Hemostasis

Question 1

Hemostasis

Answer 1

• The arrest of bleeding
  
  • hemo - blood
  • Stasis - Halt, slow
• A normal physiological response to lecalized vascular injury

Question 2

Hemostasis:

Interactions

Answer 2

• Blood Vessels
• Platelets
• Coagulation factors
• Fibrinolytic and Thrombolytic factors
• The goal is a rapid return to normal blood flow and fluidity following vascular injury

Question 3

Blood Vessels:

Normal Function

Answer 3

• Provide unimpeded movement of blood to areas of need
  
  • neuro-chemical regulation of flow
• Endothelium is a critical blood vessel component influencing vascular homeostasis
  
  • multifunctional and complex:
    
    • Forms of vascular lining
    • Secretes mediators

Question 4

Endothelium in Hemostasis:

Answer 4

• Generally induces vascular relaxation and anti-clotting
  
  • nitric acid
  • Prostacyclin
  • Alpha-2-macroglobulin
  • Thrombomodulin
  • Protein S

Question 5

Endothelial Mediators:

Anti-clotting Characteristics:

Prostacyclin

Answer 5

Enhances vascular relaxation and inhibits platelet adhesion and activation

Question 6

Endothelial Mediators:

Anti-clotting characteristics

Nitric Oxide

Answer 6

• Maintains vascular relaxation and inhibits platelet activation
• Participates with protein C and antithrombin to suppress thrombin production

Question 7

Endothelial Mediators:

Anti-clotting characteristics

Thrombomodulin

Answer 7

Binds to thrombin to initiate protein C activation

Question 8

Endothelial Mediators:

Anti-clotting Characteristics

Protein S

Answer 8

• Cofactor in Protein C pathway and independently inhibits activation of Factors Viii and X

Question 9

Endothelium in Hemostasis:

Damage

Answer 9

• Damaged endothelium has predominately pro-clotting properties
  
  • release of Tissue Factor from activated endothelium and subendothelial tissues
  • Exposure of underlying collagen and other subendothelial components provide sites for platelet adhesion

Question 10

Endothelial Mediators:

Pro-clotting characteristics

Answer 10

• Tissue Factor:
  
  • Released following endothelial injury, possibly by activated endothelium
• Von Willebrand Factor
  
  • Forms bridges for platelet adhesion and aggregation
• Plasminogen activator inhibitor - 1
  
  • inhibits fribrinolysis

Question 11

Platelets:

Normal Function

Answer 11

• Platelets are membrane-bound cytoplasmic fragments derived from megakeryocytes in the bone marrow
  
  • Thrombopoietin is the main regulator of production
    
    • colony stimulating factors, IL-3, IL-6, IL-11, also participates

Question 12

Primary Hemostasis:

Platelets

Answer 12

• Platelets are the principle mediators of primary hemostasis
• Platelets bind to damaged endothelium or subendothelium to form a primary hemostatic platelet blood loss

Question 13

Primary Hemostasis

Answer 13

• Primary vascular and platelet response to vascular injury
  
  • vascular contraction
  • Endothelial Activation
    
    • pro- and anti-clotting activity
  • Platelet plug formation
• Most effective for minor vascular injury

Question 14

Primary Hemostasis:

Vascular changes

Answer 14

• Contraction of muscle layers of the blood vessel cause transient vasoconstriction
  
  • neurogenic stimuli
  • Endothelial and platelet products
• Endothelial Activation
  
  • Pro-coagulation to limit bleeding
  • Anti-coagulation to limit clotting

Question 15

Platelets in Primary Hemostasis

Answer 15

• Sequential activities in primary hemostasis:
  
  • Adhesion
  • Aggregation
  • Secretion
  • Contraction

Question 16

Platelets in Primary Hemostasis:

Adhesion

Answer 16

• Platelets adhere to subendothelial substances at sites of vascular injury
• Coating of subendothelial collagen by von Willebrand factor accelerates adhesion by a receptor-mediated process
  
