1. Ch. 45 Blood Plasma proteins, Coagulation and Fibrinolysis
Chapt. 45
Ch. 45 Blood Plasma proteins,
Coagulation and Fibrinolysis
Student Learning Outcomes:
Describe basic components of plasma
Explain the formation of a blot clot (thrombus) – the cascade necessary for hemostasis and thrombosis:
the role of platelets, many factors, enzymes
Explain the effects of genetic defects of factors
Describe the regulatory mechanisms for the coagulation cascade, and antifibrinolysis

2. Inheritance of X-linked gene for Factor VIII hemophilia A
Pedigree of hemophilia transmission among Queen Victoria's descendants
Hartl & Jones, Genetics

3. Same electrolyte composition as extracellular fluids
Plasma components
1. Plasma proteins maintain proper distribution of water between blood and tissues
Plasma contains water, nutrients, metabolites, hormones, electrolytes, proteins
Same electrolyte composition as extracellular fluids
Many disease states alter plasma proteins – observe by electrophoresis
Osmotic pressure or plasma proteins is critical for bringing water back into blood from tissues

4. Albumin and other proteins
Albumin is major serum protein:
69-kDa glycoprotein, 60% of total plasma protein
Carries free fatty acids, zinc, Ca2+, steroid hormones, many drugs
Table 1 other serum proteins made in liver:
Ceruloplasmin binds copper, storage
Corticosteroid-binding globulin binds cortisol
Haptoglobulin binds extracellular heme
Lipoproteins bind cholesterol and fatty acids
Retinol-binding protein binds vitamin A
Sex hormone-binding globulin binds estradiol, testosterone
Transferrin transports iron

5. II. Other plasma proteins
Immune response involves plasma proteins:
Immunoglobulins (antibodies) made by B lymphocytes – bind specific antigens
Complement proteins aid in clearance of Ag-Ab;
also bind bacterial cell wall and lyse through C3b
Activation of complement is a proteolytic cascade
Protease inhibitors in plasma
control inflammatory response

6. III. Plasma proteins maintain integrity of circulatory system
Platelets are critical for clotting:
If damage to endothelial lining of blood vessels exposes subendothelial layer:
(Extracell matrix, smooth muscle cells)
Barrier (hemostatic plug, clot) forms
Platelets initiate, bind damage area
Clot formation is limited by regulation
Vessel heals, clot is degraded
Platelets from megakaryocyte (~8 nuclei) → 4000 non-nucleated platelets

7. Adhesion of platelets to subendothelium
Platelets adhere to site of blood vessel injury:
Exposes collagen, vWF and other components
(vWF (von Willebrand factor) is glycoprotein, is also in plasma, binds factor VIII to protect it; disorder → bleeding)
Then other GPs (glycoproteins) bind to fibrinogen, vWF
Platelet activation (release granules), brings more platelets (ADP is attractant); platelets release vasoconstrictors
Fig. 1

8. Fibrinogen is cleaved to fibrin to form ‘soft clot’
Fibrinogen, fibrin
Fibrinogen is cleaved to fibrin to form ‘soft clot’
Fibrinogen in blood and in platelet granules
Assists platelet aggregation
(of activated platelets)
Cleavage by thrombin protease releases fibrin monomers which aggregate
Thrombin also binds platelets through receptor, activates them
Fig. 2

9. B. Blood coagulation cascade
Thrombus (clot) is enhanced by thrombin activation
Proteins in plasma are
proproteins (zymogens)
Activated by proteolytic
cleavages, sequential
Highly regulated
Proenzymes:
serine proteases:
VII, XI, IX, X, prothrombin
Cofactor proteins bind:
Tissue factor, V, VIII
Fig. 3 PL, Ca are cofactors bound to phospholipids on platelet, vessel wall in Ca2+ complex

