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4/27/2021
MLS12A
MODULE 4: THE COAGULATION SYSTEM
A SUMMARY
THE 16 COAGULATION FACTORS
MNEMONIC: First Person Told Cancer Leads Sickness, Another Chap Said Protein High Fat + HPPV
F Fibrinogen*
S X: Stuart Prower Factor
P Prothrombin*
P XI: PTA
T Tissue Factor*
H XII: Hageman Factor
C Ionic Calcium*
F XIII: Fibrin Stabilizing Factor
L V: Labile Factor
H HMWK or Fitzgerald Factor
S VII: Stable Factor
P Pre-kallikrein or Fletcher Factor
A VIII: Antihemophilic Factor A
P PF3 (phospholipids and phosphatidylserine
C IX: Christmas Factor (Antihemophilic Factor B)
V Von Willebrand Factor
*These factors are customarily identified by their names
...
Fibrinogen: the ultimate substrate of the coagulation system
...
COFACTORS: helps the activity of the zymogens
CONTROL PROTEINS: regulators of zymogens
SUBSTRATE: fibrinogen as the ultimate substrate to generate thrombin
PLASMA PROCOAGULANT SERINE PROTEASES
INACTIVE ZYMOGEN
ACTIVE PROTEASE
COFACTOR
SUBSTRATE
Prothrombin (FII)
Thrombin
---Fibrinogen, V, VIII, IX, XI
FVII
VIIa
Tissue Factor (FIII)
IX, X
FIX
IXa
VIIIa
X
FX
Xa
Va
Prothrombin
FXI
XIa
---IX
FXII
XIIa
HMWK
XI
Pre-kallikrein
Kallikrein
HMWK
XI
FRANCISCO |Page 1 of 8
4/27/2021
OTHER PLASMA PROCOAGULANTS
Fibrinogen
Factor XII
Phospholipids
Ionic Calcium
Von Willebrand Factor
Fibrinogen: ultimate substrate of coagulation system
...
Phospholipids: the negatively charged surfaces of platelets predominated by phosphatidylserine where cofactors bind through a positively
charge Calcium ions (Ca2+)
...
Von Willebrand Factor: carries the FXIII;
▪ A deficiency in vWF will result to DECREASED levels of FVIII because FVIII are insoluble/unstable in plasma
...
However, a deficiency in FVIII will not affect the levels of vWF
...
▪ Cross-linking of the FXIII with Fibrin as the final step
...
▪ FVIII: from liver and EC
▪ PF3: from platelets
▪ vWF: from EC and platelets
HEMOSTASIS COFACTORS
Tissue Factor
FV
PROCOAGULANT
PROCOAGULANT
VIIa
Xa
FVIII
HMWK
PROCOAGULANT
PROCOAGULANT
IXa
XIIIa, pre-kallikrein
Thrombomodulin
Protein S
CONTROL (Protein C)
Antifibrinolytic (TAFI)
CONTROL
Thrombin
Thrombin
Protein C, TFPI
Protein Z
CONTROL
ZPI
FRANCISCO |Page 2 of 8
4/27/2021
▪
▪
▪
▪
COMMON CHARACTERISTICS
A deficiency generally causes bleeding disorders, EXCEPT for: XII, Pre-kallikrein, and HMWK
...
Synthesis of the factor is independent of the other
...
(FVIII, FV)
✓ MIXED FACTOR DEFICIENCY: V and X
Some factors can be assayed in the laboratory
...
2
...
IMPORTANCE OF KNOWING THE PROCOAGULANTS
Assist in the interpretation of laboratory tests
...
Monitoring of anticoagulant therapy
...
✓ Intrinsic pathway for heparin therapy, (PT test)
✓ Extrinsic pathway for coumadin therapy, (APTT test)
Design of effective replacement therapies in deficiency related hemorrhagic diseases
...
THE THREE FUNCTIONAL GROUPS
CONTACT FACTORS
PROTHROMBIN GROUP
XI, XII, PK, HMWK
II, VII, IX, X
✓ Contact Factors are the ones that start the Intrinsic Pathway
...
Vitamin K are quinone found in:
✓ Green leafy vegetables
Food Sources High in Vitamin K
✓
Kale
Asparagus
Spinach
Cabbage
Turnip greens
Green Onions
Collards
Lettuce
Mustard greens
Avocado
Swiss chard
Cauliflower
Brussel Sprouts
Parsley, fresh
Broccoli
Also produced by intestinal organs including: Bacteroides fragilis and Escherichia coli
...
▪ y-carbon + COO- = y-carboxyglutamic acid
✓ Due to the addition of COO-, y-carboxyglutamic acid gains a negative net charge enabling to attach to the Calcium ion (Ca2+)
...
VITAMIN K Deficiency
✓ Especially in the presence of Coumadin (Coumarin, Warfarin)
▪ Coumadin is an anticoagulant, a therapeutic inhibitor of vitamin K
...
Thus, without vitamin K, there would also be no ycarboxylation resulting to the production of des-y-carboxyl proteins or proteins induced by vitamin K (PIVKA)
...
