Hemostasis Flashcards
1
Q
Hemostasis
A
- The arrest of bleeding
- hemo - blood
- Stasis - Halt, slow
- A normal physiological response to lecalized vascular injury
2
Q
Hemostasis:
Interactions
A
- Blood Vessels
- Platelets
- Coagulation factors
- Fibrinolytic and Thrombolytic factors
- The goal is a rapid return to normal blood flow and fluidity following vascular injury
3
Q
Blood Vessels:
Normal Function
A
- 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
- multifunctional and complex:
4
Q
Endothelium in Hemostasis:
A
- Generally induces vascular relaxation and anti-clotting
- nitric acid
- Prostacyclin
- Alpha-2-macroglobulin
- Thrombomodulin
- Protein S
5
Q
Endothelial Mediators:
Anti-clotting Characteristics:
Prostacyclin
A
Enhances vascular relaxation and inhibits platelet adhesion and activation
6
Q
Endothelial Mediators:
Anti-clotting characteristics
Nitric Oxide
A
- Maintains vascular relaxation and inhibits platelet activation
- Participates with protein C and antithrombin to suppress thrombin production
7
Q
Endothelial Mediators:
Anti-clotting characteristics
Thrombomodulin
A
Binds to thrombin to initiate protein C activation
8
Q
Endothelial Mediators:
Anti-clotting Characteristics
Protein S
A
- Cofactor in Protein C pathway and independently inhibits activation of Factors Viii and X
9
Q
Endothelium in Hemostasis:
Damage
A
- 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
10
Q
Endothelial Mediators:
Pro-clotting characteristics
A
- 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
11
Q
Platelets:
Normal Function
A
- 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
- Thrombopoietin is the main regulator of production
12
Q
Primary Hemostasis:
Platelets
A
- Platelets are the principle mediators of primary hemostasis
- Platelets bind to damaged endothelium or subendothelium to form a primary hemostatic platelet blood loss
13
Q
Primary Hemostasis
A
- 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
14
Q
Primary Hemostasis:
Vascular changes
A
- 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
15
Q
Platelets in Primary Hemostasis
A
- Sequential activities in primary hemostasis:
- Adhesion
- Aggregation
- Secretion
- Contraction
16
Q
Platelets in Primary Hemostasis:
Adhesion
A
- 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
17
Q
Platelets in Primary Hemostasis:
Aggregation
A
- 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
18
Q
Platelets in Primary Hemostasis:
Secretion
A
- 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
19
Q
Platelet a-granule content
A
See attached photo
20
Q
Platelets in Primary Hemostasis:
Secretion
A
- Adhesion also stimulates production of platelet membrane-associated substances involved in clotting
- thromboxane
- Platelet Factor 3
21
Q
Platelets in Primary Hemostasis::
Contraction
A
- 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
22
Q
Coagulation
A
- A highly regulated cascade of reactions that form a variety of products involved in hemostasis
- Participants include
- Enzymatic coagulation factors
- Non-enzymatic co-factors
23
Q
Enzymatic Coagulation Factors:
A
- 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
- plasma proteins that circulate in inactive forms
24
Q
Non-enzymatic Coagulation Factors
A
- 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
25
Q
Hemostasis:
Coagulation
A
- Coagulation has been described by several different models
- classical coagulation pathways
- extrinsic pathway
- intrinsic pathway
- Common pathway
- Integrated model of coagulation
- classical coagulation pathways
26
Q
Hemostasis:
Intrinsic Pathway
A
- 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
27
Q
Intrinsic Pathway
A
- 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
- HMWK circulates in association with PK and Factor 11
- 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
28
Q
Hemostasis:
Extrinsic Pathway
A
- 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
29
Q
Hemostasis:
Common Pathway
A
- 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
30
Q
Common Pathway
A
- Fibrin monomers cleaved by thrombin from fibrinogen self-polymerize
- Factor 13 helps to cross-link and stabilize the fibrin polymers
31
Q
Hemostasis:
Integrated Model
A
- 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
32
Q
Hemostasis:
Regulation
A
- 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
33
Q
Antithormbin
A
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
34
Q
Inactivators:
Protein C
A
- 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
35
Q
Hemostasis:
Fibrinolysis
A
- 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
36
Q
Fibrinolysis:
FDPs
A
- 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
37
Q
Hemostasis:
Regulation
A
Fibrinolytic inactivators/inhibitors include
Plasminogen activator inhibitor-1
Antiplasmins
C1 inhibitor
38
Q
Fibrinolytic Inactivators
A
- Plasminogen activator Inhibitor-1
- inhibits Tissue Plasminogen activator and urokinase to prevent conversion of plasminogen to plasmin
39
Q
Antiplasmins
A
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
40
Q
C1 Inhibitor
A
- 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
- C1 Inhibitor inhibits:
41
Q
Hemostasis:
Regulation
A
the endpoint of hemostasis is when the damaged vessel is repaired and the platelet/fibrin clot contracts ans is lysed
