Normal Hemostasis: Objectives

1. Describe the roles of the normal hemostatic processes.

a. Vasoconstriction  Activation of the soluble coagulation system  fibrin clot (red thrombus)  Platelet stimulation  adhesion (usually to collagen) aggregation (of platelets)  Platelet plug (white thrombus)

2. Describe the two systems contributing to normal hemostasis.

a. The Soluble System (procoagulant proteins)

a.i. Proteins include:

a.i.1. Fibrinogen

a.i.2. Von Willebrand Factor (sticky glue for platelets)

b. The Cellular System (platelets)

b.i. Platelets

b.i.1. Suppliers of procoagulant proteins

b.i.2. Catalysts to reactions of the soluble coagulation system (stim. clotting)

b.i.3. Hemostasis, inflammatory response, tissue repair, and atherogenesis

3. Describe the normal production, structure, and function of platelets.

a. Production of platelets:

a.i. Pluripotent stem cell in bone marrow produces megokaryocyte

a.ii. Fragments off of the megokaryocyte’s cytoplasm

a.iii. Normal platelet count: 100,000-450,000/uL of blood

a.iv. Thrombopoietin: regulates megokaryocyte development and platelet prod.

a.iv.1. Primarily produced in the liver (a fraction is in the kidney)

b. Structure of platelets:

b.i. Contractile microfilaments extend thru submembranous space throughout the platelet cytoplasm

b.i.1. Responsible for dramatic shape changes which accompany platelet activation Normal Hemostasis: Objectives

b.ii. 4 types of granules:

b.ii.1. Alpha, dense, lysosomes, and peroxisomes

b.ii.2. Alpha-granules:

b.ii.2.a. Most abundant

b.ii.2.b. Contain both platelet specific and nonspecific peptides

b.ii.2.b.i. Contribute to and modulate coagulation inflammation, immunity, and tissue repair

b.ii.3. Dense-granules:

b.ii.3.a. Rich repositories of:

b.ii.3.a.i. Serotonin and ADP

b.ii.3.a.i.1. Leads to aggregation of platelets

b.ii.3.a.ii. ATP

b.ii.3.a.ii.1. Leads to anti-aggregation

b.ii.3.a.iii. Calcium

b.ii.3.a.iii.1. An essential coagulation factor

c. Function of platelets:

c.i. Hemostasis (promotion of immediate hemostasis)

c.i.1. By platelet adhesion and platelet aggregation (forms platelet plug)

c.ii. Inflammation response

c.iii. Tissue Repair

c.iii.1. Local release of vasocaonstrictors to decrease blood flow to injured area

c.iii.2. Catalysis of reaction of the soluble coagulation cascade leading to fibrin clot formation

c.iv. Atherogenesis

4. Describe the initial steps to evaluate the integrity of platelet structure and function. Normal Hemostasis: Objectives

a. Platelet count: part of the CBC (100,000-450,000 platelets/uL blood)

b. MPV (Platelet volume measurement)

b.i. Platelet volume increases when production accelerates

c. Platelet Function: whole blood platelet function or bleeding time

c.i. Assess coagulation effectiveness

d. Platelet aggregometry (expensive)

5. Explain the role of the vascular endothelium in normal hemostasis.

a. A vascular break or injury causes a hemostatic plug to form (platelet-fibrin meshwork)

6. Describe the intrinsic, extrinsic, and common pathways of coagulation being aware of which coagulation factors are a part of each pathway.

a. Intrinsic Pathway:

a.i. Components:

a.i.1. F XII (12)

a.i.1.a. Notices negatively charged surfaces, esp Collagen

a.i.1.a.i. Begins intrinsic cascade

a.i.2. F XI (11)

a.i.2.a. Activated by small amount of F XII

a.i.3. F IX (9)

a.i.4. F VIII (8) – low = hemophilia

a.i.5. PK (PreKallikrein) – inflammation

a.i.5.a. Leads to kaliikrein activation, which leads to HK activation

a.i.6. HK (high molecular weight Kininogen) – inflammation

a.i.6.a. Then: activation of blood coagulation, fibrinolysis, completment pathway, inflammation Normal Hemostasis: Objectives

b. Extrinsic Pathway:

b.i. The major pathway of activation of coagulation in vivo

b.ii. Components:

b.ii.1. Tissue Factor (TF, F III) factor 3

b.ii.1.a. Functions as a cofactor/receptor which (in presence of Ca) activates Factor VII

b.ii.2. Tissue factor inhibitor

b.ii.3. Plasma Factor VII (7)

b.ii.3.a. Requires vitamin K for synthesis

b.ii.4. Activated VII leads to Factor IX and (or straight to) Factor X activation

b.iii. Tissue Plasminogen Activator (t-PA)

b.iii.1. Inhibits clot formation by its release from endothelial cells

c. Common Pathway:

c.i. Prothrombin Complex (F X, F V in the presence of Ca)

c.i.1. Leads to Prothrombin FII  Thrombin (FII)

c.ii. Thrombin leads to: Fibrinogen  Fibrin

c.ii.1. Fibrin monomer (activated from fibrinogen  fibrin)

c.ii.1.a. Factor XIII (13) leads to fibrin polymers

c.ii.1.a.i. Fibrin polymers anchor the filaments

7. Understand and be able to describe the role of the Vitamin K in hemostasis.

a. Vit K is necessary for post-ribosomal CARBOXYLATION of the terminal glutamic acid residues of all Vit K dependent proteins

b. Vitamin K-Dependent Coagulation Proteins: (1972)

b.i. F X

b.ii. F IX

b.iii. F VII Normal Hemostasis: Objectives

b.iv. F II

c. Vitamin K-Dependent Anti-coagulation proteins:

c.i. Protein C and Protein S

c.i.1. Inactivate cofactors V and VIII

c.i.2. Prevent Clotting

8. Innumerate and describe the major mechanisms which regulate the hemostatic process including:

a. Antithrombin III: Do not affect factors V and VIII

a.i. Quick anti-clotting abilities to slow down all the clotting pathways

b. Protein C: Inactivates cofactors V and VIII to prevent clotting

c. Protein S: Inactivates cofactors V and VIII to prevent clotting

d. Plasminogen-Plasmin System: breaks down and inhibits fibrin polymerization

d.i. Products of split fibrin are anticoagulants

d.ii. Example is: t-PA