INTAKE OF ORAL ANTICOAGULANTS=VIT K deficiency=no y-carboxylation=no coagulation reaction=no clotting
VITAMIN K-DEPENDENT PROTHROMBIN GROUP IN 3 COMPLEXES
COMPLEX
COMPONENTS
INTRINSIC TENASE
EXTRINSIC TENASE
IXa, VIIIa, PL, Ca
VIIa, TF, PL, Ca2+
PROTHROMBINASE
Xa, Va, PL, Ca2+
2+
ACTIVATES
X
IX, X
Prothrombin
PROTHROMBINASE: converts prothrombin to thrombin
✓ Multistep hydrolytic process
✓ Releases thrombin and a peptide fragment prothrombin 1
...
2)
▪ Prothrombin fragment 1
...
✓ Prothrombin can have two products:
1
...
Peptide fragment prothrombin:
...
✓ Primary function: to cleave FPA and FPB
✓ FPA and FPB are measurable in plasma and serve as a marker for thrombin activation
FACTOR VII
✓ Stable beta-globulin
✓ Activation of thromboplastin and acceleration of thrombin generation/formation
FACTOR X (STUART PROWER)
✓ Stable alpha-globulin
✓ Not consumed during clotting
✓ Activated by FX and FV in the presence of calcium ions
THROMBIN FUNCTIONS
1
...
Activates FXIII
▪ Forms covalent bonds between the D domains of the fibrin polymer to cross-link and stabilize the fibrin clot
3
...
When bound to thrombomodulin:
▪ Activates the protein C pathway to suppress coagulation
▪ Activates TAFI to suppress fibrinolysis
CONTACT FACTORS
Activated by contact with negatively charged foreign substances
...
✓ APTT (Activated Partial Thromboplastin): Test to measure contact factors
✓ Commonly deficient: FXII
FXII (HAGEMAN FACTOR)
✓ Stable, not consumed during clotting
✓ Transforms pre-K to kallikrein and cleaves HMWK to form bradykinin
✓ Activate in-vitro: glass, ellagic, kaolin
✓ Activated in-vivo: foreign substance such bacterial cell membranes, prosthesis, stents
✓ Test reagent for PTT and APTT
HMWK
✓ Cofactor to FXIIa and pre-kallikrein in the intrinsic contact factor complex
FACTOR XI
✓ Found in serum, partially consumed
✓ Intrinsic thromboplastin – generating mechanism
✓ Activated by:
▪ Contact factor complex
▪ Thrombin during coagulation generated from TF activation
✓ Deficiencies can cause mild and variable bleeding (Rosenthal syndrome)
✓
✓
FIBRINOGEN GROUP
FACTOR V
✓ Extremely labile, deteriorate rapidly, soluble plasma factor, consumed in clotting process
✓ 24 hour half life
✓ Glycoprotein circulating in plasma
✓ Present in platelet alpha granules
✓ They are released by platelets at the site of injury as a cofactor to Xa
...
✓ Regulation: Thrombomodulin-bound thrombin activates Protein C and Protein C inactivates Va
...
Deteriorates more rapidly than the other factors in stored blood
Thawed component of plasma: level drops to approximately 50% after 5 days
Females are carrier of Hemophila A
Males expresses the condition
Hemophilia B deficiency is Factor IX deficiency
Von Willebrand Factor
✓ Acute phase protein (as with FVIII)
✓ Produced in ECs and megakaryocytes
✓ Functions: platelet adhesion and transports the procoagulant FVIIII
✓ Cleaved by ADAMTS13 because if not, there will be large fractions of VWF leading to Thrombocytic Thrombocytopenic Purpura
...
✓ Levels vary by ABO blood type
...
✓ Function: Primary substrate of thrombin
✓ Fibrinogen -> Fibrin monomer -> Polymerized Fibrin clot
✓ Essential for platelet aggregation: links the activated platelets through their GPIIb/IIIa platelet fibrinogen receptor
✓ Platelet alpha-granules absorb, transport, and release abundant fibrinogen
...
Fibrinogen Molecule
✓ Mirror-image dimer, each half consisting of three non-identical polypeptides: A-alpha, B-beta, and gamma
...
(positively charged)
✓ 2D domains: three carboxyl terminals on each outer end of the molecule
...
Cleaves fibrinopeptides A and B – fibrin monomer
▪ Marker for thrombin generation
2
...
Exposed fibrin monomers A and B chain ends (E domain) have an immediate affinity for portions of the D domain of
neighboring monomers, spontaneously polymerizing to form fibrin polymer
...
Fibrin Stabilizing Factor (FXIII)
✓ Fibrin Clot + FXIII+ Ionized calcium -> stable fibrin clot
✓ Alpha-transglutaminase
✓ Heterodimer:
1
...
Beta subunit: liver
FIBRIN CLOT FORMATION
✓ Fibronectin: plasma protein involved in cell adhesion
...
✓ A2-antiplasmin: rendering the fibrin mesh resistant to fibrinolysis
...
Attaches to free plasmin preventing
fibrinolysis
...
Activates platelets through cleavage of protease activated receptors (PAR-1 and PAR-4)
2
...
Activates FVIII and dissociates it from VWF
4
...
Splits FPA and FPB from fibrinogen and forms a preliminary fibrin network