Hemostasis

Question 1

What is Hemostasis?

Answer 1

• The arrest of bleeding
  
  • Hemo = blood
  • Stasis = Halt, slow
• A normal physiological response to localized vascular injury
• It is a complex process
• A balanced interaction between:
  
  • Blood vessels
  • Platelets
  • Coagulation factors
  • Tibrinolytic and thrombolytic factors

Question 2

What is the goal of hemostasis?

Answer 2

Rapid return to norml blood flow and fluidity following vascular injury

Question 3

What is the norml functino of blood vessels?

Answer 3

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

Question 4

What role does normal endothelium play in homeostasis?

Answer 4

• Normal endothelium generally induces vascular relaxation and anti-clotting properties
  
  • Nitric oxide
  • Prostacyclin
  • Alpha-2-macroglobulin
  • Thrombomodulin
  • Protein S

Question 5

What are the Anti-clotting characteritics and what do they do?

Answer 5

• Prostacyclin
  
  • Enhanves vascular relaxation nd inhibis platelet adhesion and activation
• Nitric oxide
  
  • Maintains vascular relaxation and inhibits platelet activation
  • Participates with Protein C and antithrombin to suppress thrombin production
• Thrombomodulin
  
  • Binds thrombin to intitiate Protein C activation
• Protein S
  
  • ​Cofactor in Protein C pathoway and independently inhibits activation of Factors VIII and X

Question 6

What role does Damaged endothelium play in hemostasis

Answer 6

• Damaged endothelium has predominately pro-clotting properties
  
  • Release of Tissue Factor from activted endothelium and subendothelial tissues
  • Exposure of underlying collagen and other subendothelil conponents provide sites for platelet adhesion

Question 7

What are the Pro–clotting characteristics and their function?

Answer 7

• Tissue Factor:
  
  • Released following endothelial injury, possibly by activated endothelium
• Von willebrand Factor:
  
  • Forms bridges for platelet adhesion and aggresion
• Plasminogen Activator Inhibitor-1:
  
  • Inhibits fibrinolysis

Question 8

What is the normal function of platelets

Answer 8

• Platelets
  
  • membrane-bound cytoplasmic fragments derived from megakaryocytes in the bone marrow
    
    • Trhombopoietin is the main regulator of production
    • Colony stimulating factors: IL-3, IL-6, IL-11 also participate

Question 9

What is the platelets role in Primary Hemostasis?

Answer 9

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

Question 10

What is Primary Hemostasis?

Answer 10

• The 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 11

What vascular changes occur during Primary Hemostais?

Answer 11

• Contraction of mucsle layers of the blood vessle cause transient vasoconstriction
  
  • Neurogenic stimuli
  • Endotherlial and platelt products
• Endothelial activation
  
  • Pro-coagulation to limit bleeding
  • Anti-coagulation to limit clotting

Question 12

What happens with platelets during primary hemostasis?

Answer 12

• Sequential activities in primary hemostasis
  
  1. Adhesion
  2. Aggregation​​
  3. Secretion
  4. Contraction

Question 13

What happens during Adhesion of Platelets in Primary Hemostasis?

Answer 13

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

Question 14

What happens to platelets during Aggregation in Primary Hemostasis

Answer 14

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

Question 15

What happens to platelets during secretion in primary hemostasis?

Answer 15

• Conformational change indued by adhesion/aggregtion results in granule release:
  
  • Platelet granules contain numerous preformed substances
• Adhesions stimulates production of platelet membrane-associated substances involved in clotting
  
  • Thromboxane
  • Platelet Factor 3 (anionic membrane phospholipids including phosphatidylserine)

Question 16

What is the content of a Platelet a-granule ?

Answer 16

• Factor V
• Fibrinogen
• Thormbospondin
• Fibronectin
• Transforming growth factor-beta (TGF-beta)
• Epidermal growth factor
• Albuminn
• B-Thromboglobulin
• Platelet Factor 4
• Platelet-derived growth factor (PDGF)
• Endothelial cell growth factor (ECGF)

Question 17

What is the content of a Platelet Dense granule?

Answer 17

• ATP
• GTP
• Calcium
• Serotonin
• ADP
• GDP
• Magnesium
• 5’ hydroxytryptamine

Question 18

What happens to platelets during contraction in Primary Hemostasis?

Answer 18

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

Question 19

What is Coagulation?

Answer 19

• A highly regulated cascde of reactions that form a variety of products involved in hemostasis
• Participants include:
  
  • Enxymatic coagulation factors
  • Non-enzymtic co-factors
• Described by severl different models:
  
  • Classical Coagulation pathways
  • Integrated model of coagulation

Question 20

What are the Enzymatic Coagulation Factors?

Answer 20

• Proenzymes
  
  • Plasma proteins that circulate in inactive forms
    
    • Produced mainly in hepatocytes
  • Upon activation, they gin teh suffix “a”
    
    • Exception: Prekallikrein → Kallikrein
  • Include Factors II, VII, IX, X, XI, XII, XIII, Prekallikrein

Question 21

What are teh Non-enzymatic Coagulation Factors?

Answer 21

• Cofactors
  
  • Non-enzymatic participants that are necessary for enxymatic coagulation reations
• Cofacotrs include Factors I, III, V, VIII, High Molecular Weight Kininogen, Ca⁺², and phospholipids
  
  • Ionized free calcium is required

Question 22

What are the Classical Coagulation pathways?

