Journal of Medicine Vol 2 - Amrita Institute of Medical Sciences and ...

Amrita Journal of Medicine
Hypercoagulable States
thrombin enzymatic active site. The rate of thrombin inhibition
by Antithrombin III is increased markedly by
glycosaminoglycans (e.g. heparin).
Familial reductions in plasma Antithrombin III, Protein
C, or Protein S activity due to either reduced plasma
protein levels (i.e. altered protein expression), or normal
levels of a dysfunctional protein (i.e. altered protein structure),
are strongly associated with deep vein thrombosis
and pulmonary embolism (venous thromboembolism),
and validate the important role of these proteins in the
natural anticoagulant system.
Our understanding of these mechanisms continues to
evolve as new genetic abnormalities are defined and new
anticoagulant pathways are discovered.
ANTITHROMBIN, PROTEIN C, AND
PROTEIN S
Deficiencies of Antithrombin, Protein C, and Protein
S are inherited in an autosomal dominant pattern. All
three generally present with a first episode of thrombosis
between the ages of 10 and 50 years.
Adults with heterozygous Protein C or Protein S deficiency
may experience skin necrosis shortly after starting
warfarin therapy without concomitant heparin therapy.
Both Protein C and Protein S are vitamin K-dependent
cofactors whose levels may drop precipitously after initiation
of warfarin, leading to transient hypercoagulation.
Several acquired conditions, including liver disease and
disseminated intravascular coagulation, can lead to decreased
activity of Protein C and Protein S. A decreased
Protein S level has also been specifically noted to occur
with pregnancy, oral contraceptive use, and the nephrotic
syndrome.
Acquired Antithrombin deficiency is seen with liver
disease, oral contraceptive use, the nephrotic syndrome,
pregnancy, and disseminated intravascular coagulation.
FACTOR V LEIDEN
APC resistance is most commonly due to a point
mutation in the gene encoding factor V. Factor V Leiden
is the single most common inherited thrombophilic defect.
Heterozygosity for factor V Leiden mutation imparts
a sevenfold increased lifetime risk of venous thromboembolism,
whereas homozygous expression confers an
80-fold increased risk.
Although Antithrombin, Protein S, and Protein C deficiencies
usually present with thrombosis relatively early
in life, the risk of thrombosis due to factor V Leiden increases
with age. Coinheritance of other thrombophilic
mutations, such as Protein C deficiency, Prothrombin
20210, or Hyperhomocystinemia, further increases thrombotic
risk.
PROTHROMBIN 20210
Prothrombin 20210 is an autosomal dominant inherited
defect. Prothrombin 20210 confers a weaker
thrombotic risk (about threefold) than factor V Leiden 1,2 .
Coinheritance of both Factor V Leiden and Prothrombin
20210 compounds the risk of venous thromboembolism,
pregnancy-associated venous thromboembolism, and recurrent
venous thromboembolism.
Table 2: Unusual Venous Thrombotic Presentations of Certain Hypercoagulable States
VTE Presentation
Cerebral vein thrombosis
Cerebral vein thrombosis in women using oral contraceptive
pills
Inferior vena cava, renal vein, mesenteric vein, portal and
hepatic vein thrombosis
Migratory superficial thrombophlebitis (Trousseau’s syndrome)
Recurrent superficial thrombophlebitis
Warfarin skin necrosis
Neonatal purpura fulminans
Unexplained fetal loss (three or more first-trimester
miscarriages or one second- or third-trimester unexplained
death of a morphologically normal fetus)
Hypercoagulable Condition
Prothrombin G20210A, Antiphospholipid antibodies,
Antithrombin deficiency, Essential Thrombocythemia,
Paroxysmal Nocturnal Hemoglobinuria
Prothrombin G20210A
Antiphospholipid antibodies, Cancer, Antithrombin deficiency,
Myeloproliferative syndromes, Paroxysmal
Nocturnal Hemoglobinuria
Cancer (particularly adenocarcinoma of the gastrointestinal
tract)
Factor V Leiden, Polycythemia Vera, Deficiencies of natural
anticoagulants
Protein C and Protein S deficiencies
Homozygous Protein C and Protein S deficiencies
Antiphospholipid antibodies
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