Introduction to Hemostasis

Explain the Primary Hemostatis

SEE NOTES

Primary hemostasis starts when platelets come in contact with exposed ___, ___, and ____ of endothelial tissue.

collagen, microfilaments, and the basement membrane

In Primary Hemostasis

• _____ constrict, allowing platelets to adhere to exposed tissue,

  which causes ______ release (promotes _____, acts as an energy source) and synthesis of _____ from ____ acid (promotes activation, release, and aggregation).

• Platelets begin to ____, which causes the release of additional ADP, ATP, and serotonin (substance that promotes______).

• ______ are exposed, which allows binding of _____ from secondary hemostasis (e.g., fibrinogen binds at the glycoprotein Ilb/IIIa receptor).

• Small blood vessels constrict, allowing platelets to adhere to exposed tissue, which causes ADP/ATP release (promotes platelet aggregation, acts as an energy source) and synthesis of thromboxane A2 from arachidonic acid

  (promotes activation, release, and aggregation).

• Platelets begin to aggregrate, which causes the release of additional ADP, ATP, and serotonin (substance that promotes vasoconstriction).

• Platelet receptor sites are exposed, which allows binding of coagulation proteins from secondary hemostasis (e.g., fibrinogen binds at the glycoprotein Ilb/IIIa receptor).

Secondary Hemostasis:

• The goal is generation of sufficient_____ to convert fibrinogen to ___.

• Secondary hemostasis involves activation of intrinsic, extrinsic, and common coagulation pathway factors.

• The goal is generation of sufficient thrombin to convert fibrinogen to fibrin clot.

• Secondary hemostasis involves activation of intrinsic, extrinsic, and common coagulation pathway factors.

Secondary Hemostasis:

• Fibrin clot includes the____ formed in ____ and ____ formed in ____.

• Intrinsic pathway is activated when _____ are exposed to ____.

• The intrinsic pathway includes factors____

• Fibrin clot includes the platelet plug formed in primary hemostasis and fibrin formed in secondary hemostasis.

• Intrinsic pathway is activated when coagulation proteins are exposed to subendothelial collagen.

• The intrinsic pathway includes factors XII (Hageman), XI (plasma thromboplastin antecedent), prekallikrein (Fletcher), HMWK (Fitzgerald), IX (plasma thromboplastin component/Christmas factor), and VIII (antihemophiliac).

Secondary Hemostasis:

• Extrinsic pathway (dominant in ___ pathway) starts with the release of ___ from injured _____ and subendothelium.

• Tissue factor is found in most ___, ____, and ____.

• Factor_____ is in this pathway.

• Extrinsic pathway (dominant in vivo pathway) starts with the release of tissue factor from injured blood vessel endothelial cells and subendothelium.

• Tissue factor is found in most tissues, organs, and large blood vessels.

• Factor VII (stable factor) is in this pathway.

Secondary Hemostasis:

• Common pathway begins with _____ by either the extrinsic

  (main in vivo) or intrinsic pathway.

• It includes factors ______

• Common pathway begins with factor X activation by either the extrinsic (main in vivo) or intrinsic pathway.

• It includes factors X (Stuart-Prower), V (proaccelerin/labile factor), II (prothrombin), and I (fibrinogen).

link the extrinsic, intrinsic, and common pathways.

Alternative pathways

• Coagulation factors are also known as _____.

• They are found in the____, along with nonenzymatic cofactors and calcium.

• _____ are substrates having no biologic activity until converted by enzymes to active forms called ____

• Coagulation factors are also known as enzyme precursors or zymogens.

• They are found in the plasma, along with nonenzymatic cofactors andcalcium.

• Zymogens are substrates having no biologic activity until converted by enzymes to active forms called serine proteases.

• The zymogens include___

• The serine proteases are ____

• The zymogens include II, VII, IX, X, XI, XII, and prekallikrein.

• The serine proteases are IIa, VIIa, IXa, Xa, XIa, Xlla, and kallikrein.

