Procoagulant Genetic Factors in a Pooled Cohort of 582 Chronic Fatigue Syndrome,
Fibromyalgia and Related Chronic Illness ...
Procoagulant Genetic Factors in a Pooled
Cohort of 582 Chronic Fatigue Syndrome,
   Fibromyalgia and Related Chronic
     ...
CHRONIC FATIGUE SYNDROME
               Coagulation Testing in CFS
New findings indicate that a significant proportion of ...
Low Level Activation of Coagulation in
Chronic Fatigue Syndrome and Fibromyalgia
     Initial Study: Case-Control, Associa...
Low Level Activation of Coagulation in
   Chronic Fatigue Syndrome and Fibromyalgia
  Table 1. ISAC* test results for CFS/...
Low Level Activation of Coagulation in
   Chronic Fatigue Syndrome and Fibromyalgia
                           Conclusions...
Low Level Activation of Coagulation in
Chronic Fatigue Syndrome and Fibromyalgia
             Genetic Influence Hypothesis...
Procoagulant Genetic Factors in CFS/FM
     and Related Chronic Illnesses
Hereditary and Acquired Hypercoagulability State...
Procoagulant Genetic Factors in CFS/FM
     and Related Chronic Illnesses
   7 Procoagulant Genetic Factors Tested
       ...
Low Level Activation of Coagulation in
 Chronic Fatigue Syndrome and Fibromyalgia
       - Genetic Procoagulant Factors
CF...
Procoagulant Genetic Factors in CFS/FM
     and Related Chronic Illnesses
      Present Study: Database Mining
Database of...
Genetic Procoagulant Factors in CFS/FM
          & Related Chronic Illnesses

Hereditary Thrombosis Risk Panel (HTRP) Scor...
Procoagulant Genetic Factors in CFS/FM and Related Chronic Illnesses

                Observed Abnormality Rates
         ...
Genetic Procoagulant Factors in CFS/FM & Related Chronic Illnesses

                    Conclusions (N=582)
1. A concerted...
Multiple Etiologies of Activation
 Viruses- Bacteria -  Yeast -    Vaccine contaminants?
 HHV6,    Mycoplasma, Candida    ...
Procoagulant Genetic Factors in a Pooled Cohort of 582 ...
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Procoagulant Genetic Factors in a Pooled Cohort of 582 ...

