HEMA 2: MIDTERMS PART 1

hemostasis

prevents blood loss after vessel injury

Plasma proteins, Cellular elements

key components of the hemostatic system (2)

Coagulation

 process whereby, on vessel injury, plasma proteins, tissue factors, and calcium interact on the surface of platelets to form fibrin clot

14 classical coagulation factor, Platelet phospholipid, VWF

procoagulants

plasma

procoagulants are found and transported by

Factor III and IV

Nearly all are glycoproteins synthesized in the liver except

Fibrinogen

 is the substrate for the enzymatic action of thrombin, the primary enzyme of the coagulation system

Thrombin

converts fibrinogen to fibrin

zymogens

are proenzyme with potential proteolytic activity

Control/regulatory glycoproteins

regulate the coagulation process to avoid unnecessary formation of fibrin clot and maintains blood in fluid state.

1935

Fibrinogen and Prothrombin (Factor II) were identified

1945-1950

Factors V and VII were identified

1950s

Factors IX and X were identified

International Committee for the Standardization of the Nomenclature of the Blood Clotting Factors

In 1958, the ___ officially named the plasma procoagulants and cofactors using Roman numerals in the order of their initial description or discovery.

platelet factor 3

Platelet phospholipids were once collectively called

Factor I, II, III, IV, VI

Factors NOT usually identified by their Roman numerals

Factor VI

has a similar activity to activated factor V; therefore, it is withdrawn from the group

High molecular weight kininogen

belongs to the kinin systems

Prekallikrein

belongs to kallikrein system

Substrate, Zymogen/ enzyme precursor, Ionized calcium, Cofactor

Coagulation factors

substrate

substance on which enzyme acts

Fibrinogen

only substrate in the cascade that does not become an activated enzyme

Zymogen/ enzyme precursor

They have no biologic activity until converted by enzymes to active forms

Factor II, VII, IX, X, XI, XII, PK, XIII

Examples of Zymogen/ Precursor (8)

Cofactors

• Are non-enzymatic proteins

• component that aids in the activation of zymogen to active enzyme

• Each binds its particular serine protease

Factor III, V, VIII, HMWK

examples of cofactors (4)

stability and reactivity

Cofactor + serine protease

Protein S

cofactor of ACP

Cofactor

creates more potent reaction

serine proteases, transglutaminase/ tansamidase

When zymogens (inactive form) are converted into enzymes (active form) they become  either

serine proteases

proteolytic enzymes of trypsin family that activates other specific factors in the coagulation sequence

serine protease

use serine as the active site and acts on its substrate by hydrolyzing peptide bond, digesting the primary backbone & producing small polypeptide fragments.

1. Thrombin

2. VIIa

3. IXa

4. Xa

5. Xia

6. XIIa

7. Kallikrein

example of serine proteases (7)

Transglutaminase/ transamidase

Catalyzes the transfer of amino acid in gamma chains of fibrin polymer

transglutaminase/ transamidase

Cross-links fibrin polymer, thus, providing physical strength to fibrin clot

Factor XIIIa

example of transglutaminase

plasmin

enzyme to digest fibrin clot

Fibrinogen

Factor I

341,000

MW of Factor I

200-400 mg/dl

normal value of factor I in plasma

3-4 days

half life of Factor I

Factor I (fibrinogen)

• Upon exposure to thrombin will form fibrin

• Manufactured in the liver

• Active in intrinsic and extrinsic pathways

• Absent in serum.

Prothrombin

Factor II

63,000

a-2 globulin with MW of

Factor II (prothrombin)

Converted to thrombin when exposed to Va, Xa, PF3 and Ca++

Tissue Thromboplastin

Factor III

Calcium

Factor IV

Proaccelerin

Factor V

Proconvertin

Factor VII

Anti-hemophilic Factor A

Factor VIII

Plasma thromboplastin component

Factor IX

Stuart-Prower Factor

Factor X

Plasma thromboplastin antecedent

Factor XI

Hageman

Factor XII

Fibrin Stabilizing Factor

Factor XIII

Thrombomodulin, Protein S, Protein Z

Part of control system (3)

Va, Xa, PF3 and Ca++

Factor II is converted to thrombin when exposed to (4)

Pro-portion (fragment 1.2), Thrombin portion (pre-thrombin 2)

2 portion of Factor II

60 hours

half life of factor II

Pro-portion (fragment 1.2)

responsible for the binding the prothrombin molecule

tissue factor and phospholipids

factor III is a mixture of

Factor III

 a lipoprotein found in tissues, membranes of fibroblasts, smooth muscle cells, and monocytes during inflammation and sepsis.

Factor III

Exceptionally high concentrations are found in the brain and lungs

Factor III

it has no enzymatic activity

Factor III

Acts as a cofactor in activating extrinsic pathway

brain and lungs

factor III is exceptionally high concentrations are found in the

Factor IV

Required in the several steps in coagulation pathway.

Very important in every step of the cascades

Factor V

a cofactor that speeds the transformation of prothrombin to thrombin

Factor V

It is the most unstable factor and deteriorates rapidly at room temperature

12-14 hours

half life of Factor V

300,000

A globulin with MW (Factor V)

Factor X

Factor VII activated by tissue thromboplastin, After activation, it activates Factor

60,000

B globulin with MW (Factor VII)

4-6 hours

Half life of Factor VII

FACTOR VII (PROCONVERTIN)

It is activated by tissue thromboplastin

Factor VII

used to delineate/differentiate factor VII (increase PT alone) and liver disease (increase all factors)

>1,000,000

A glycoprotein with MW (Factor VIII)

VIII:C, VIII:vWF

two functional subunits of Factor VIII

Factor VIII:C

is the active and small portion of the molecule and can be measured by the clotting assays.

Kupfer cells of the liver

Factor VIII:C production site is in

Factor VIII:vWF

is the total factor VIII molecule consisting of a low molecular weight unit (VIII) and a high molecular weight unit (vWF)

Factor VIII:vWF

It increases the half life of factor VIII

Factor VIIIR:Ag

is the antigenic portion of the molecule capable of stimulating antibody production and measured by immunoassay (FVIII)

Factor VIIIR:RCo

• demonstrates ristocetin cofactor activity

• important in platelet aggregation

A cofactor

• Active in Intrinsic pathway

• Necessary for formation of plasma thromboplastin

A cofactor

Deteriorates rapidly in stored plasma (even in refrigerated temperature)

abnormalities of Factor VIII

are the most common hereditary coagulation disorders

12 hours

Half life of A cofactor

Hemophiliac A

Factor VIII deficiency

VWF

• Acts as a carrier for the coagulant portion of the Factor VIII complex; constitutes greater that 90% of this complex

VWF

Synthesized in the endothelium and megakaryocytes and present in the α granules of the platelets

Factor VIII related antigen (VIIIR:Ag)

vWf:Ag which was previously termed

Ristocetin co-factor activity

is the property that causes platelet aggregation with ristocetin

Factor IX

• Absent in adsorbed plasma

• Active in intrinsic system

• Necessary to form plasma thromboplastin

Factor IX

• Necessary to form plasma thromboplastin

24 hours

Half life of Factor IX

62,000

glycoprotein MW of Factor IX

Factor II, VII, IX, X

Vitamin K dependent (4)

Factor X

• Absent in adsorbed plasma

• Active in intrinsic and extrinsic system

Factor X

• Activated form acts with Va, Ca++ and PF3 to form active thromboplastin