Chronic Fatigue Syndrome (CFS) &/or Fibromyalgia (FM)
as a Variation of Antiphospholipid Antibody Syndrome (APS): An Explanatory Model and Approach to Laboratory Diagnosis.

D Berg, LH Berg , J Couvaras & H Harrison A
  BLOOD COAGULATION & FIBRINOLYSIS 1999,10:p 1 - 4. (In press)


Chronic Fatigue Syndrome and Fibromyalgia have been considered diagnoses of exclusion where no other diagnosis fit well. In 1987, the AMA recognized FM as a major cause of disability1. In 1994, CFS was defined by specific requirements of fatigue, duration, associated symptoms, initial clinical and laboratory evaluation, and medical or psychiatric exclusions2.  At the most recent meeting of the American Association of Chronic Fatigue Syndrome, the prevalence, prognostic factors, pediatric and adult population studies, potential causal organisms, disruption of normal body functions, autoantibody identification and psychological implications were presented.

Antiphospholipid Antibody Syndrome3 (APS) is defined by both laboratory and clinical findings. Laboratory findings include, antiCardiolipin antibodies (aCL), Lupus Anticoagulants (LA), anti-PhosphatidylSerine antibodies (aPS), anti- anti-B2GPI antibodies, and clinical findings of thrombocytopenia4, neurological complications5, venous thrombosis, arterial thrombosis, and/or recurrent fetal loss. Patients with primary APS (PAPS) have no clinical or laboratory evidence of another definable autoimmune disease6. Antiphospholipid (APL) antibodies have been long associated with a hypercoagulable state, involving both procoagulant activity as well as inhibition of anticoagulant and fibrinolytic activity7.

In CFS &/or FM patients, the principal antibodies found to date are the anti- anti-B2GPI antibodies (unpublished data). This preceeds the generation of a hypercoagulable state based on our proposed model.  Endothelial cells are protected in the microvascular circulation by anti-B2GPI and Annexin V proteins. This protective layer helps ECs maintain an anticoagulant environment. Exposure to pathogens, such as Herpesviruses [HV] (HHV6, EBV), CMV, mycoplasma, chlamydia pneumonia, result in both active persistent infection8 and latency in mononuclear and EC cells9.  Some pathogens like CMV and herpesviruses constitutively express phosphatidylserine- like procoagulant activity, capable of binding Xa and Va to form the prothrombinase complex10.  HHV6 is found in about 70% of all CFS patients11.  In several studies, this same 70% infection rate is seen in Multiple Sclerosis (MS) patients with HHV612,13. HHV6 is also implicated in Chronic Myelopathy14. Endothelial cells serve as a reservoir for harboring HHV615. Infected ECs lose their ability to synthesize prostacyclin with associated incapacity to deter platelet adhesion16.  In addition, CMV & HV express Tissue Factor (TF) antigen on each virus surface17. Herpesviruses can induce a prothrombotic phenotype in vascular ECs.  This phenotype markedly reduces heparan sulfate proteoglycan synthesis and surface expression by ECs18. Thrombomodulin (TM) expression is also reduced in infected endothelium. Activation of EC is seen by surface expression of P-Selectin and vonWillebrand Factor (vWF). Thrombin generated after the assembly of the prothrombinase complex on the virally infected endothelium mobilizes vWF from the Weibel-Palade body to the EC surface where it acts as a platelet receptor17. Cell-independent thrombin generation may be the earliest event in vascular pathology mediated by HV19.

Since exposure and expression of PhosphatidylSerine (PS) is part of the infectious process, these exposed phospholipids activate the immune system to form antiphospholipid antibodies. The primary targets of these IgG, IgM,& IgA antibodies are the protective proteins for ECs, specifically anti-B2GPI and Annexin V. Both proteins bind to cells via Ca++ binding20, just as the vitamin K dependent coagulation factors. In pregnancy loss, hypercoagulability may be due to the reduction of surface bound Annexin V by APL antibodies21.  As in other APS diseases, there is an increased incidence of thrombocytopenia in HHV6 patients22. With the loss of this protective layer due to APL antibodies, coagulation proteins can bind, react and form thrombin (IIa). If this process in not properly inhibited (Thrombin/AntiThrombin complexes), then excess thrombin can convert fibrinogen to soluble fibrin monomer (SFM).  SFM is a sticky protein that increases blood viscosity and can coat EC surfaces as fibrin or fibrinoid material.

The explanation of why one person may become chronically ill and another patient recover when both are exposed to the same pathogen comes in part from the dental community. Glueck,  McMahan, Triplett, et al., have identified that 73% of patients with Neuralgia-Inducing Cavitational Osteonecrosis have some form of genetic predisposition for thrombophilia or hypofibrinolysis23, including: APC Resistance, anticardiolipin antibodies, protein C or protein S deficiencies, increased Lp(a) or PAI-1 or decreased  tPA activity. These patients responded well to oral anticoagulant therapy.