10. Blood coagulation process
Blood coagulation is complex cascade
Platelets adhere, plasma proteins react to subendothelium
Common path at Xa
Platelet membrane is
scaffold for formation
g-carboxylated clotting
proteins chelate to
membrane surface
(- PL, Ca2+)
Thrombin is critical:
Positive feedback
Accelerate process
Cleaves XIII → XIIIa
Fig. 3 positive feedback by thrombin

11. Table 45.2 Proteins of blood coagulation
Factor descriptive name function/active form
Coagulation factors
I Fibrinogen Fibrin
II Prothrombin Serine protease
III Tissue factor Receptor, cofactor
IV Ca2+ Cofactor
V Proaccelerin, labile factor Cofactor
VII Proconvertin Serine protease
VIII Antihemophilia factor A Cofactor
IX Antihemophilia factor B Serine protease
X Stuart-Prower factor Serine protease
XI Plasma thromboplastin antecedent Serine protease
XIII Fibrin-stabilizing factor Ca2+-dep transglutaminase
Regulatory factors
Thrombomodulin endothelial cell receptor, binds thrombin
Protein C activated by thrombomodulin-bound thrombin; serine protease
Protein S cofactor; binds activated protein C

12. Crosslink fibrin monomers
1. Fibrin molecules cross link to form hard clot:
Thrombin forms Factor XIIIa
Factor XIIIa catalyzes transamidation reaction (Gln-Lys)
3D mesh of fibrin fibers traps platelets, cells
Factor XIIIa is only enzyme that is not a serine protease
Fig. 4

13. g-carboxyglutamate in clotting factors
Vitamin K is critical for clotting:
Coenzyme for g-carboxyglutamate
Modified residues on clotting proteases, done in liver
Proteases bind platelets through the Ca2+ and PL-
Assembly of factors, enzymes on
complexes speeds up cascade
Warfarin, rat poison, inhibits
carboxylase, resembles VitK
Fig. 5

14. Regulation of blood clotting
Thrombin has prothrombotic role: (Fig. 3)
Feedback amplification
Stimulates its own formation by activating factors V, VII, XI
Activates platelet aggregation, release factor VIII from vWF,
Thrombin has antithrombotic role:
Binds thrombomodulin, abolishes function of thrombin
protein C and cofactor protein S form activated protein C (APC)
Destroy factors Va, VIIIa
Fig. 6

15. Serpins: Serine protease inhibitors:
Natural products ~10% of plasma proteins
Each has reactive site like substrate, binds enzyme
Antithrombin III (AT III) inactivates Thrombin
Heparin (glycosaminoglycan) binds ATIII, allosteric enhance
ATIII-heparin also inactivates XIIIa, Xa, IXa, Xa proteases
ATT III + heparin

16. Plasmin degrades clot – highly regulated process:
Plasmin is serine protease, from plasminogen
APC releases tPA from tissues (plasminogen activator)
APC inactivates inhibitor of t-PA (PAI-I)
Scu-PA is single-chain urokinase, can degrade fibrin
Streptokinase binds plasminogen, allosteric modifier so that plasmin is formed
Circulating a-antiplasmin
blocks soluble plasmin in blood
T-PA and streptokinase treat
Myocardial infarction
Fig. 7

17. Plasma contains water, nutrients, hormones, electrolytes, proteins
Key concepts
Key concepts:
Plasma contains water, nutrients, hormones, electrolytes, proteins
Plasma proteins provide osmotic pressure for fluid balance
Plasma proteins and platelets maintain integrity of circulatory system
Clot formation is carefully regulated process to prevent overclotting (thrombosis) or underclotting (bleeding)
Hemophilia A is lack of Factor VIII
heparin, warfarin inhibit clotting; tPA dissolves

18. Review question: Review question
3. A recent surgery patient receiving warfarin therapy was found to be bleeding internally. The clotting process is impaired in this patient because of which of the following?
Inability of the liver to synthesize clotting factors
Specific inhibition of factor XIII activation
Inability to form clotting factor complexes on membranes.
Reduction of plasma calcium levels
Enhancement of protein C activity