Polygenic Contributions of
Procoagulant Genetic Factors in
and D. Berg2.
U of Arizona College of Medicine1,
and HEMEX Labs2,
Chronic Fatigue Syndrome and Related Chronic Illnesses.
Hypercoagulability due to
thrombophilic and hypofibrinolytic genetic factors is commonly
evaluated in the context of thromboembolic disease, cardiac,
and/or gynecologic/obstetric risks. We have recently discovered
low level activation of coagulation in patients with active
Chronic Fatigue Syndrome and/or Fibromyalgia (CFS/FM) [Ref:
Blood Coag Fibrinol 10:435-438] and have also found an
association of CFS with increased defects in thrombophilia and
hypofibrinolytic activities [AJHG Suppl 69:564]. We postulate
that such procoagulant genetic defects may be predispositional
in individuals who become ill. These early studies were done in
well-defined, yet limited cohorts with sample sizes too small to
statistically evaluate whether there was a significant additive
or polygenic contribution if more than one marker was
positive. To approach the latter question, we have analyzed a
database of 582 adults screened for suspected CFS/FM or related
chronic illness over the past 2 years. We used the ISAC panel
of tests (fibrinogen, prothrombin fragment 1+2, thrombin-antithrombin
complexes, soluble fibrin monomer, and platelet surface P-selectin)
for measuring low-level activation of coagulation. For
Hereditary Thrombotic Risk Panel (HTRP) data, we analyzed seven
markers with known Mendelian characteristics: antithrombin,
protein C, protein S, activated protein C resistance (APCR),
prothrombin (F2), lipoprotein Lp(a), and plasminogen activator
inhibitor-1 (PAI-1). The cohort was stratified by ISAC outcomes
and HTRP score (one point for each positive genetic factor).
461 patients (72%) had positive ISAC results; 404 (69%) were
positive for one or more HTRP markers and all marker positivity
rates were increased over general population values. HTRP
abnormality rate increases were seen as a function of ISAC
number up to 81% HTRP-positivity with 4 ISAC results positive.
Stepwise increments in abnormality rates were evident for APCR
(to 0.155), F2 levels (to 0.512), and PAI-1 levels (to 0.241).
Lp(a), a potent hypofibrinolytic protein, was increased in more
than 30% of all patients regardless of ISAC score. The genetic
correlation of the positive predictive value / likelihood ratio
for HTRP score to ISAC-positivity shows that a patient with an
HTRP score of 2 or more is 3.5 times more likely to be ISAC-positive
than someone with an HTRP score of 0 or 1. These data support
the hypothesis of genetic contribution(s) to CFS/FM and are
consistent with family histories. CFS/FM and related chronic
illnesses are disabling and yield significant lost work
productivity, medical expenses and disrupted quality of life.
Comprehensive coagulation genetic screening in healthy adults
who are at risk by family history of thromboembolic disease, or
who have had a thrombophilic abnormality discovered through
Factor V Leiden (APCR) screening may be warranted as effective
interventions to prevent or treat CFS/FM become available.
in Medicine, May, 2002, (in press)