Our hypothesis is that a majority of individuals diagnosed as Chronic Fatigue Syndrome (CFS) &/or Fibromyalgia (FM) on clinical criteria may be defined as AntiPhospholipid Syndrome (APS) with the endothelial cell (EC) as the disease target with or without platelet activation (PA). These patients have a hypercoagulable state demonstrated by increased markers of coagulation activation and increased blood viscosity due to the generation of Soluble Fibrin Monomer (SFM). Because the CFS / FM process may be triggered by a variety of pathogens, we suggest that pathogen-mediated immune activation may induce antibodies, e.g., anti-B2GPI, anti-AnnexinV antibodies, that dislodge protective proteins from EC surfaces, thereby exposing PhosphatidylSerine (PS) on the EC surfaces in capillary beds.  This PS exposure would allow binding of the coagulation tenase and prothombinase complexes to EC surfaces, with subsequent thrombin generation, SFM formation and low level fibrin deposition that could create local pathology by blocking nutrients and oxygen delivery in the microcirculation.  A hereditary defect in a coagulation regulatory protein, such as protein C, protein S, Factor VL, prothrombin gene mutation, PAI-1, Lp(a), or elevated homocysteine is probably predispositional. Because this hypercoagulability does not result in a thrombosis, but rather in fibrin deposition, we suggest that an appropriate name for this antiphospholipid antibody process would be Immune System Activation of Coagulation (ISAC) syndrome. This model provides an explanation for the therapeutic benefits reported with low dose anticoagulant therapy (heparin followed by warfarin) in the majority of CFS/FM patients.


At the American Association of Chronic Fatigue Syndrome meeting, we presented a retrospective study of 20 patients looking at a hypercoagulable state that could be reversed with anticoagulant therapies24. Since then, we have conducted a blinded prospective study of 54 CFS &/or FM patients and 23 controls, using a panel of 5 tests to determine if patients could be differentiated from controls.  The tests included: fibrinogen (FIB), prothrombin fragment 1+2 (F1+2), thrombin/antithrombin complexes (T/AT), soluble fibrin monomer (SFM) and platelet activation by flow cytometry (PA) using CD62P and ADP with mean values for each group shown in the following table.

TESTS:   FIB mg/dl F1+2 nM  T/AT ug/l SFM nmol/l PA Plt Act CD62P %
Ref Rng N <310 <1.1 1.0 - 4.1 <20 Normal <26
Controls 23 280 1.0 1.6 10 0% POS 17.5
# Abn / N   2/23 3/23 4/23 3/23 0/23 5/23
Patients 54 367 1.2 1.6 22 42% POS 22
# Abn / N   45/54 26/54 25/54 32/54 22/52 21/52
P Value   <0.001 <0.005 <0.025 <0.001 <0.001 <0.10


The criterion to separate patients from controls was positivity in 2 or more assays for classification as a patient. The P value for laboratory diagnosis based on this criterion was <0.001. Diagnostic data were obtained after all laboratory studies were completed.  22 of the 23 controls were correctly identified. One control was positive in two assays for a false positivity rate of 4%. Of the 54 patients, 4 had normal values, for a false negative rate of only 7.4%. This shows that 92+ % of CFS &/or FM patients had a demonstrable hypercoagulable state. What then is the underlying disease process?


CFS &/or FM patients who have a hereditary deficiency for thrombophilia or hypofibrinolysis may be unable to control thrombin generation properly. We have found that 3 out of 4 CFS &/or FM patients have a genetic deficiency (unpublished data). Certain pathogens induce the immune system generation of APL antibodies and can be a triggering mechanism for APS. Once antibodies are formed, protective proteins are dislodged from endothelial cells, exposing PhosphatidylSerine. Coagulation proteins bind on exposed PS surfaces, generating thrombin on the EC surface. Excess thrombin converts fibrinogen to soluble fibrin monomer, which may be deposited on the EC surface and/or circulate in the plasma. Fibrin deposition leads to decreased oxygen, nutrient and cellular passage to tissues around the micro circulation. This hypercoagulable state may cause localized pathology in many tissues, yielding the systemic compromises and symptoms characteristic of the CFS/FM complex.

Since this hypercoagulable state does not necessarily result in a thrombosis, but rather in fibrin deposition, we suggest that an alternative name for this antiphospholipid antibody process would be Immune System Activation of Coagulation (ISAC) instead of antibody mediated thrombosis25. Once this hypercoagulable state is detected, appropriate anticoagulant therapies may be given to relieve patient symptoms. These studies will be presented in a separate report.


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