  1. 1. Procoagulant Genetic Factors in a Pooled Cohort of 582 Chronic Fatigue Syndrome, Fibromyalgia and Related Chronic Illness Cases1. H. Harrison1,2, C. A. Ryser3, J. Brewer4,5, and D. Berg2. Univ AZ Col of Med1, and HEMEX Labs2, Phoenix, AZ; Health Centers of America3, Plaza Internal Med4, and Univ MO School of Med5, Kansas City, MO. Objectives: Hypercoagulability due to procoagulant (thrombophilic or hypofibrinolytic) genetic factors is commonly evaluated in the context of thromboembolic disease, cardiac, and/or gynecologic/obstetric risks. We have reported 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 in a cohort of patients with HHV6 and CFS. We postulate that such procoagulant genetic defects may be predispositional or permissive in individuals who become chronically ill. These studies were done in well-defined, yet limited cohorts that had sample sizes too small to statistically evaluate whether there was a significant additive or polygenic contribution if more than one marker was positive, and too small to detect enrichment of the less prevalent genetic deficiencies. This study represents the results of “database mining” to achieve a larger N. Methods: We analyzed a database of 582 adults screened for suspected CFS/FM or related chronic illness and whose testing included both the ISAC and HTRP panels of coagulation testing. 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). Results: The cohort was stratified by ISAC scores (one point for each abnormal result) and HTRP scores (one point for each positive genetic factor). 72% (421/582) of patients had positive ISAC results as defined by the criterion of two or more results being abnormal; 69% (404/582) were positive for one or more genetic markers. All marker abnormality rates were increased over general population values. The HTRP abnormality rate increased as a proportionate function of ISAC score 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). Lipoprotein Lp(a), a hypofibrinolytic protein, was increased in more than 30% of all patients regardless of ISAC score. Overall 69.4% of the cohort was positive for one or more of the procoagulant protein markers [gp=20%], 25.4% for two or more [gp=4%], and 4.5% for 3 or more [gp=0.8%]. Analysis of the positive predictive value and likelihood ratios of HTRP score and 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 one with an HTRP score of 1 or less. Conclusions: These data support the general hypothesis of concerted genetic contribution(s) of coagulation protein abnormalities to CFS/FM and are consistent with family histories. The pooled CFS/FM and related chronic illnesses are associated with increased rates of abnormalities for all markers except APCR. CFS patients with normal HTRP results may warrant testing for rarer inheritable thrombopathies. Genetic testing to identify the type of procoagulant defect may be warranted as effective interventions to prevent or treat CFS/FM become available. 1) Oral Presentation, 7th International Biennial Conference on Chronic Fatigue Syndrome, Oct, 2004, Madison, WI, USA – In Press
  2. 2. Procoagulant Genetic Factors in a Pooled Cohort of 582 Chronic Fatigue Syndrome, Fibromyalgia and Related Chronic Illnesses 1 Harold H. Harrison, M.D., Ph.D.*,1,2,, Carol Ann Ryser, M.D.3, Joseph H. Brewer, M.D. 4,5, David E. Berg, M.S 2. University of Arizona College of Medicine 1 and HEMEX Laboratories 2, Phoenix, AZ; Health Centers of America 3, Plaza Internal Medicine 4 and University of Missouri School of Medicine5, Kansas City, MO. 1) AACFS Lecture, Oct, 2004, Madison, WI: In Press *E-mail: Genedoc169@aol.com
  3. 3. CHRONIC FATIGUE SYNDROME Coagulation Testing in CFS New findings indicate that a significant proportion of patients with CFS/FM have a low level, subthrombotic activation of coagulation via immune-mediated APS-like pathophysiology. (Ref: Blood Coag Fibrinol 10: 435-8, 1999.) This Immune System Activation of Coagulation (ISAC) is detected by measuring five assays of plasma proteins and platelet function: 1) Fibrinogen (increased) 2) Prothrombin cleavage fragment 1+2 (F1+2, increased) 3) Thrombin / antithrombin complexes (TAT, increased) 4) Soluble fibrin monomer (SFM, increased) 5) Platelet activation (surface CD62P, increased)
  4. 4. Low Level Activation of Coagulation in Chronic Fatigue Syndrome and Fibromyalgia Initial Study: Case-Control, Associative 1. Patients (54), Controls (23). 2. Patients assigned as CFS by CDC/NIH criteria. 3. Healthy controls matched for age, sex, sample travel. 4. Three clinical sites (Pt / Ctl), N: Rochester, NY (15 pts / 5 ctls, N=20) Houston, TX (19 pts, 8 ctls, N=27) Phoenix, AZ (20 pts, 10 ctls, N=30) Ref: Blood Coag Fibrinol 10: 435-8, 1999.
  5. 5. Low Level Activation of Coagulation in Chronic Fatigue Syndrome and Fibromyalgia Table 1. ISAC* test results for CFS/FM patients and controls Test FIB F1+2 TAT SFM CD62P PA Score 2 or more Ref Range 180-310 mg/dL 0 - 1.1 nmol/L 1.0 - 4.1 ug/L 0 - 17 nmol/L 0 - 27% Normal None A. Controls (N=23) (#Abn / N) 2 / 23 3 / 23 4 / 23 3 / 23 5 / 23 0 / 23 1 / 23 rate 0.087 0.130 0.174 0.130 0.217 0.000 0.043 Mean 280 1.0 1.6 10 17.5 B. Patients (N=54) (#Abn / N) 45 / 54 26 / 54 25 / 54 32 / 54 21 / 54 22 / 54 50 / 54 rate 0.833 0.481 0.463 0.593 0.389 0.407 0.926 Mean 367 1.2 1.6 22 22 P Value <0.001 <0.005 <0.005 <0.001 <0.10 <0.001 <0.001 *ISAC (Immune System Activation of Coagulation) panel includes: fibrinogen (FIB), prothrombin cleavage fragment 1+2 (F1+2), thrombin-antithrombin complexes (TAT), soluble fibrin monomer (SFM), and platelet surface P-selectin (CD62P) before and after stimulation by ADP (PA score). Ref: Blood Coag Fibrinol 10: 435-8, 1999.
