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Protein C
 Protein C is a major physiological
anticoagulant.
 It is a vitamin K-dependent serine protease
enzyme, that is activated by thrombin into
activated protein C (APC).
 The activated form (with protein S and
phospholipid as a cofactor) degrades Factor
Va and Factor VIIIa.
 The protein C pathway’s key enzyme,
activated protein C, provides physiologic
antithrombotic activity and exhibits both antiinflammatory.
Role in disease
The Protein C Anticoagulant
Pathway:
 Thrombin escaping from a site of vascular injury
binds to its receptor thrombomodulin (TM) on the
intact cell surface.
 As a result, thrombin loses its procoagulant
properties and instead becomes a potent activator of
protein C.
 Activated protein C (APC) functions as a circulating
anticoagulant, which specifically degrades and
inactivates the phospholipid-bound factors Va and
VIIIa.
 This effectively down-regulates the coagulation
cascade and limits clot formation to sites of vascular
injury.
Protein C deficiency
 Protein C deficiency is a rare genetic feature
that predisposes to venous thrombosis and
habitual abortion.
 The disease belongs to a group of genetic
disorders know as thrombophilias.
 Activated protein C resistance is the inability
of protein C to cleave factors V and/or VIII.
 This may be hereditary or acquired.
Pathophysiology
 The main function of protein C is its
anticoagulant property as an inhibitor of
coagulation factors V and VIII.
 There are two main types of protein C
mutations that lead to protein C deficiency:
 Type I: Quantitative
 Type II: Qualitative
Protein S.
 Protein S is a vitamin K-dependent
plasma glycoprotein synthesized in the
liver.
 In the circulation, Protein S exists in
two forms: a free form and a complex
form bound to complement protein C4b
Function
 The best characterized function of Protein S is
its role in the anti coagulation pathway, it
functions as a cofactor to Protein C in the
inactivation of Factors Va and VIIIa.
 Only the free form has cofactor activity.
 The property of Protein S enhances the
phagocytosis of the apoptotic cell, allowing it to
be removed 'cleanly' without any symptoms of
tissue damage such as inflammation occurring.
Protein S deficiency
 Protein S deficiency is a disorder
associated with increased risk of venous
thrombosis.
 Decreased (antigen) levels or impaired
function (activity) of protein S, leads to
decreased degradation of factor Va and
factor VIIIa and an increased tendency to
venous thrombosis.
Type of Protein S deficiency:
1. Hereditary
2. Acquired
Protein S deficiency can also be acquired due to :
 Vitamin K deficiency or Treatment with warfarin
which generally also impairs the coagulation
system itself (factors II, VII, IX and X), and
therefore predisposes to bleeding rather than
thrombosis.
 Systemic sex hormone therapy and pregnancy
 Liver disease and certain chronic infections (for
example HIV).
Some characteristics of protein C
system components.
component
Plasma
concentration
Half-life
(hours)
Further
information
Protein C
4 (µg/ml)
6
Neutralizes Va and
VIIIa, enhances
fibrinolysis,
Thrombomodulin
0 (µg/ml) *
?
Potentiates action
of thrombin on
protein C
Protein S
35 (µg/ml)
?
Promotes protein C
binding to
platelets
phospholipids
Activated protein C
inhibitor
5 (µg/ml)
?
Inhibits protein C
C4B- binding protein
160 (µg/ml)
?
Binds protein S in
an inactive
form.
Factor V Leiden mutation
 Factor V Leiden (sometimes Factor
VLeiden) is the name given to a variant of
human factor V that causes a
hypercoagulability disorder.
 In this disorder the Leiden variant of factor
V, cannot be inactivated by activated protein
C.
Pathophysiology
 In the normal person, factor V functions as a
cofactor to allow factor X to activate an enzyme
called thrombin. Thrombin in turn cleaves
fibrinogen to fibrin, which polymerizes to form the
dense meshwork that makes up the majority of a
clot.
 Activated protein C (aPC) is a natural
anticoagulant that acts to limit the extent of
clotting by cleaving and degrading factor V.
 Such mutation makes factor V less suseptable to
cleavage by APC.
 Factor V Leiden is a condition in which the
coagulation factor cannot be destroyed by
aPC.
 When factor V remains active, it facilitates
overproduction of thrombin leading to
excess fibrin generation and excess clotting.
 The excessive clotting that occurs in this
disorder is almost always restricted to the
veins, where the clotting may cause a deep
vein thrombosis (DVT).
 It is also known as protein C-resistance
(APC-R)
This will lead to many problems, such as:
 Women with the disorder have an increased
risk of miscarriage stillbirth, as well as
preeclampsia due to clotting in the placenta,
umbilical cord, or the fetus.
 Patients with vein thrombosis have this
condition.
Diagnosis
 Suspicion of factor V Leiden being the cause for
any thrombotic event should be considered in any
white patient below the age of 45, or in any person
with a family history of venous thrombosis.
 This disease can be diagnosed by watching the
aPTT as activated protein C is added. With a
normal patient, adding APC increases the aPTT. In
patients with factor V Leiden, adding APC to
plasma of Factor V leiden will fail to prolong APTT.
 There is also a simple genetic test that can be
done for this disorder, and will give a quick
diagnosis.
Antithrombin (AT) deficiency
 Antithrombin (AT) is a small protein
molecule that inactivates several enzymes
of the coagulation system.
 It is a glycoprotein produced by the liver and
consists of 432 amino acids, and contains
three disulfide bonds.
Function
 The physiological target of antithrombin are
those of the contact activation pathway
(formerly known as the intrinsic pathway),
namely the activated forms of Factor X (Xa),
Factor IX (IXa), Factor XI (XIa), Factor XII
(XIIa) and Factor II (thrombin) (IIa) and also
the activated form of Factor VII (VIIa) from
the tissue factor pathway (formerly known
as the extrinsic pathway)
Pathology:
 Inherited.
 Causes recurrent venous thrombosis,
occasionally causes arterial thrombosis.
 AT concentrate are available and are used
to prevent thrombosis during surgery or
childbirth.
 The disease leads to increased prothrombin
levels.
Hyperhomocysteinemia
 Definition: An amino acid produced by the body,
derived from the digestion of protein-rich foods.
 Homocystein is derived from dietary methionin and
is metabolized either by the remethylation or the
trans-sulphuration pathways.
 As a consequence of the biochemical reactions in
which homocysteine is involved, deficiencies of
the vitamins folic acid, pyridoxine (B6), or B12
(which use as cofactors) can lead to high
homocysteine levels.
 Supplementation with folic acid or B12
reduces the concentration of homocysteine
in the bloodstream.
 Normal fasting homocysteine plasma levels
are between 5,0 and 15,9 mmol/l.
 Hyperhomocysteinemia is a medical
condition characterized by an abnormally
large level of homocysteine in the blood.
Classical Hyperhomocysteinemia
Is a rare autosomal recessive disorder
but it can also be acquired
 Vascular disease and thrombosis are
major features of the disease.
 Higher levels are associated with
increased risk of both venous and
arterial thrombosis.
Acquired risk factors:
-Decreased folate levels.
– Decreased vitamin B12 levels.
– Decreased vitamin B6 levels.
– Drugs (e.g. cyclosporine).
– Renal damage.
– Smoking.
– The risk is increased with age and it is higher in
men and menopausal women.