Haemostasis and Thrombosis

- a dynamic process of maintaining fluidity of the blood, repairing vascular injury and limiting blood loss while avoiding vessel occlusion ( Thrombosis) and inadequate perfusion of vital organs.

• formation of platelets which adhere to injured tissue
  
• Blood clotting factors : the protein circulating in the plasma.
  
• Results in formation of insoluble fibrin clot that reinforces the initial platelet plug.
  
• Fibrinolysis : happens when healing and tissues repair are under way.

3 systems

1. intrinsic pathway
   
2. extrinsic pathway
   
3. common pathway
   

Here's a very good website to explain these 3 pathways.

http://www.hopkinsmedicine.org/hematology/Coagulation.swf

Intrinsic pathway

Basic :

Blood on -ve charged surface
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XII --- Kininogen + Prekallikrein
_________________________
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Kallikrein
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XIIa + XI
_______
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IX (IXa) + VIIIa (cofactor) -----> convert X to Xa---> ( initiation of common pathway)

• initiated when blood comes into contact with -ve charged surface
  
• Factor XII interacts with high molecular weight - kininogon and prekallikrei. ---> to produce Kallikrein which activates factor XII ( XIIa)
  
• The activated factor XIIa then activates factor XI which activates factor IX
  
• the factor IXa together with activated factor VIIIa ---> as a cofactor which converts factor X to factor Xa.
  

Extrinsic Pathway

basic :

Tissue factor from damaged tissue
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VII bind to it and form VIIa
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Activates X to form Xa

• when tissue factor is exposed to the blood on the damaged tissue, The factor VII binds to it to form factor VIIa
  
• which activates factor X to to form factor Xa, leading to the initiation of common pathway.
  

Common pathway

Xa ( activation) +V
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Prothrombin------- Thrombin
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formation of fibrin ( stablised by XIIIa)

• the activation of Factor Xa is the point that intrinsic and extrinsic pathway converge to form a common pathway of coagulation cascade.
  
• Factor Xa together with activated V as cofactor, converts prothrombin to thrombin with a subsequent formation of fibrin which is stabilised by factor XIIIa and form a stable clot.
  

Fibrinolysis

Plasmin (fibrinolysin)
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digests fibrin clots and II, V, VII, XII

• Clot dissolution
  
• mediated by plasminogen which circulates in plasma as an inactive form, which converts to its active form plasmin ( fibrinolysin) .
  
• This occurs when plasminogen binds to fibrin in the presence of plasminogen activator.
  
• Fibrinolysin digests fibrin clots and hydrolyses factors II, V, VIII and XII.

Thrombosis

- the development of thrombus in the arterial or venous circulation
- if venous thrombus breaks off and enter:

• Right circulation and lodge in the pulmonary arterial circulation->pulmonary emoblism (PE)
  
• Left circulation and lodge peripheral arterial --> cause stroke

Venous Thromboembolism

1. Deep vein thrombosis (DVT)
   
2. Pulmonary Embolism (PE)
   

Risk factor

• Age
  
• immobility
  
• major surgery in recent weeks
  
• pregnancy
  
• malignancy - cancer
  
• oestrogens
  
• inherited coagulation disorders. Previous venous thrombosis

Diagnosis

DVT

-clinical symptoms
- RF

• D-dimer : is a small protein fragment present in the blood after blood clotting generated by fibrinolysis
• the concention of D-dimer can be determined by a blood test.
  

• Duplux ultrasonography scan :

PE

• Pulmonary arteriography
  
• ventilation perfusion scanning
  

Treatment

Nonpharmacologic prevention - external pneumatic compressio, graduated compression socking or venous foot pumps. ( these devices increase venous outflow and reduce stasis within the leg veins.
pharmacologic prevention - Venous thromboembolism

• unfractionated heparin
• oral anticoagulants - warfain
  
• low molecular weight heparin

Unfractionated heparin (UFH)

Mechanism of action

• the major mechanism by which heparin blocks coagulation is by catalysing the inhibition of thrombin. UFH acts as an anticoagulant by catalysing the inactivation of thrombin (factor IIa) , activated factor X ( factor Xa) , and activated factor IX (IXa) by antithrombin
  

- used to prevent thrombosis ( venous , unstable angina)
- prevent blood clotting

Caution

• HIT
  
• Hyperkalaemia -
  

- short duration of action

Low molecular weight heparin

- longer duration of action compared to UFH

Oral anticoagulant - Warfarin

Mechanism of action

• is a vitamin K antagonist and interferes with the synthesis of coagulation factors.
  
• Because vitamin K is essential for production of prothrombin and factor VII, IX and X ( vitamin K is important for postranslational carboxylation of glutamic acid residues of these proteins)
  
• Warfarin blocks vitamin K reductase, needed for vitamin K to act as a cofactor in the synthesis of coagulation faction.
  

SF

• many drug interactions
  
• may lead to increased bleeding
  

Heparin-induced thrombocytopenia (HIT)
- is the development of a low blood count (thrombocytopenia) due to the administration of various forms of heparin.

- stop treatment and use heparinoid or hirudin

Heparinoid ( e.g. Danaparoid)
- a mixture of low molecular weight sulphated glycosaminoglycuronans

Mechanism of action

• inhibits factor Xa resulting inhibition of thrombus generation and thrombus formation
  

Hirudin ( Lepirudin and Bivaluridin)

- a direct thrombin inhibitor
- action independent of antithrombin.

Lepriudin

- a recomninant hirudin
caution
- risk of bleeding

Bivaluridin
Caution
- an exposure to lepirudin

Fondaparinux - a synthetic pentasaccharide

• bind to antithrombin thus inhiits activated factor X
  

SF : haemorrhage.

Pharmacological prevention - Arterial thromboembolism

- if affecting the cerebral circulation results TIAs ( transient ischaemic attacks or cerebral infarction ( a form of stroke)

Antiplatelets

1. Aspirin
   
2. clipidogrel
   
3. Glycoprotein IIb/IIIa inhibitors
   
4. Dipyridamole
   
5. Clopidogrel