3. Intrinsic pathway Formation of prothombin activator is the central event in the clotting pathway For its formation the pathway that is initiated by the platelets (which are within the blood itself) is called intrinsic pathway Factor XII (in contact with collagen) + kallikrein & HMW kininogen  XIIa XII  XI  IX  X are sequentially activated Factor X + platelet phospholipid + factor V  prothrombin activator

4. Extrinsic pathway Due to release of tissue thromboplastin (factor III) by injured tissues Glycoprotein & phospholipid component of thromboplastin convert factor X  Xa Xa + V + Ca ++  prothrombin activator Factor X is converging point of both pathways

5. Vitamin K-dependant factors include factor II, VII, IX & X. So, in case of vitamin K deficiency both intrinsic & extrinsic pathway are affected Increased clotting time & normal bleeding time (opposite in vitamin C deficiency) Bleeding time is an indication of platelet function PT, aPTT & CT are parameters of clotting defects aPTT is prolonged with deficiency of XII, XI, IX, VIII, II, I & thrombin PT is prolonged in VII, V, II, I & thrombin PT & aPTT both are prolonged (but PT is a more sensitive test to detect Vitamin K deficiency because factor VII has a short t 1/2 so even with mild Vit K deficiency only PT is prolonged Factor XII, kallikrein, HMW kininogen are called contact factors Paradoxical situation: in deficiency of contact factors PTT is extremely prolonged but there is no evidence of clinical bleeding

6. Cause of isolated prolongation of PT: Warfarin therapy Liver disease Factor VII disease

7. Hemophilia A (Classical hemophilia) Due to reduced activity of factor VIIIc (part of intrinsic pathway) Factor VIII  VIIIc + vWF aPTT prolonged & Clotting time is increased Bleeding time is normal, PT is also unaffected Deficiency of vWF leads to: von Willebrand disease Von Willebrand factor facilitates platelets adhesion by linking platelet membrane receptors to vascular endothelium  its deficiency leads to defect in platelet adhesion & aggregation  prolonged bleeding time It is plasma carrier for factor VIII so in vWD both aPTT & bleeding time is increased (due to defective platelet aggregation )

8. Hemophilia B Deficiency/absence of factor IX Intrinsic pathway affected aPTT prolonged PT, BT normal