Chronic Fatigue Syndrome (CFS) &/or Fibromyalgia
as a Variation of Antiphospholipid Antibody Syndrome (APS): An
Explanatory Model and Approach to Laboratory Diagnosis.
D Berg, LH Berg , J Couvaras & H
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.
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antibodies (unpublished data).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
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
||PA Plt Act
||1.0 - 4.1
|# Abn / N
|# Abn / N
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
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
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