SUPPLEMENTAL HANDOUTS IN PHYSIOLOGY

HEMOSTASIS & BLOOD COAGULATION

CLOTTING FACTORS
-almost all (except a few) are formed by the liver; diseases of the liver (hepatitis, cirrhosis & yellow
atrophy w/c is caused by degeneration of the liver by toxins, infections or other agents) can depress the
clotting system causing a tendency to bleed
CLOTTING FACTOR SYNONYMS
FIBRINOGEN FACTOR I
PROTHROMBIN FACTOR II
TISSUE FACTOR FACTOR III OR TISUE THROMBOPLASTIN
CALCIUM FACTOR IV
FACTOR V PROACCELERIN; LABILE FACTOR; Ac GLOBULIN
FACTOR VII SERUM PROTHROMBIN CONVERSION ACCELERATOR (SPCA);
PROCONVERTIN; STABLE FACTOR
FACTOR VIII ANTIHEMOPHILIC FACTOR (AHF); ANTIHEMOPHILIC FACTOR
GLOBULIN (AHG); ANTIHEMOPHILIC FACTOR A
FACTOR IX PLASMA THROMBOPLASTIN COMPONENT (PTC); CHRISTMAS
FACTOR; ANTIHEMOPHILIC FACTOR B
FACTOR X STUART FACTOR; STUART-PROWER FACTOR
FACTOR XI PLASMA THROMBOPLASTIN ANTECEDENT (PTA);
ANTIHEMOPHILIC FACTOR C
FACTOR XII HAGEMAN FACTOR
PREKALLIKREIN FLETCHER FACTOR
HIGH MOLECULAR WEIGHT FITZGERALD FACTOR; HMWK (HIGH MOLECULAR-WEIGHT
KINONOGEN KININOGEN
PLATELETS

3 ESSENTIAL STEPS
1.FORMATION OF PROTHROMBIN ACTIVATOR
-formed upon damage to blood vessel or special substances in the blood
2.CONVERSION OF PROTHROMBIN INTO THROMBIN
-by prothrombin activator in the presence of sufficient amounts of calcium ions
3.CONVERSION OF FIBRINOGEN TO FIBRIN (BY THROMBIN)
-by thrombin

PROTHROMBIN
-an alpha 2 globulin (plasma protein)
-unstable & can easily split into smaller compounds, like thrombin
-source: liver (failure to produce prothrombin leads to provide normal blood coagulation)
-normal activation requires the presence of vitamin K (also required for activation of other blood clotting
factors; lack of vitamin K leads to the development of bleeding tendency)

THROMBIN
-protein enzyme w/ weak proteolytic activity
-removes 4 low-molecular weight peptides from each molecule of fibrinogen to form one fibrin
monomer; fibrin monomer molecules polymerize with other monomer to form fibrin fibers & form the
reticulum of the blood clot

FIBRINOGEN
-high molecular weight (MW=340,000)
-formed in the liver (failure leads to low levels of prothrombin & fibrinogen)
-large molecular size makes it unable to leak into interstitial fluids; interstitial fluids do not normally
coagulate; pathologic increase in capillary permeability causes fibrinogen to leak into tissue fluid results
to clotting of fluids

FIBRIN-STABILIZING FACTOR
-present in small amounts in normal plasma globulins; also released from platelets entrapped in the clot
-strengthens the fibrin reticulum (which is initially weak & can be easily broken apart)
-activated by thrombin (that also causes fibrin formation); acts as an enzyme causing the formation of
covalent bonds among the fibrin monomers & multiple cross-linkages between adjacent fibrin fiber
providing three-dimensional strength to the blood clot
CLOT RETRACTION
-blood clot contracts within a few minutes after formation expressing fluid (serum; all fibrinogen & blood
clotting factors are removed; serum does not clot)
-platelets play an important role by:
1.attaching to fibrin fibers bonding them together
2.releasing procoagulants (fibrin-stabilizing factor) causing formation of more cross-linking bonds
between adjacent fibers
3.DIRECTLY activating platelet thrombosthenin, actin & myosin molecules (contractile proteins w/c
causes contraction of platelet spicules to help compress the fibrin meshwork into a smaller mass)
-contraction activated & accelerated by thrombin & calcium ions (released from residuals in platelet
endoplasmic reticulum & golgi complex)

INTRAVASCULAR ANTICOAGULANTS THAT PREVENT BLOOD CLOTTING IN THE NORMAL VASCULAR

SYSTEM
-most important factors for preventing clotting in the normal vascular system:
1.Smoothness of the endothelial cell surface – prevents contact activation of the intrinsic clotting system
2.Layer of glycocalyx on the endothelium - repels clotting factors and platelets, thus preventing
activation of clotting-
3.A protein bound with the endothelial membrane, thrombomodulin – binds thombin; slows the clotting
process by removing thrombin; thrombomodulin-thrombin complex activates a plasma protein, protein
C, that acts as an anticoagulant (by inactivating activated Factors V & VIII)

