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General Pathology VDMP832 > Hemostasis > Flashcards

Hemostasis Flashcards

1
Q

Hemostasis

A
  • The arrest of bleeding
    • hemo - blood
    • Stasis - Halt, slow
  • A normal physiological response to lecalized vascular injury
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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
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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
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4
Q

Endothelium in Hemostasis:

A
  • Generally induces vascular relaxation and anti-clotting
    • nitric acid
    • Prostacyclin
    • Alpha-2-macroglobulin
    • Thrombomodulin
    • Protein S
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5
Q

Endothelial Mediators:

Anti-clotting Characteristics:

Prostacyclin

A

Enhances vascular relaxation and inhibits platelet adhesion and activation

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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
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7
Q

Endothelial Mediators:

Anti-clotting characteristics

Thrombomodulin

A

Binds to thrombin to initiate protein C activation

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8
Q

Endothelial Mediators:

Anti-clotting Characteristics

Protein S

A
  • Cofactor in Protein C pathway and independently inhibits activation of Factors Viii and X
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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
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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
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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
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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
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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
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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
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15
Q

Platelets in Primary Hemostasis

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

General Pathology VDMP832 (26 decks)

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