Coagulation Lecture 2 - Secondary Hemostasis

• FII

• FVII

• FIX

• FX

• FXI

• FXII

• FXIII

• Prekalikrein

8 coagulation factors that are zymogens

Prothrombin

FII is also known as…

Proconvertin

FVII is also known as…

• Plasma thromboplastin component

• Christmas factor

FIX is also known as… (2)

Stuart-Prower factor

FX is also known as…

Plasma thromboplastin antecedent

FXI is also known as…

Hageman factor

FXII is also known as…

• Plasma transglutaminase

• Fibrin-stabilizing factor

FXIII functions as a (——) and is also known as (——)

Fletcher

Prekalikrein is also known as…

FXIII

All coagulation factors are serine proteases except…

• High molecular weight kininogen (HMWK)

• Tissue factor

• FV

• FVIII

• Protein S

• Thrombomodulin

• Protein Z

7 coagulation proteins that are cofactors (stabilize and accelerate proteolytic reactions)

• FXIIa

• PK

High molecular weight kininogen (HMWK) is a cofactor for… (2)

FVIIa

Tissue factor is a cofactor for…

FXa

FV is a cofactor for…

FIXa

FVIII is a cofactor for…

Activated protein C

Protein S is a cofactor for…

Thrombin (in protein C activation)

Thrombomodulin is a cofactor for…

Protein Z-dependent protease inhibitor (ZPI)

Protein Z is a cofactor for…

Fitzgerald

High molecular weight kininogen (HMWK) is also known as…

• FIII

• Tissue thromboplastin

Tissue factors are also known as… (2)

• Labile factor

• Proaccelerin

FV is (nonlabile/labile) and is also known as (——)

AHF A

FVIII is also known as…

• Anti-thrombin

• Protein C

• Heparin co-factor II

• TFPI (tissue factor pathway inhibitor)

Regulatory proteins in coagulation (4)

FIV

Ca+ is which coagulation factor?

PF3

Coagulation phospholipid factor

Fibrinogen

Factor I is also known as…

Prothrombin

Factor II is also known as…

• vWF

• ECs (Weibel-Palade granules

• MKs (PLT alpha granules)

Almost all coagulation factors are synthesized by the liver except (——) which is made by (—2—)

vWF

Heaviest coagulation factor (500-20,000 kd)

VII

Coagulation factor with the shortest half life (3-6h)

HMWK

Coagulation with the longest half-life

VIII

Coagulation factor carried in plasma as bound to vWF to maintain 12h half-life

Ionized calcium

Is crucial for coagulation complexes to bind to platelet or cell membrane phospholipids

Conversion of fibrinogen (ultimate substrate) into stable fibrin clot

Outcome of coagulation

• SCZ27910 (prothrombin group)

• 𝛄-carboxylated

• 10-12 glutamic acid

Vitamin K dependent coagulation proteins are known as (——); they require vitamin K to become (——), or functional; All of these proteins have (——) residues at N terminal

Prothrombin group

Is important for assembly of coagulation complexes to generate thrombin

• Tissue factor

• VIIa

• Ca2+

• Phospholipid

Complex 1 (extrinsic tenase) is composed of… (4)

• X → Xa

• IX → IXa

Complex 1 (extrinsic tenase) activates… (2)

• IXa

• VIIIa

• Phospholipid (PLT surface)

• Ca2+

Complex 2 (intrinsic tenase) is composed of… (4)

X → Xa

Complex 2 (intrinsic tenase) activates…

• Xa

• Va

• Phospholipid

• Ca2+

Complex 3 (prothrombinase) is composed of… (4)

Prothrombin → thrombin

Complex 3 (prothrombinase) activates…

FVIII and vWF

(—2—) are the KEY factors in coagulation (severe bleeding in hemophilia A and vWD)

FVIII and FIX

Factors (—2—) are encoded by genes on X chromosome

FVIII

Is degraded in stored plasma faster than other factors

FVIII

Is bound to and carried by vWF in plasma

• 240kd

• 500-2000kd

vWF is multimeric, with subunits of (—size—) that can be polymerized to (—size—) in MK and ECs

ADAMTS13 (a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13)

vWF polymers are degraded to smaller multimers by (——) in blood vessels with higher shear rate

• PLTs

• Collagen

(bridges PLTs to subendothelium during PLT adhesion)

vWF has receptors for (—2—)

ABO groups (O group has the lower level)

vWF is associated with which blood group?

• vWF

• FVIII

Coagulation factors that are acute phase reactants (2)

• FXII

• PK

• HMWK

Constitutes the contact system (contact factors, contact factor complex) (3)

aPTT test

The contact system is the basis of which test?