ANTITHROMBIN ACTION OF FIBRIN AND ANTITHROMBIN III

-powerful anticoagulants that remove thrombin from the blood preventing the development of
thromboembolism:
1.Fibrin fibers – formed during the clotting process
2.Antithrombin III or antithrombin-heparin cofactor – an alpha-globulin
-as a clot is formed, 85-90% of thrombin formed from prothrombin becomes adsorbed to the fibrin
fibers as they develop; helps prevent the spread of thrombin into the remaining blood & prevents
excessive spread of the clot
-thrombin that does not adsorb to the fibrin fibers combines with antithrombin II which blocks the effect
of thrombin on the fibrinogen & inactivates the thrombin itself

HEPARIN
-a powerful anticoagulant with normally low concentration in the blood; significant anticoagulant effects
occur only under special physiologic conditions
-widely used as a drug in higher concentrations to prevent intravascular clotting
-molecule has a highly negatively charged conjugated polysaccharide with little or nor anticoagulant
properties; when combines with antithrombin III, the effectiveness of the latter for removing thrombin
increases hundredfold to a thousandfold, thus acting as an anticoagulant; in the presence of excess
heparin, removal of free thrombin from the circulating blood by antithrombin III becomes instantaneous
-heparin-antithrombin III complex: removes activated Factors XII, XI, X and XI in addition to thrombin

PLASMIN: CAUSES LYSIS OF BLOOD CLOTS

-plasminogen (profibrinolysin; a plasma protein containing a euglobulin) when activated, becomes
plasmin (fibrinolysin)
-plasmin: a proteolytic enzyme digests fibrin fibers & some protein coagulants (fibrinogen, Factor V,
Factor VIII, prothrombin and Factor XII; when formed, cause lysis of a clot by destroying many of the
clotting factors

ACTIVATION OF PLASMINOGEN TO PLASMIN

-Tissue Plasminogen Activator (t-PA): release from injured tissues & vascular endothelium; a powerful
activator of plasminogen which is converted to plasmin
-Plasmin: removes remaining unnecessary blood clot; removes minute clots from tiny peripheral vessels
that might be occluded by them

CONDITIONS CAUSING EXCESSIVE BLEEDING IN HUMANS

1.Vitamin K deficiency
2.Hemophilia
3.Thrombocytopenia
Vitamin K deficiency
-Vitamin K: synthesized in the intestinal tract by bacteria; essential factor to a liver carboxylase that adds
a carboxyl group to glutamic acid residues on 5 important clotting factors (prothrombin, Factor VII,
Factor IX, Factor X & protein C); absence of vitamin K causes insufficiency of these factors leading to
serious bleeding tendencies
-causes of deficiency:
1.Neonates – before they establish their intestinal bacterial flora
2.Gastrointestinal diseases – due to poor absorption of fats (because the vitamin is fat soluble; absorbed
w/fats into the blood)
3.Failure of the liver to secrete bile into the GIT (obstruction of the bile ducts or as a result of liver
diseases; lack of bile prevents adequate absorption & digestion of fats & depresses vitamin K absorption)

Warfarin
-oral anticoagulant which inhibits vitamin K epoxide reductase (VKOR c1 w/c converts the inactive
oxidized from of vitamin K to its active, reduced form); decreases the available active form of vitamin K in
tissues; amounts of active prothrombin, & Factors VII, IX and X, all formed in the liver, begin to fall

Hemophilia
-bleeding disease exclusive among males; transmitted by female chromosome (mother is carrier &
transmits the disease to half of male offspring); patient experiences prolonged severe bleeding
-85% of cases: abnormality or deficiency of Factor VIII (Hemophilia A or Classic Hemophilia)
(15% of cases: abnormality or deficiency of Factor IX) (Hemophilia B)
-bleeding does not usually occur except after trauma; bleeding lasts for days after tooth extraction
-Factor VIII has 2 active components: large (MW=millions) & small (MW=230,000); small component is
most important in intrinsic pathway for clotting; deficiency of this causes classic hemophilia; loss of large
component causes Von Willebrand Disease
-treatment: Injection of purified factor VIII (or recombinant Factor VIII)

Thrombocytopenia
-presence of very low platelet count; tendency to bleed from many small venules or capillaries (vs.
Hemophilia where bleeding comes from larger vessels
-presents w/small punctate hemorrhages throughout all the body tissues; skin w/many small, purplish
blotches (thrombocytopenic purpura)
-bleeding occurs when platelets fall below 50,000 ul; levels as low as 10,000 are fatal
-some cases have unknown etiology (Idiopathic Thrombocytopenia)
-treatment: fresh whole blood transfusion (w/large number of platelets); splenectomy may be helpful

THROMBOEMBOLIC CONDITIONS
-THROMBUS: an abnormal clot that develops in a blood vessel
-EMBOLUS: freely moving clot in circulation resulting from breaking away from attachment
-emboli originating in large arteries or in the left side of the heart: flow peripherally & plug arteries or
arterioles in the brain, kidneys or elsewhere
-emboli that originate in the venous system or in the right side of the heart generally flow into the lungs
to cause pulmonary arterial embolism
-causes of thromboembolic conditions:
1.a roughened endothelial surface of a vessel (caused by arteriosclerosis, infection or trauma)
2.blood often clots when it flows very slowly through blood vessels where small quantities of thrombin
& other procoagulants are formed
-treament: administration of genetically engineered t-PA (tissue plasminogen activator)

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