  6. 6. Low Level Activation of Coagulation in Chronic Fatigue Syndrome and Fibromyalgia Conclusions 1. Majority of patients (92.6%) with clinically-defined CFS/FM have a low level activation of coagulation. 2. Strongest discriminant for separating patients from controls is “two or more” of 5 test results positive in the ISAC panel. 3. May be a final common pathway of pathogen induction of antiphospholipid antibodies and endothelial activation. 4. Demonstrates organic basis of illness and potential utility of anticoagulation treatment. 5. Hereditary influences of thrombophilia or hypofibrinolysis may predispose or be permissive to activation in CFS/FM. Ref: Blood Coag Fibrinol 10: 435-8, 1999.
  7. 7. Low Level Activation of Coagulation in Chronic Fatigue Syndrome and Fibromyalgia Genetic Influence Hypothesis If procoagulant genetic factors, either thrombophilic or hypofibrinolytic, are permissive or predispositional to low level activation of coagulation in CFS/FM, there should be an increased prevalence of inheritable abnormalities in the patient population as compared with the general population. (Null Hypothesis: There is no difference in inheritable abnormality prevalence rates between CFS/FM patients and the general population.)
  8. 8. Procoagulant Genetic Factors in CFS/FM and Related Chronic Illnesses Hereditary and Acquired Hypercoagulability States Hereditary Antithrombin (fka antithrombin III) Protein C Protein S Prothrombin (Factor II), G20210A polymorphism Activated Protein C Resistance (Factor V Leiden) Lipoprotein (a) Plasminogen Activator Inhibitor 1 (PAI-1) Acquired Antiphospholipid Syndrome & Subgroups CFS / FM
  9. 9. Procoagulant Genetic Factors in CFS/FM and Related Chronic Illnesses 7 Procoagulant Genetic Factors Tested Gen. Pop. Abnl Rates Thrombophilic Antithrombin (AT) 0.02 to 0.5% Protein C (PC) 0.2 to 0.5% Protein S (PS) 0.2 to 0.5% Prothrombin (F2) 2 to 5% Act. Protein C Resistance (APCR) 5 to 7% Hypofibrinolytic Lipoprotein (a) [Lp(a)] 5% Plasminogen Act. Inh. 1 (PAI-1) 2% Total: ~20%
  10. 10. Low Level Activation of Coagulation in Chronic Fatigue Syndrome and Fibromyalgia - Genetic Procoagulant Factors CFS / HHV6 Cohort: Sequential Case Ascertainment 1. Sequential patients, one clinical site (N=45) 2. Patients assigned as CFS by CDC/NIH criteria. 3. Patients positive for HHV6 by blood culture. 4. All tested with ISAC and HTRP panels. 5. HTRP abnormality rates compared with general population rates. Overall 84.4% of the patient cohort was positive for one or more of these markers. Ref: Harrison, et al. Poster, AACFS 7th International Conference, 2004
  11. 11. Procoagulant Genetic Factors in CFS/FM and Related Chronic Illnesses Present Study: Database Mining Database of Activation of Coagulation (ISAC) and Hereditary Thrombosis Risk Panel (HTRP) scores in Chronic Illness patients (less well defined than smaller, specific CFS/FM cohorts). 582 adults (women/men = 2.3) ISAC Score: One point per each abnormal result of FIB, F1+2, TAT, SFM, or Plt Act. HTRP Score: One point per each abnormal result of AT, PC, PS, F2, APCR, LP(a), or PAI-1.
  12. 12. Genetic Procoagulant Factors in CFS/FM & Related Chronic Illnesses Hereditary Thrombosis Risk Panel (HTRP) Score vs. Immune System Activation of Coagulation (ISAC) Score (N=582) ISAC HTRP Score --> HTRP +ve HTRP +ve Score 0 1 2 3 4 N 1 or more Rate 0 15 20 4 0 0 39 24 0.6154 1 50 57 12 3 0 122 72 0.5902 2 66 76 40 8 0 190 124 0.6526 3 34 77 45 11 1 168 134 0.7976 4 11 25 19 2 1 58 47 0.8103 5 2 1 2 0 0 5 3 0.6000 N 178 256 122 24 2 582 404 0.6942 ISAC Neg 65 77 16 3 0 161 ISAC Pos 113 179 106 21 2 421 Pos Rate 0.635 0.699 0.869 0.875 1.000 0.723
  13. 13. Procoagulant Genetic Factors in CFS/FM and Related Chronic Illnesses Observed Abnormality Rates CFS/FM Pts CFS / CI Rel Risk Gen. Pop. HHV6 Cohort Database Ratio Abnl Rates (N=45) (N=582) (CI / Gen. Pop.) Thrombophilic factors AT 0.02 to 0.5% 0.0% 1.2% 2.4 PC 0.2 to 0.5% 0.0% 1.2% 2.4 PS 0.2 to 0.5% 6.7% 4.8% ~10 F2 2 to 5% 42.2% 36.1% 7.2 APCR 5 to 7% 6.7% 6.7% 1 Hypofibrinolytic factors Lp (a) 5% 33.3% 32.5% 6.5 PAI-1 2% 26.7% 17.5% 8.8
  14. 14. Genetic Procoagulant Factors in CFS/FM & Related Chronic Illnesses Conclusions (N=582) 1. A concerted / polygenic effect was observed in that overall 65.2% of the database cohort was positive for one or more of the procoagulant genetic markers [gpf=20%, OR=3.2], 52.9% for two or more [gpf=4%, OR=13.2], and 31.6% for 3 or more [gp<1%, OR=39.5]. 2. Positivity for the factors cited represents a probable permissive or predispositional condition, yet the incidence of CFS/FM is far lower; thus, environmental factors. 3. Distinguishing thrombophilic and hypofibrinolytic procoagulant factors may help to guide therapy. 4. Patients with normal results for these seven markers may warrant testing for rarer inheritable disorders. 5. Testing family members may help assess their risks of developing CFS/FM as well as TED.
  15. 15. Multiple Etiologies of Activation Viruses- Bacteria - Yeast - Vaccine contaminants? HHV6, Mycoplasma, Candida Toxins, allergens? CMV, Chlamydia Parasites? EBV Antiphospholipid Ab, Immune System Anti-B2GP1 Ab Activation Fibrinogen Thrombin Inflammation + Prothrombin F1+2 (IIa) Thrombin-Antithrombin Coag Gene Defect Platelet Activation Soluble Fibrin Monomer (SFM) Coag Activation Fibrin Deposition & Tissue Ischemia / Hypoxia - Clinical symptoms in Chronic Fatigue Syndrome

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