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Thrombophilia
Nontapak Thiangpak
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Outline Introduction
Anticoagulant mechanisms
Antithrombin deficiency
Protein C Anticoagulant Pathway Protein C deficiency Protein S
deficiency Discovery of APC resistance/FV Leiden Identification of
a prothrombin mutation
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Introduction Genetic and circumstantial risk factors
affecting
one or more of the 3 categories of Virchowstriad.
Circumstantial factors; Increasing age. Immobilization.
Surgery.
Pregnancy.OCP.
Hormone replacement.
Inflammatory conditions.
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Introduction Most common is thrombosis in the lower
limbs. Genetic risk factors affect the natural
anticoagulant mechanisms; imbalancebetween procoagulant and
anticoagulant.
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Multiple anticoagulant
mechanisms controlblood coagulation
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Anticoagulant Mechanisms Tissue factor pathway inhibitor (TFPI);
binds and
inhibits newly formed FXa that is associated with
the TF-FVIIa complex.
The activated coagulation enzymes can all beinhibited by the
circulating serine proteaseinhibitor (serpin) antithrombin
(AT).
Regulation of the 2 cofactors FVIIIa and FVa bythe protein C
(PC) anticoagulant system.
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Antithrombin
deficiency
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Antithrombin deficiency As early as 1905, Morawitz proposed
the
concept of antithrombin. 1963 an assay for AT in plasma was
presented. 1965 Egeberg reported the presence of
AT deficiency in a family.
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Antithrombin deficiency AT is a multifunctional serpin,
inhibiting
essentially all the active enzymes of the
coagulation pathway.
AT is a slow inhibitor, but the heparansulfate (HS) family of
glycosaminoglycanspresent on intact endothelium stimulatesits
inhibitory activity.
The AT-binding region in heparin has beenlocalized to a
pentasaccharide sequence.
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Antithrombin deficiency No case of type I homozygous AT
deficiency has been described. There have been several type
II
homozygotes described with mutations inthe heparin-binding
region ofAT.
Heterozygous type I AT deficiency isrelatively rare in the
general population;10-fold increased risk of thrombosis.
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Protein C
AnticoagulantPathway
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Protein C anticoagulant pathway Protein C was isolated and
identified as a
vitamin Kdependent protein by Stenflo in 1976.
Anticoagulant properties after its activation bythrombin.
Thrombin itself is a poor activator of protein C.
Thrombomodulin (TM) as a cofactor for thereaction discovery by
Owen and Esmon in 1981.
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Protein C anticoagulant pathway TM is present on the surface of
endothelial cells. Thrombin binds with high affinity to TM. Loss of
the procoagulant activities of thrombin
and gain of the ability to activate protein C. Concentration of
TM in the microcirculation is
crucial for local protein C activation.
In recent years, an endothelial cell protein Creceptor (EPCR)
has been identified.
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Protein C anticoagulant pathway APC inhibits the coagulation
pathway by
specifically cleaving of peptide bonds in
FVIIIa and FVa. APC is slowly inhibited by either the
protein C inhibitor (PCI) or by 1-
antitrypsin.
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Protein C anticoagulant pathway Soon after the report on protein
C,
DiScipio discovered protein S. Walker showed that protein S
functions as
a cofactor to APC. 2 forms in plasma; free protein S
(30-40%)
complex with C4b-binding protein (C4BP). Free protein S serves
as an APC cofactor. Bound protein S provide local control of
complement system activation.
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Protein C anticoagulant pathway FVIIIa and FVa are both highly
sensitive to
APC. The activity of APC is stimulated by
protein S.
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Protein C deficiency
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Protein C deficiency In 1981, Griffin et al were the first to
describe
heterozygous protein C deficiency in a familywith a history of
recurring thrombosis.
Homozygous protein C deficiency was found tobe associated with
severe neonatal purpurafulminans.
Type I deficiency; decreased proteinconcentration. Type II
deficiency; normal protein C
concentration, low protein C activity.
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Protein C deficiency Protein C deficiency was found slightly
more often than AT deficiency, but still in
less than 5%.
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Protein S deficiency In 1984, the first thrombosis patients
with
protein S deficiency were described. Type I; free and total
protein S levels were
low. Type II;functional deficiency. Type III; only the free form
was low.
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Discovery of APC
resistance/FV Leiden
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Discovery of APC resistance In studies of thrombosis cohorts
performed
during the 1980s, Deficiencies of AT, protein C, and protein
S were identified in lessthan 10%.
Even though positive family histories were
present in up to 40% of the cases.
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Identification of
a prothrombinmutation
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Prothrombin mutation The mutation is located in the 3
untranslated region of the prothrombin
gene; does not change the structure ofprothrombin.
Slightly increased plasma levels of
prothrombin, a lifelong 3-to 4-foldincreased risk of venous
thrombosis.
