Polygenic Contributions of Procoagulant Genetic Factors in
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.

Genetics in Medicine, May, 2002, (in press)