Section 5: Normal Hemostasis - Coagulation Cascade

How hematocrit can affect a coagulation specimen

- Low Hematocrit = more plasma = needs more anticoagulant

- High Hematocrit = less plasma = needs less anticoagulant

Use of Platelet Poor Plasma (PPP)

Used for Coagulation Studies

Use of Platelet Rich Plasma (PRP)

Used for Platelet Studies

Factor I Common Name

Fibrinogen

Factor Ia Common Name

Fibrin (Monomer)

Factor II Common Name

Prothrombin

Factor IIa Common Name

Thrombin

Factor III Common Name

Tissue Factor III (TF III)

Factor IV Common Name

Calcium (Ca++)

Factor V Common Name

Labile Factor

Factor VII Common Name

Proconvertin or Stable Factor

Factor VIII Common Name

von Willebrand Factor Complex

Factor IX Common Name

Christmas Factor

Factor X Common Name

Stuart-Prower Factor

Factor XI (common name+ description)

Plasma Thromboplastin Antecedent (PTA).

• Made in the liver

• Contact factor

• Travels in blood complexed with 

high molecular weight kininogen 

(HMWK)

Factor XII Common Name

Hageman Factor

Factor XIII Common Name

Fibrin Stabilizing Factor

Prekallikrein (PK) Common Name

Fletcher Factor

High Molecular Weight Kininogen (HMWK) Common Name

Fitzgerald Factor

Site of formation of the coagulation factors

Liver

"Magic 4" Coagulation Factors

• Factor II, Factor VII, Factor IX, Factor X

• All produced in the Liver

• All Vitamin K dependent- Vit K. participates in oxidation RXN that adds a 2nd carboxyl group to make it a complete factor

• All depleted by Warfarin therapy

Function of Thrombin

- converts Fibrinogen to Fibrin

- enhances the activity/modifies Factors V and VIII

- activates Factor XIII with the help of Ca++

- can alternatively activate XI

Contact Factors

Factor XI, Factor XII, Prekallikrein (PK), High Molecular Weight Kininogen (HMWK)

• Initiate the intrinsic coag pathway

• While they initiate the intrinsic cascade in vitro, their def does not cause bleeding in vivo

• More often associated with abnormal clotting (thrombosis) due to poor activation of fibrinolysis

• Factor XII is auto-activated on exposed surfaces → activates XI and PK (with HMWK as cofactor).

• PK becomes kallikrein, which amplifies Factor XII activation and generates bradykinins from HMWK.

Factor I - Fibrinogen

- made in liver

-Monomers polymerize to form a clot

- cross links platelets in aggregation

- acute phase reactant

- high levels associated with MI and stroke

- low levels associated with bleeding

-absorbed in platelets alpha granules

Factor II - Prothrombin

- made in the liver

- one of the Magic Four

- Vitamin K dependent

- active form: responsible for conversion of fibrinogen to fibrin

-activates Factors V, VIII, XI, XIII, Protein C & TAFI

-Responsible for conversion of fibrinogen to fibrin

Factor III - Tissue Factor III

- found in all tissues (especially brain, liver, lung, placenta)

- released from injured tissues

- cofactor for activation of Factor VII

- part of "Extrinsic Tenase complex” that activates Factor X

-No known deficiencies of TFIII

Factor IV - Calcium (Ca++)

- mediator of platelet activation

- required in several steps of the cascade

Note: in coag screening tests, must add Ca++ to overcome anticoagulant from sodium citrate tube (light blue)

Factor V - Labile Factor

-activity rapidly decreases at temp

- made in the liver

- attaches to receptor of activated platelets

- thrombin modifies or activates Factor V

- works in complex with Xa, Ca++ & PF3 to activate prothrombin

- inactivated by Protein C and protein S

Factor VII - Proconvertin or Stable Factor

- made in the liver

- one of the Magic Four

- Vitamin K dependent

- TF III and Ca++ activate it

- complex of TF III / Ca++ / and the activated form of this activate X

- can also activate factor IX (alternate pathway)

VIII - von Willebrand Factor Complex

- produced in several tissues (mostly liver)

- heat labile

- thrombin modifies or activates it

- works in complex with IXa, Ca++ and PF3 to activate Factor X

- deficiency of this is Hemophilia A

- unstable when not bound to vWF

- inactivated by Protein C and S

-Carrier molec for factor VIII:C

-Produced by MGK and endothelial cells

-stimulated by DDAVP

Factor IX (Christmas Factor)

