Biochem Bloodclotting Exam 7

This is tissue factor pathway inhibitor which is an anticoagulant. It binds extrinsic tenase (complex of factor VIIa,CA2+,TF) and prevents conversion of prothrombin to thrombin (factor X to Xa).

Heparin is an anticoagulant. It increases the affinity of anti-thrombin for thrombin (factor IIa). This prevents conversion of fibrinogen to fibrin (factor II to IIa).

• Punch Line: Inactivates factor VIII and factor V. THese are the two, 3 form cofactors required in intrinsic tenase (factor IXa complex) and prothrombinase complex (factor Xa complex) respectively.
• Anitcoagulative pathway. Thrombomodulin is an endothelial membrane bound molecule (by Ca2+ bridge) which can complex with free floating thrombin (IIa). The complex activates protein C (PC) to APC. APC in turn combines with its cofactor protein S (PS). This APC/PS complex can now inactivate two important molecules, intrinsic tenase complex and prothrombinase complex by inactivating the 3 form cofactors that go with each.

increased risk of venous thrombosis

Plasmin is a serine protease. It dissolves fibrin clots by breaking fibrin.

The transglutaminase, factor XIII crosslinks fibrin by making glutamine/lysine bonds.

tPA (tissue plasminogen activator); urokinase

• alpha2-plasmin inhibitor: clot formation
• APC/PS complex: clot degradation
• Thrombomodulin/IIa complex: clot degradation
• PAI-1(plasminogen activator inhibitor): clot formation

Most common hemorrhagic disorder due to a deficiency in factor VIII. x-linked disease (passed from mother to son)

Hemorrhagic disorder due to a defect in factor IX (intrinsic tenase)

Hemorrhagic disorder due to a defect in vWF. Affects collagen binding GP1B95 and chapperone of factor VIII so factor VIII degrades.

Hemorrhagic disorder due to a defect in GP-1B95

Hemorrhagic disorder due to a defect in GP-2b/3a

Thrombin (factor IIa); It can travel through the blood vessel and form clots (by converting fibrinogen to fibrin) in a region of blood vessel that is not injured. Anticoagulatants are present in the blood to prevent this.

Factors VIII and V. Thrombin also triggers the intracellular cascade in the cellular response via thrombin receptor.

• Cellular response is platelet activation by collagen. Following the intracellular cascade there is
• 1. Secretion of vasoconstrictors (seratonin and throm. A2), growth factors, Ca2+, and ADP
• 2. Activation of GP-2B/3A
• 3. Conformational change in platelet to explose PL and Ca2+
• 4. formation of Hemostatic plug by aggregation of platelets through fibrin and GP-2B/3A.

Collagen is exposed from the endothelium. Collagen binds three cell surface molecules (integrin a2B2, GP-1B95 via VWF, and GP-6). GP-6 and activation of thrombin receptor by thrombin (from molecular response) triggers the intracellular cascade. Eventually this leads to platelet aggregation.

• The IC cascade is triggered by
• 1. activation of GP-6 by collagen binding
• 2. activation of the thrombin receptor by thrombin (molecular response).
• The IC cascade is as follows: PIP2 makes DAG and IP3. IP3 releases intracellular Ca2+. The Ca2+ allows conversion of phospholipids to Thromboxane A2 via COX enzyme. Ca2+, DAG and Thromb A2 all 3 trigger the final stages of platelet activation and aggregation.

Anticoagulant. Aspirin is a COX inhibitor so it prevents platelet activation and blood coagulation.

Vitamin K is a cofactor for the enzyme carboxylase. Carboxylase typically coverts glu residue to a gla residue. Gla is a stonger Ca2+ chelator and aids in bringing proteins (factors IX, VII, X, PC, and PS) to the platelet surface. Ca2+ acts a bridge between the Gla residue and the (-) charged head groups of platelet phospholipids.

Warfarin is an orally administered anti-coagulant. It prevents reactivation of Vitamin K. This in turn blocks carboxylase activity and activation of cascade clotting factors. The amount of warfarin must be carefully administered since the therapeutic range is small. To much warfarin can cause hemorraging.

Anticoagulant. Blocks ADP receptor and prevents platelet activation.

Anticoagulant. Blocks GP-2B/3A and prevents platelet aggregation.

Anticoagulant derived from leeches. Blocks thrombin.

• Arterial thrombosis is a result of artherosclerotic plaque, which if ruptures the endothelial cells of the vessel wall, will initial platelet formation (need platelet therapy).
• Venous thromboembolism is a blood clot in the upper leg due to vascular defect. This clot if released can travel to the pulmonary artery and cause a problem there.

stop coagulation with a Ca2+ chelator.

Tests all factors except factor VII. Initiate coag. with Ca2+ and (-) surface.

Tests everything in extrinsic and common pathway. Intiate coag. with ca2+ and tissue factor.

Tests specifically for fibrinogen (factor II). Initiate coag. with Ca2+ and thrombin.

• It transfers a FUC group from GDP-Fuc to precursor type 2 to produce H-antigen.
• H locus FUT-1 encodes H antigen on RBCs (very rare to be h/h except in Indian population).
• Se locus on FUT-2 encodes H antigen on body secretions (20% se/se; can still have antigen on RBC)

• A antigen: A transferase ---> GalNAc
• B antigen: B transferase ---> Gal

Phenotype h/h se/se; Will produce anti-H, anti-A, and anti-B antibodies

mostly IgM; do not cross the placental membrane

IgG mostly; These proteins can cross the placental membrane and under certain conditions, can attack the fetal erythrocytes.