FXII

Coagulation factor activated by negatively charged surfaces

• PK → K

  • K → FXII

FXIIa converts (——) and the products from that reaction activates (——)

• FXI

• FIX

Contact factor complex (HMWK + PK + FXIIa) activates (——), and in turn, activates (——)

Thrombin generated by the extrinsic tenase

The most important activator of FXI is…

• Does not cause bleeding

• Prolonged aPTT

Deficiencies of the contact system factors causes… (2)

Thombin

Key serine protease in coagulation with multiple function

• Cleaving fibrinopeptides A and B (FPA and FPB) from fibrinogen

• Trigger spontaneous polymerization

• Clot initiation

Major functions of thrombin (3)

• FV (positive feedback)

• FVIII (positive feedback)

• FXI (positive feedback)

• TAFI (thrombin activatable fibrinolysis inhibitor)

• FXIII (stabilize fibrin clot)

  
  

Thrombin activates… (5)

Thrombomodulin

Thrombin bound to (——) activates protein C

Aggregation

Thrombin triggers (——) of PLTs

Fibrinogen

Primary substrate of thrombin

200-400mg/dL

Reference interval of fibrinogen in plasma

GP23A

Fibrinogen is essential for PLT aggregation through binding the (——) receptor

⍺ granules

PLTs absorb fibrinogen and store it in…

• Does not affect PT or PTT

• Clinical bleeding

Deficiency in FXIII effect on coagulation tests and symptoms

FVII

In the extrinsic pathway, (——) is the primary initiator of in vivo coagulation

VII → X → V → prothrombin → fibrinogen

Extrinsic pathway reaction order

Prothrombin time (PT) test

The extrinsic pathway is assessed by which test?

XII → pre-K → HMWK → XI → IX → VIII → X → V → prothrombin → fibrinogen

Intrinsic pathway reaction order

Activated partial thromboplastin time (aPTT) test

The intrinsic pathway is assessed by which test?

• X

• V

• Prothrombin

• Fibrinogen

The common coagulation pathway includes which factors? (4)

• Prothrombin time (PT) test

• Activated partial thromboplastin time (aPTT) test)

• Thrombin time (TT)

The common coagulation pathway is assessed by which tests? (3)

Extrinsic tenase complex

(Initiation) In vivo, (——) is the main initiator of thrombin generation

• 1-2%

• TF

(—%—) FVIIa circulates but is inert, requiring (——)

• >95%

• PLT membrane

In propagation, (—%—) thombin is generated, with the reactions being on the (——)

FX 50-100 fold higher

In large PLT aggregates, intrinsic tenase activates…

Burst of thrombin

Prothrombinase complex generates…

With Xa, binds TF:VIIa (blocks the complex)

Tissue factor pathway inhibitor (TFPI) function

EC surface receptor for thrombin

Thrombomodulin function

Serine protease (inhibits Va and VIIIa)

Protein C function

Cofactor (for protein C)

Protein S function

Serpin (serine protease inhibitor)

Antithrombin acts as a…

Serpin (serine protease inhibitor)

Heparin cofactor II function

Serpin (serine protease inhibitor)

Protein Z-dependent protease inhibitor functions as a…

Fibrinolysis

Final stage of hemostatic activation (hours after)

As the fibrin is forming

When do fibrinolytic proteins bind to fibrin?

Plasminogen

Main substrate of fibrinolysis, that is produced by the liver

• TPA (tissue plasminogen activator; more effective)

• UPA (urokinase plasminogen activator)

In fibrinolysis, ECs secrete (—2—)

Fibrin-bound plasminogen

TPA degrades (——) to generate plasmin

Fibrin (and fibrinogen) → fragments (X, Y, D, E, D-D)

Plasmin degrades…

• Fibrin-derived

• Thrombosis

• Fibrinolysis

D-D (D dimer) is (——)-derived and is a diagnostic test for (—2—)

Plasminogen activator inhibitor-1 (PAI-1)

The main inhibitor of fibrinolysis, binds to and inactivates TPA and UPA, it’s a serpin, produced mostly by ECs and MKs

⍺2-antiplasmin (⍺2-AP)

Produced by the liver, binds to and inactivates free plasmin (not plasmin bound to fibrin)

Thrombin activatable fibrinolysis inhibitor (TAFI)

Synthesized by the liver, activated by the thrombin-thrombomodulin complex, blocks binding of TPA and plasminogen to fibrin and formation of plasmin

Trauma-induced (acquired bleeding disorders)

Systemic shock leading to acute reduction in ADAMTS13, coagulation factor activation, TF release, and hyperfibrinolysis

SCZ27910 (vitamin K dependent factors)

In liver disease, there is a reduction in plasma levels of which factors?

• FVII reduced (short half life)

• PT prolonged (mild liver disease)

Coagulation characteristics associated with the beginning of liver disease (2)