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2224 Part XII: Hemostasis and Thrombosis Chapter 130: Hereditary Thrombophilia 2225

and female carriers, suggesting another evolutionary benefit. 51–53 The TABLE 130–2. Acquired Conditions That Can Yield
mechanism for this increased fertility is unknown.
False-Positive Thrombophilia Test Results
Prothrombin G20210A Acquired Conditions That Can
The prothrombin G20210A mutation was discovered in 1996 by genetic Test Cause Abnormal Test Results
analysis of the prothrombin gene in families with a strong tendency of Increased activated protein Pregnancy, use of oral contracep-
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VTE and confirmed in a case-control study of patients with VTE. The C (APC) resistance tives, stroke, presence of lupus
mutation is located in the 3′-untranslated region of the prothrombin anticoagulant, increased factor
gene and augments translation and stability of prothrombin messen- VIII levels, autoantibodies against
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ger RNA. This leads to an average 32 percent higher blood levels of APC
the zymogen prothrombin that is structurally identical to the protein Factor V Leiden —
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produced by patients with the wild-type gene. In unselected patients Prothrombin G20210A —
with VTE, the prevalence of prothrombin G20210A is approximately 6
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percent. Like factor V Leiden, the prothrombin G20210A mutation is Hyperhomocysteinemia Deficiencies of folate (vitamin B ),
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found largely in whites and genetic linkage disequilibrium studies date vitamin B , or vitamin B , old age,
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6
the mutation back to 24,000 years ago. 47,56 Within Europe, the prevalence renal failure, excessive consump-
of the mutation increases from 3 to 5 percent in Southern Europe and tion of coffee, smoking
the Middle East to 1 to 2 percent in Northern Europe, which opposes Increased factor VIII levels Pregnancy, use of oral contracep-
the observed geographical gradient of factor V Leiden. 56 tives, exercise, stress, older age,
acute phase response, liver dis-
Increased Levels of Factor VIII ease, hyperthyroidism, cancer
Most of coagulation FVIII circulates in complex with VWF. Therefore, Decreased level of Liver disease, use of vitamin
determinants of VWF, including ABO-blood group and endothelial protein C K antagonist (VKA), vitamin
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stimulation, indirectly also determine FVIII levels. Furthermore, K deficiency, childhood, dissemi-
many other factors have been associated with high FVIII levels, nated intravascular coagulation,
including increasing age, high body mass index, diabetes mellitus, and presence of autoantibodies
against protein C
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hypertriglyceridemia. High FVIII levels are part of acute phase reac-
tions and sustained increases are observed during pregnancy, surgery, Decreased level of Liver disease, use of VKA, vitamin
chronic inflammation, malignancy, liver disease, hyperthyroidism, free protein S K deficiency, pregnancy, use of
renal disease. In most of these conditions, there is a concordant increase oral contraceptives, nephrotic
of FVIII and VWF levels. Apart from ABO blood group, the genetic syndrome, childhood, presence
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of autoantibodies against protein
causes of high FVIII levels are largely unknown. Nevertheless, persis- S, disseminated intravascular
tence over time and familial clustering of high FVIII levels in patients coagulation
with VTE implies that genetic factors are prevalent. In a family study of
consecutive patients with persistently elevated levels of FVIII of at least Decreased level of Use of heparin, thrombosis,
150 percent and venous or arterial thrombosis, the prevalence of high antithrombin disseminated intravascular coag-
ulation, liver disease, nephrotic
FVIII in first degree family members was 40 percent, which is almost in syndrome
the range to what one would expect from an autosomal dominant inher-
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itance. Despite the uncertainty about the mechanisms of high FVIII
levels, the association between high FVIII levels and venous thrombosis methylenetetrahydrofolate reductase (MTHFR), c.C677T, leads to an
is well established. The very clear dose-dependent relationship between alanine to valine substitution at position 222 resulting in a variant enzyme
FVIII levels and the risk of VTE suggests that elevated FVIII is causative with reduced activity and increased thermolability. Homozygosity for this
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for thrombosis. Interestingly, increased FVIII levels in patients with polymorphism leads to 24 percent increased homocysteine levels and is
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VTE are usually not influenced by acute-phase reactions. The preva- the most common genetic cause of mild hyperhomocysteinemia. The
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lence of elevated FVIII levels is high: 25 percent of patients with a first prevalence is 10 to 20 percent in whites and 10 percent in Orientals, but
episode of deep-vein thrombosis and 11 percent of healthy control sub- it is rare in Africans. Many other conditions are associated with hyper-
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jects have FVIII levels of 150 percent or higher. Hence, an increased homocysteinemia, including renal failure, hypothyroidism, smoking,
level of FVIII is the most common familial, albeit not monogenetic, excessive coffee consumption, inflammatory bowel disease, psoriasis,
thrombophilia with an estimated population attributable risk of 15 per- and rheumatoid arthritis. Severe hyperhomocysteinemia (plasma levels
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cent. Whether measurement of FVIII levels should be part of a heredi- exceeding 100 μmol/L), also named homocystinuria, is a rare autosomal
tary thrombophilia panel is debatable as FVIII levels may be transiently recessive disorder clearly associated with vascular occlusive disease.
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increased by a multitude of external factors including the acute VTE Because of this association, mildly increased levels (exceeding the 95th
episode itself (Table 130–2). This leads to a significant proportion of percentile of the normal population) were studied as a risk factor for
"false-positive" test results, a necessity for repeat testing, and potentially venous and arterial thrombosis. In the Leiden Thrombophilia Study mild
unnecessary concern among tested patients. hyperhomocysteinemia was associated with a 2.5-fold increased risk of
first VTE. Interestingly, the association of homocysteine levels with
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Mild Hyperhomocysteinemia VTE was stronger in men than in women and increased with age. The
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Homocysteine is an intermediate in the metabolism of the amino acids mechanism by which hyperhomocysteinemia would lead to thrombosis
methionine and cysteine and participates in several metabolic path- is unknown. A 2005 meta-analysis that included more than 50 studies
ways. Some of the enzymes involved in homocysteine metabolism with more than 8000 cases of VTE confirmed the association of VTE
are dependent on vitamin B , folic acid, and vitamin B , and deficien- with hyperhomocysteinemia and also demonstrated a 20 percent higher
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6
cies lead to hyperhomocysteinemia. A polymorphism in the enzyme VTE risk in MTHFR 677TT carriers compared with 677CC carriers.
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