Coagulation Factors

• Cofactors assist in the activation of zymogens and include ____

• In its active form, factor XIII is a ____.

• ____ is the only substrate in the cascade that does not become an activated enzyme.

• Cofactors assist in the activation of zymogens and include V, VIII, tissuefactor, and high molecular weight kininogen (HMWK).

• In its active form, factor XIII is a transglutaminase.

• Fibrinogen is the only substrate in the cascade that does not become an activated enzyme.

Contact group

• Includes ____

• Produced in the ____

• Requires contact with a ____ for activation

• Includes prekallikrein, HMWK, and factors XI and XII

• Produced in the liver

• Requires contact with a foreign surface for activation

Prothrombin group

• Includes factors____

• Produced in the ___

• ____ is required for synthesis of functional factors, with ___ necessary for binding to phospholipid (PF3) surfaces.

• Includes factors II, VII, IX, and X

• Produced in the liver

• Vitamin K is required for synthesis of functional factors, with calcium binding sites necessary for binding to phospholipid (PF3) surfaces.

Fibrinogen group

• Includes factors ____

• Produced in the ____

• Consumed in the ____

• Includes factors I, V, VIII, and XIII

• Produced in the liver

• Consumed in the clotting process

• Factors ____ serve as substrates for the fibrinolytic enzyme plasmin.

• Factors I and V are found in ____

• Factors I, V, and VIII serve as substrates for the fibrinolytic enzyme plasmin.

• Factors I and V are found in platelets

Conversion of fibrinogen to fibrin is a three-step process.

1. ___ and ___ are cleaved by thrombin, forming ____.

2. ____ spontaneously polymerize, forming ___. This is the endpoint for clot-based tests.

3. ___ occurs, requiring thrombin activation of ___ and ___.

1. Fibrinogen alpha and beta fibrinopeptides are cleaved by thrombin, forming soluble fibrin monomers.

2. Fibrin monomers spontaneously polymerize, forming soluble fibrin polymers. This is the endpoint for clot-based tests.

3. Clot stabilization occurs, requiring thrombin activation of XIII and calcium.

VIII/vWF complex

• Factor VIII is synthesized in the liver and is composed of two fractions.

• VIII:C (_____ factor) is the coagulation portion that acts as a cofactor in the intrinsic coagulation pathway.

• ____ is the antigenic property of factor VIII.

• Both VIII:C and VIII:Ag are deficient in ____.

• Factor VIII is synthesized in the liver and is composed of two fractions.

• VIII:C (antihemophilic factor) is the coagulation portion that acts as a cofactor in the intrinsic coagulation pathway.

• VIII: Ag is the antigenic property of factor VIII.

• Both VIII:C and VIII:Ag are deficient in hemophilia A.

VIII/vWF complex

• von Willebrand factor (vWF) is synthesized by ___ and ___ and is composed of two fractions.

• ____ (ristocetin cofactor) is needed for ____ to collagen in vivo; it is needed for a normal response to ristocetin on aggregation studies in vitro.

• ____ is the antigenic property of vWF.

• Both vWF:RCo and vWF:Ag are deficient in ___

• von Willebrand factor (vWF) is synthesized by endothelial cells and megakaryocytes and is composed of two fractions.

• vWF:RCo (ristocetin cofactor) is needed for platelet adhesion to collagen in vivo; it is needed for a normal response to ristocetin on aggregation studies in vitro.

• vWF:Ag is the antigenic property of vWF.

• Both vWF:RCo and vWF:Ag are deficient in von Willebrand Disease

• The complement system is activated during ____ and ___.

• Contains more than _____, primarily to mediate inflammatory response and immune and allergic reactions.

• The complement system is activated during coagulation and fibrinolysis.

• Contains more than 30 circulating blood proteins, primarily to mediate inflammatory response and immune and allergic reactions.

Complement System and Coagulation System Interaction

• Complement functions in lysing ____.

• Plasmin (in association with antibody-antigen complexes) activates ___ and causes cleavage of ___ to ___ and ___.

