HEMA 2: MIDTERMS PART II

Factors I, V, VIII, XIII

Fibrinogen Group (4)

Fibrinogen group

• consumed in coagulation

• present in plasma, not in aged serum

• synthesized in liver

• HAVE THE HIGHEST MW OF ALL FACTORS

• MOST LABILE

Factors II, VII, IX and X

Prothrombin Group

Prothrombin Group

• All are serine proteases when activated, except for CHON Z (for ZPI) and S (part of protein C system), which are cofactors.

• Requires Vitamin K for their synthesis in the liver

Vitamin K

enables the γ-carboxylation of glutamic acid residues on these factors, making them capable of binding calcium ions, which is crucial for their activity.

Vitamin K

is a quinone found in green leafy vegetables

Bacteroides fragilis and Escherichia coli

Vitamin K is also produced by the intestinal organisms

Dietary vitamin K Deficiency, Antibiotics that sterilize intestinal tract, Oral anticoagulant therapy

Inhibitors of Vit K

barium sulfate + plasma

precipitates prothrombin group, hence what’s only left is fibrinogen group which is unprecipitated

des-γ-carboxyl proteins or proteins induced by vitamin K antagonists (PIVKA factors)

In vitamin K deficiency or in the presence of the anticoagulant drug warfarin (a therapeutic inhibitor of vitamin K), the vitamin K–dependent procoagulants (FVII, IX, X) are released from the liver without the second carboxyl group added to the γ carbon, called the

Factor XI, XII, HMWK, PK

Contact group

Contact Group

• Activates the intrinsic pathway of coagulation when exposed to negatively charged particle/substrate (in vivo: collagen; in vitro: kaolin/glass tube) or to foreign surfaces, such as in the presence of mechanical heart valves or bacterial membranes

Contact Group

Plays a role in infammation and the generation of bradykinin

Bacterial membranes

activates intrinsic factor, leading to formation of unwanted clot

kinin

peptides of low MW composed of amino acids

coagulation and the kinin system

involved in chemotaxis and sensation of pain, mediate infammatory process, increase vascular permeability, vasodilation, hypotension and induce contraction of smooth muscle

Intrinsic coagulation activation, Activation of fibrinolysis, Kinin formation, Complement system activation

Coagulation and the kinin system play roles in (4)

COAGULATION & THE COMPLEMENT SYSTEM

• Function in lysing Ab-coated cells

• Plasmin activates C1 which will cleave C3 to C3a and C3b

• C1 inactivator inhibits complement activation, XIIa, XIa, plasmin and kallikrein

Morawitz theory, Howell’s theory, Cascade/ Waterfall theory

Theories of Blood Coagulation

Extrinsic/ Tissue Factor Pathway, Intrinsic/ Contact Activation Pathway, Common Pathway

Cascade/ Waterfall theory involves 3 pathways (3)

Extrinsic/Tissue Factor Pathway

activated by the release of tissue thromboplastin into the plasma from injured tissue cells

Intrinsic/ Contact Activation Pathway

• activated by exposure of contact factors to the sub-endothelium (collagen).

• “Intrinsic” because all components are found in circulating blood/ plasma. (This means that all factors are already found in blood or plasma, not unlike in extrinsic pathway, where “tissue factor” came from tissues, not in plasma).

Common Pathway

• begins with the activation of Factor X by either intrinsic/extrinsic pathways.

• This theory is what’s been followed up to this day, used by clinicians, and people who are teaching hematology

Stage I – Generation of Thromboplastin Activity, Stage II – Formation of Thrombin, Stage III – Formation of Fibrin clot

3 STAGES OF COAGULATION

Factor VII, Factor III,

main components of Extrinsic Pathway

Factor XII, Factor XI, Factor IX, Factor VIII, HMWK, Prekallikrein

main components of Intrinsic Pathway? (6)

Factor X, Factor V, Factor II, Factor I, Factor XII

main components of the Common Pathway? (5)

CELL-BASED MODEL OF COAGULATION

it emphasizes the crucial roles of cellular surfaces, particularly tissue factor-bearing cells and platelets, in the coagulation process.

initiation, amplification, propagation, termination

Phases of the Cell-based model

Protein C (PC), Protein S (PS), Endothelial protein C receptor (EPCR), Activated protein C (ACP)

Protein C system (4)

Protein C (PC)

A vitamin K-dependent zymogen activated by thrombin when bound to thrombomodulin on endothelial cells

Protein S

Serves as a cofactor to APC, enhancing its ability to inactivate Factors Va and VIIIa

Protein S (PS)

• About 40% is free, 60% is covalently bound to the complement control protein C4b-binding protein (C4bBP)

• Only free plasma protein S can serve as the APC cofactor.

• Protein S-C4bBP binding is of particular interest in inflammatory conditions because C4bBP is an acute-phase reactant

Endothelial Protein C Receptor (EPCR)

is a transmembrane protein that binds protein C adjacent to the thrombomodulin-thrombin complex (to have activated protein C

Activated Protein C (APC)

Once activated, it degrades Factors Va and VIIIa, reducing thrombin formation

AT3

Antithrombin was formerly known as

Antithrombin

First of the coagulation regulatory proteins to be identifed as a cause of thrombosis when defcient.

ANTITHROMBIN

First to be assayed routinely in the clinical hemostasis laboratory

heparin

is a member of the glycosaminoglycan family of carbohydrates

thrombin generation

Laboratory measurement of TAT is used as an indicator of

tissue factor pathway inhibitor

is a Kunitz-type (referring to its chemical structure) serine protease inhibitor and is the principal regulator of the TF pathway (extrinsic psthway)

TISSUE FACTOR PATHWAY INHIBITOR (TFPI)

Binds to Factor Xa, and the resulting complex then inhibits the TF-FVIIa complex, providing a feedback mechanism to control clot formation

thrombomodulin

It also plays a role in regulating fbrinolysis through activation of TAFI

thrombomodulin

An endothelial cell membrane protein that binds thrombin, altering its substrate specificity from procoagulant to anticoagulant activities

thrombin-thrombomodulin

complex activates Protein C, initiating the anticoagulant pathway

Protein Z

A cofactor for Z-dependent protease inhibitor (ZPI), is a potent inhibitor of FXa

Protein Z

is a vitamin K–dependent plasma glycoprotein that is synthesized in the liver, however, it lacks an activation site.

Serpins α1-protease inhibitor and α2- macroglobulin

are able to inhibit serine proteases and thrombin reversibly, providing a secondary line of regulation in coagulation

protein C inhibitor

is a non-specifc, heparin-binding serpin that inhibits a variety of proteases, including APC, thrombin, FXa, FXIa, and urokinase.