  • Platelet GPIb binds to vWF on the damaged surface

Question 17

Platelets in Primary Hemostasis:

Aggregation

Answer 17

• Platelets stick to each other to build up an adequate platelet mass for primary hemostasis
• Conformational change induces expression of GPIIb-IIIa
  
  • Fibrinogen forms bridges between platelets

Question 18

Platelets in Primary Hemostasis:

Secretion

Answer 18

• Conformational change induced by adhesion/aggregation results in granule release:
  
  • platelet granules contain numerous preformed substances
• Adhesion also stimulates production of platelet membrane-associated substances involved in clotting
  
  • thromboxane
  • Platelet factor 3

Question 19

Platelet a-granule content

Answer 19

See attached photo

Question 20

Platelets in Primary Hemostasis:

Secretion

Answer 20

• Adhesion also stimulates production of platelet membrane-associated substances involved in clotting
  
  • thromboxane
  • Platelet Factor 3

Question 21

Platelets in Primary Hemostasis::

Contraction

Answer 21

• Contraciton minimizes the size of the primary hemostatic plug
  
  • platelet actin and myosin and interplatelet fibrinogen bridges are the major mediators
• This occurs during the resolution stages of primary hemostasis
  
  • lysis of fibrin formed by secondary hemostasis will occur concurrenlty
  • Contraction and fibrinolysis minimize the size of the platelet/fibrin plug and initiates vascular repair

Question 22

Coagulation

Answer 22

• A highly regulated cascade of reactions that form a variety of products involved in hemostasis
• Participants include
  
  • Enzymatic coagulation factors
  • Non-enzymatic co-factors

Question 23

Enzymatic Coagulation Factors:

Answer 23

• Proenzymes
  
  • plasma proteins that circulate in inactive forms
    
    • produced mainly in hepatocytes
  • Upon activation, they gain the suffix”a”
    
    • prekallikrein is an exception, the activated form is called kallikrein
  • These include Factors 2, 7, 9, 10, 11, 12, 13 and prekallikrein

Question 24

Non-enzymatic Coagulation Factors

Answer 24

• Cofactors
  
  • non-enzymatic participants that are necessary for enzymatic coagulation reactions
• Cofactors include Factors 1, 3, 5, 8, High molecular weight kininogen, Ca2+, and phospholipids
  
  • ionized free calcium is required

Question 25

Hemostasis: Coagulation

Answer 25

* Coagulation has been described by several different models * classical coagulation pathways * extrinsic pathway * intrinsic pathway * Common pathway * Integrated model of coagulation

Question 26

Hemostasis: Intrinsic Pathway

Answer 26

* Activation of Factor 12 (Hageman factor) * Factor 12a initiates the cascade leading to activation of factor 10 * Factor 12a also initiates some important non-coagulant pathways

Question 27

Intrinsic Pathway

Answer 27

* Contact factors initiate the pathway by binding negatively charged surfaces, like collagen * HMWK circulates in association with PK and Factor 11 * binding of HMWK brings reactants into close association on the activating surface. * 12a facilitates binding of HMWK to the activating surface * Intrinsic coagulation is probably initiated secondary to extrinsic and common pathway activation * it propafates and amplifies thrombin formation initiated by the extrinsic pathway * Intrinsic coagulation likely plays a secondary role in vivo * individuals with deficiencies of Factor 12, HMWK, and PK don't have bleeding tendencies

Question 28

Hemostasis: Extrinsic Pathway

Answer 28

* This pathway is activated by the release of Tissue Factor 3 by damaged endothelial surfaces * also referred to as the Tissue Factor Pathway * Factor 3 reacts with Factor 7 to cause the activation of Factor 10

Question 29

Hemostasis: Common Pathway

Answer 29

* This pathway is initiated by activated Factor 10 * factor 10a can be generated by both intrinsic and extrinsic pathways * A major step in the pathway is the conversion of prothrombin (Factor 2) itno thrombin (2a) * Prothrombin is converted to thrombin by the prothrombinase complex * this complex consists of Factors 10a and 5a, and calcium of hte phospholipid surface