- made in the liver

- one of the Magic Four

- Vitamin K dependent

- actives by factors XIa or VIIa (alternate pathway)

- works in complex with VIII(a), Ca++ and PF3 to activate X

- deficiency in this is Hemophilia B

Factor X - Stuart Prower

- made in the liver

- one of the Magic Four

- activated by both intrinsic and extrinsic complexes

Extrinsic complex -TF III / VIIa / Ca++

Intrinsic Complex - IXa / VIII(a) / Ca++ / PF3

- works in complex with V(a) / Ca++ / PF3 to activate prothrombin

Factor XI

- made in the liver

- contact factor (may auto-activate in vitro by glass)

- travels in blood complexed with High Molecular Weight Kininogen (HMWK)

- activated by Factor XIIa (alternate activation by thrombin)

- only contact factor that a deficiency causes bleeding (Hemophilia C)

Factor XII - Hageman Factor

- made in the liver

- contact factor

- activated by contact with sub-endothelial tissue

- the activated form activates Factor XI with cofactor HMWK & also activates Prekallikrein to Kallikrein

- deficiency does not cause bleeding but may see abnormal clotting

Factor XIII - Fibrin Stabilizing Factor

- made in the liver

- activated by thrombin and Ca++

- forms convalescent bonds between D-domains in polymerized fibrin

- not tested for in coagulation screening tests

-must detect a deficiency with urea clot lysis

Prekallikrein (PK) - Fletcher Factor

- made in liver

- contact factor

- activated by XIIa

- attached to HMWK (cofactor for PK activation)

- deficiency does not cause bleeding but may see abnormal clotting

High Molecular Weight Kininogen

- made in liver

- contact factor

- complexes with XI and PK

- cofactor with XIIa to activate XI

- acts as substrate for Kallikrein in production of kinins

- deficiency does not cause bleeding but may see abnormal clotting

Kallikrein

Kallikren activates:

- more XII

- plasminogen to plasmin

- hydrolyzes Bradykinins from HMWK to initiate Kinin system

Bradykinins

- increase vascular permeability

- contract smooth muscle

- dilate small blood vessels

- induce pain and inflammation

- release prostaglandins from tissues

Platelet Factor 3 (PF3)

- on platelet membrane. Acts as phospholipid surface that supports coag cascade

- provides binding site for Vitamin K dependent factors

- not a true factor, more of and activity of plasma membrane

Intrinsic "Tenase" Complex

Factor IXa, Ca++, PF3, FVIII:C(a)

Required for conversion of Factor X to Factor Xa

Extrinsic "Tenase" Complex

Factor VIIa, Ca++, TF III

Required for conversion of Factor X to Factor Xa

Prothrombinase Complex

Factor Xa, Factor V(a), PF3, Ca++

Required for conversion of Prothrombin to Thrombin

Warfarin Mechanism of Action

• Arrests Vit K in it’s storage form making it unavailable to produce complete factors

• Warfarin inhibits vitamin K recycling, preventing γ-carboxylation of glutamate residues on II, VII, IX, X.

• This prevents proper binding of factors to phospholipid surfaces (via Ca²⁺), rendering them incomplete/inactive.

Factor VIII Complex Subunits

• VIII**:C**** (coagulant portion):** Cofactor in intrinsic tenase

• vWF: Carrier protein; prevents degradation of VIII, mediates platelet adhesion

Hemophilia A

• Factor Deficiency: Factor VIII

• Common Name: von Willebrand factor complex

• Classification: Neither magic 4 nor contact factor

• Pathophysiology: X-linked disorder; deficiency disrupts intrinsic tenase complex → ↓ thrombin generation → impaired clot formation

Hemophilia B

• Factor Deficiency: Factor IX

• Common Name: Christmas factor

• Classification: Magic 4 (vitamin K–dependent)

• Pathophysiology: X-linked disorder; deficiency impairs activation of Factor X via intrinsic pathway → ↓ thrombin burst → poor clot stability

Hemophilia C

• Factor Deficiency: Factor XI

• Common Name: Plasma thromboplastin antecedent

• Classification: Contact factor

• Pathophysiology: Autosomal recessive disorder (especially in Ashkenazi Jews); deficiency impairs amplification of thrombin generation → usually mild bleeding tendency