Answer 22

• Extrinsic pathway
• Intrinsic pathway
• Common pathway

Question 23

What is the Coagulation Intrinsic Pathway?

Answer 23

• Activation of Factor XII (Hageman Factor) is the key stp
  
  • Factor XIIa initiates the cascade leading to activation of Factor X
  • Factor XII initiates some important non-coagulant pathways
• Contact factors (Factor XII, HMWK, and PK) initiate te pathway by binding negatively charged surfaces, like collagen
  
  • HMWK circulates in association with PK and Factor XI
    
    • Binding of HMWK brings reactants into close association on the activating surface
    • XIIa facilitates binding of HMWK to the activating surface
• Probbly initiated secondary to extrinsic and common pathway activation
  
  • Propagates and amplifies thrombin formation initiated by the extrinsic pathway
• Likely plays secondary role in vivo
  
  • individuals with deficiencies of Factor XII, HMWK, and PK don’t have bleeding tendencies

Question 24

What is the Coagulation Extrinsic Pathway?

Answer 24

• Activated by the release of Tissue Factor (TF, Factor III) by damaged endothelial surfaces
  
  • “Tissue Factor Pathway”
• Factor III reacts with Factor VII to cause the activation of Factor X

Question 25

What is the Coagulation Common Pathway?

Answer 25

* This pathway is initiated by activated Factor X * Factor Xa can be generated by both intrinsic and extrinsic pathways * Major step in the pathway is the conversion of protrhombin (Factr II) to thrombin (Factor IIa) * Prothrobin (Factor II) is converted by the prothombinase complex * Complex consists of Factors Xa and Va, and cacium on a phospholipid surface * Fibrin monomers cleaved by trhombin from fibrinogen self-polymerize * Factor XIII helps to cross-link and stabilize the fibrin polymers

Question 26

What is the Integrated Model of Coagulation?

Answer 26

* Many points of interaction between each of the classical pathways * A web-like integrated model may more appropriately demonstrate the integration and amplifcation that occur *in vivo* * Key Points: * TF-VIIa activates X (common) and IX (intrinsic) * Thrombin-initiated activation of Factors V, VIII, and XI amplifies intrinsic and common pathways * Activation of extrinsic Factor VII by Factors XIIa and IXa and kallikrein

Question 27

How is Hemostasis regulated?

Answer 27

* 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 hemostasis include: * Depletion of activted coagulation factors * Clearance of activaed coagulation factors * most are complexed by inhibitors and then cleared from teh circulation by hepatocytes orteh mononuclear/phagocyte system * Inactivation of activated coagulation factors or products

Question 28

What are the Coagulation inactivators/inhibitors?

Answer 28

* Antithrombin (Antithrombin III) * Protein S: Protein C: Thrombomodulin * Tissue Factor Pathway Inhibitor

Question 29

What is Antithrombin?

Answer 29

* The MAJOR circulating anti-coagulant * Antithrombin degrades all activated cogulation factors except fr Factor VIIa * It accounts for about 80% of the thrombin-activity of plasma

Question 30

What is Protein C?

Answer 30

* A Vitamin K-dependent anti-coagulant and pro-fibrinolytic agent * Protein C is actvated by thrombin * Activated Protein C complexes with Protein S on phospholipid surfaces and inactivates factors Va and VIIa

Question 31

What is Fibrinolysis?

Answer 31

* Dissolution of clots is important to maintain flow and fluidity of blood through the damaged area * It is ctivated simultaneously with coagulation * Plasmin is the major mediator of fibrinolysis * Must be well balanced and timed: * Too fast/excessive - clot may degrade before vascular repair occurs * Too slow/minimal - clot persistened may lead to permanent vessel alteration and reduce blood flow

Question 32

What are Fibrin Degradation Products?

Answer 32

* Produce an anti-thrombotic, pro-hemorrhagic state * Major fragments include X, D, Y, and E * They impair platelet function * They compete with fibrinogen for binding sites on thrombin and platelets * They interfere with fibrin polymerization * They increase during coagulation, DIC, inflammation, hemorrhage, or drecreased clearance dur to lier or kidney disease

Question 33

What are the Fibrinolytic inactivators/inhibitors?

Answer 33

* Plaminogen activator inhibitor - 1 * Antiplamins * C1 inhibitor

Question 34

What does plaminogen activator inhibitor -1 do

Answer 34

* inhibits tissue plaminogen activator and urokinaseto prevent conversion of plaminogen to plasmin

Question 35

What do antiplamins do?

Answer 35

* Function cooperatively to prevent excessive plamin activity * a - 2 - antiplamin is the first to bind and neutralize plamsin * rapid inhibition of circulating plamin so fibrinolysis remains localized * a - 2- macrolobulin binds excess plasmin after a-2-antiplasmin becoes saturated * a-1-antitrypsin binds plasmin after a-2-macroglobulin becomes saturated

Question 36

What is C1 inhibitor

Answer 36

* Modulated the complement, coagulatin, kinin, and fibrinolytic pathways * Inhibits: * Activation of C1 * Cleavage of C2 and C4 * Coagulation factors XIIa and XIa * Activation of plaminogen * Activation of kallikrein

Question 37

What is the endpoint of hemostasis?

Answer 37

* When the damaged vessel is repared and the platelet/fibrin clot contracts and is lysed