IS CFS/FM  DUE TO AN UNDEFINED HYPERCOAGULABLE STATE BROUGHT ON BY IMMUNE ACTIVATION OF COAGULATION? DOES ADDING ANTICOAGULANT THERAPY IMPROVE CSF/FM PATIENT SYMPTOMS? ¹       D Berg, LH Berg, J Couvaras.

 Chronic Fatigue Syndrome may be due to a hypercoagulable state induced by immune activation of the coagulation (IAC) system.  Using new coagulation assays that identify low levels of coagulation activation, this study was designed to quantitate such changes in CFS/FM patients, if any.
 Patient studies in habitual pregnancy loss have shown that  immune activation of coagulation produces an intermediate fibrinogen molecule called Soluble Fibrin Monomer (SFM). Increased SFM causes the body to reflexively produce more fibrinogen, resulting in elevated fibrinogen and both increase blood viscosity. Additionally, platelets may become activated, adding a substrate surface for continued thrombin generation, converting fibrinogen into SFM. This IAC may be due to inflammatory processes, viruses, or acquired coagulation inhibitors (lupus anticoagulants, anti-Phospholipid antibodies, antiPhosphatidylSerine antibodies), and exacerbated by hereditary coagulation defects. These defects include Protein C, Protein S, AT deficiencies, APC Resistance, and elevated Factor II, X or VIII, which allow activation without the necessary control mechanisms to easily shut the hypercoagulable state down. Most patients with increased fibrinogen and SFM levels also have activated platelets and a faster RATE of clotting kinetics (Sonoclot). These four screening tests define immune activation of coagulation.
  Applying the same principles of IAC to CFS, a pilot study of 20 patients with rheumatology defined CFS/ fibromyalgia was begun to see if these activation markers were elevated as in habitual pregnancy loss. In this study, there was a high correlation of abnormal test values in the four screening tests (fibrinogen, SFM, PA Score & Sonoclot Rate).
 

The high percentages of increased SFM and the Sonoclot rate elevation, with moderate increase in fibrinogen levels (mean average: 326 mg/dl - Ref Range: 180-310 mg/dl), indicates activation of  coagulation in these patients. In addition, 60% of patients also had platelet activation.
 16 patients with defined CFS or FM, who had positive baseline studies, were then treated with placebo saline injections BID and an oral placebo (if PA Score was elevated) for one week, followed by anticoagulant therapy of standard heparin, SQ 5000-8000 units BID. Patients with platelet activation were also given 81mgs ASA daily. The four coagulation tests were repeated weekly. Dose adjustments were made, if needed, to decrease SFM and PA Scores and maintain the patient in the normal range. Heparin therapy was given for one month. Patients were then  rated on their subjective responses in their improvement to headache, fatigue and pain: no improvement, some, moderate, or significant improvement.
 
 

9 patients were then converted to 1.0-2.5 mgs coumadin daily. The patients were then maintained on low dose coumadin, some for up to a year.  There appears to be significant improvement of patients using anticoagulant medications.
  Most patients reported feeling like their old selves within 48-96 hours of heparin therapy with increased energy levels. This suggests that these medications are acting on the hypercoagulable state by simply shutting down the thrombin generation, resulting in a decrease of blood viscosity as SFM is removed from the circulation and the fibrinogen level begins to return to normal. This is intriguing evidence of a practical treatment to improve patients quality of life and decrease their major complaints and symptoms.
 The final question is simply: As we age, do the endothelial cells lose their ability to produce enough heparans to maintain an anticoagulant environment and prevent inappropriate thrombin generation, leading to increased SFM levels and increased blood viscosity?

^{1  Submitted 5/98.  Accepted for presentation: American Association Chronic Fatigue Syndrome, Oct, 98.}
 
 

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