Question 30

Common Pathway

Answer 30

* Fibrin monomers cleaved by thrombin from fibrinogen self-polymerize * Factor 13 helps to cross-link and stabilize the fibrin polymers

Question 31

Hemostasis: Integrated Model

Answer 31

* There are many points of interaction between each of these classical pathways * A web-like integrated model may more appropriately demonstrate the integration and amplification that occur in vivo * Key points of integration * TF-7a activates 1p, and 9 * Thrombin-initiated activation of Factors 5, 8, and 11 amplifies intrinsic and common pathways * Activation of extrinsic Factor 7 by Factors 12a and 9a and kallikrein

Question 32

Hemostasis: Regulation

Answer 32

* Hemostasis is a fine balance between pro and anti clotting mechanisms * Major function of regulatory pathways is to confine hemostasis to only those locations it is needed * Factors that regulate: * depletion of activated coagulation factors * Clearance of activated coagulation factors * Inactivation of activated coagulation factors or products * Coagulation Inactivators/inhibitors * antithrombin * Protein S; Protein C; Thrombomodulin * Tissue Factor Pathway inhibitor

Question 33

Antithormbin

Answer 33

The major circulating anti-coagulant degrades all activated coagulation facotrs except for factor 12a accounts for about 80% of the thrombin inactivating activity of plasma

Question 34

Inactivators: Protein C

Answer 34

* Is a Vitamin K-dependent anti-coagulant and pro-fibrinolytic agent * Activated by thrombin * Activated complexes with protein S on phospholipid surfaces and inactivates factor 5a and 12a

Question 35

Hemostasis: Fibrinolysis

Answer 35

* Dissolution of clots is important to maintain flow and fluidity of blood through the damaged area * activated simultaneously with coagulation * Plasmin is the major mediator of fibrinolysis * Must be well balanced and timed * If excessive or too rapid, the clot may degrade before vascular repair occurs * If minimal or too slow, clot persistence may lead to permanent vessel alteration and reduced blood flow

Question 36

Fibrinolysis: FDPs

Answer 36

* Fibrin degradation products produce an anti-thrombotic, pro-hemorrhagic state * major fragments include X, D, Y, and E * impair platelet function * They compete with firbrinogen for binding sites of thrombin and platelets * Interfere with fibrin polymerization * The increase during coagulation, DIC, inflammation, hemorrhage, or decreased clearance due to liver or kidney disease

Question 37

Hemostasis: Regulation

Answer 37

Fibrinolytic inactivators/inhibitors include Plasminogen activator inhibitor-1 Antiplasmins C1 inhibitor

Question 38

Fibrinolytic Inactivators

Answer 38

* Plasminogen activator Inhibitor-1 * inhibits Tissue Plasminogen activator and urokinase to prevent conversion of plasminogen to plasmin

Question 39

Antiplasmins

Answer 39

These Function cooperatively to prevent excessive plasmin activity * a-2 antiplasmin is the first to bind and neutralize plasmin * there is a rapid inhibition of ciruclating plasmin so fibrinolysis remains localized * a-2 macroglobulin binds excess plasmin after a-2-antiplasmin becomes saturated * a-1 antitrypsin binds plasmin after a-2-macroglobulin becomes saturated

Question 40

C1 Inhibitor

Answer 40

* C1 inhibitor modulates the complement coagulation, kinin, and fibrinolytic pathways * C1 Inhibitor inhibits: * Activation of C1 * Cleavage of C2 and C4 * Coagulation facotrs 12a and 11a * Activation of plasminogen * Activation of kallikrein

Question 41

Hemostasis: Regulation

Answer 41

the endpoint of hemostasis is when the damaged vessel is repaired and the platelet/fibrin clot contracts ans is lysed