutation in factor IX

26
Q

what is von Willebrand disease? symptoms?

A

failure to clot leading to haemorrhage due to an inherited defect or deficiency in vWF

symptoms - bleeding of mucous membranes, mostly mild but can vary in severity

27
Q

examples of thrombophilia/ clotting disorders

A

factor V Leiden mutation
antithrombin deficiency
protein C & protein S deficiency

28
Q

what is factor V Leiden mutation?

A

mutation in factor V interferes with clotting cascade - causes resistance to activated protein C (a natural anticoagulant)

makes mutant factor V resistant to degradation - it’s continually active and no longer regulated

increases risk of deep vein thrombosis/DVT

29
Q

what is antithrombin deficiency?

A

deficiency in antithrombin - no inactivation/ regulation of thrombin, factor IXa or Xa

increases clotting - predisposed risk to DVT

30
Q

what is protein C & protein S deficiency?

A

protein C and protein S are natural anticoagulants - lack of their activity increases risk of DVT

protein C is activated by thrombin-thrombomodulin binding = protein C activated to APC which degrades key factors

protein S is a co-factor for protein C to APC activation

31
Q

how does Virchow’s triad relate to DVT?

A

Virchow’s triad = increased risk of thrombosis related to 3 factors:
1. hypercoagulability
2. stasis
3. vessel wall injury

changes in blood constituents, normal blood flow or damage to endothelial layer can increase risk for DVT

32
Q

symptoms of DVT?

A

pain & tenderness of veins

limb swelling – often unilateral/ affecting one limb

superficial venous distension

increased skin temperature

skin discoloration

potential ulceration

33
Q

what is disseminated intravascular coagulation?

A

the simultaneous occurrence of widespread blood clotting and bleeding throughout the body

occurs as a complication of other conditions - e.g. cancer, sepsis

34
Q

how does DIC happen?

A

in response to sepsis there’s widespread activation of clotting factors in the body = leads to formation of small clots throughout blood vessels

eventually this continuous clotting depletes the factors involved - decreases ability of blood to clot and leads to excessive bleeding

can cause tissue and organ damage, also death in young children

35
Q

what are anticoagulants? - examples? use?

A

e.g. warfarin, heparin, direct oral anticoagulants

target specific clotting factors and prevent the clot from getting bigger - let natural fibrinolysis break up the clot

36
Q

what are thrombolytics/ fibrinolytics? - examples? use?

A

e.g. plasminogen activators: tPA, streptokinase

given in the case of a medical emergency - e.g. pulmonary embolism = breaks up the clot by activating fibrinolysis

37
Q

what investigations are conducted pre-treating a venous thromboembolism?

A

clotting screen - e.g. prothrombin time, thrombin time
full blood count
renal scree
liver function tests if there’s a suspicion of liver dysfunction

38
Q

treatments for DVT?

A

anticoagulants - e.g. warfarin, heparin, DOACs

increase antithrombin activity = heparin binds to heparin binding sites on endothelial cells

39
Q

treatments for pulmonary embolism?

A

thrombolytic agents
- e.g. Alteplase as a tissue plasminogen activator = converts plasminogen to plasmin for fibrinolysis
- e.g. Streptokinase

followed by anticoagulant to prevent recurrence

40
Q

what is Alteplase?

A

a tissue plasminogen activator - thrombolytic

Molecular Basis of Disease (32 decks)

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