• ____ increases vascular permeability, and ___ causes immune adherence of erythrocytes to neutrophils, which enhances phagocytosis.

• Complement activation is regulated by _____, which also inhibits several coagulation factors.

• Complement functions in lysing antibody-coated cells.

• Plasmin (in association with antibody-antigen complexes) activates Cl and causes cleavage of C3 to C3a and C3b.

• C3a increases vascular permeability, and C3b causes immune adherence of erythrocytes to neutrophils, which enhances phagocytosis.

• Complement activation is regulated by Cl inactivator, which also inhibits several coagulation factors.

• The kinin system contains four plasma proteins: ______

• Generates ____, an active peptide, and ____, a proteolytic enzyme.

• The kinin system contains four plasma proteins: factors XII and XI, prekallikrein (Fletcher factor), and HMWK (Fitzgerald factor).

• Generates bradykinin, an active peptide, and kallikrein, a proteolytic enzyme.

Kinin System and Cogulation System Interaction

• Involved in ____ and pain sensation

• Function: Mediate inflammatory responses, promote ____, and activator of ____ and complement pathways

• Involved in chemotaxis and pain sensation

• Function: Mediate inflammatory responses, promote vasodilatation, and activator of intrinsic coagulation and complement pathways

Fibrinolytic System:

• Keeps ____ and is important in ____.

• During this process, ____ is activated to ____.

• Keeps blood vessels clear and is important in clot dissolution.

• During this process, plasminogen is activated to plasmin.

Plasminogen

1. ____produced in the liver

2. ____ (inert) found in the plasma

1. Glycoprotein produced in the liver

2. Zymogen (inert) found in the plasma

Plasminogen

Converted to plasmin by plasminogen activators:

1. Intrinsic activators are ______.

2. Extrinsic activators are _____

3. Exogenous activators (therapeutic agents) include _____. They are administered to lyse existing clots

1. Intrinsic activators are Xlla, kallikrein, and HMWK.

2. Extrinsic activators are tissue-type plasminogen activator (t-PA) and

   urokinase-type plasminogen activator (u-PA).

3. Exogenous activators (therapeutic agents) include t-PA, streptokinase,

   and urokinase. They are administered to lyse existing clots

Plasmin

• Not normally found in circulation; the precursor plasminogen is found in circulation

• Degrades _____, ______, factors ____ and ____

• Activates the _____

• Not normally found in circulation; the precursor plasminogen is found in circulation

• Degrades fibrin clots (fibrinolysis), fibrinogen (fibrinogenolysis), factors V and VIII

• Activates the complement system

Antithrombin (AT)

1. Produced in the liver

2. Principal inhibitor of ____

3. Inhibits the____

4. _____ enhances the action of antithrombin.

1. Produced in the liver

2. Principal inhibitor of coagulation

3. Inhibits the serine proteases

4. Therapeutic heparin enhances the action of antithrombin.

1. Produced in the liver

2. Principal inhibitor of coagulation

3. Inhibits the serine proteases

4. Therapeutic heparin enhances the action of antithrombin

Antithrombin (AT)

1 . Vitamin K-dependent regulatory proteins

2. Activated when thrombin binds to thrombomodulin on the endothelial cell surface

3. Inhibit factors V and VIII to provide negative feedback on the cascade

Proteins C and S

Inhibits factor VIIa-tissue factor complex

Tissue Factor Pathway Inhibitor

Inhibits thrombin, Xa, kallikrein, and plasmin

a2 -Macroglobulin

Inhibits XIa and inactivates plasmin

a2-Antitrypsin

Inhibits Cl from the complement cascade, and Xlla, XIa, kallikrein, and plasmin

C1 Inhibitor

Principal inhibitor of fibrinolysis; neutralizes plasmin

a2 -Antiplasmin

1. Important inhibitor of fibrinolysis

2. Prevents activation of plasminogen by t-PA; released from endothelial cells upon damage

PAI-1 (plasminogen activator inhibitor-1)