Gulf War Illness a potential link with chronic fatigue syndrome
Sand-man
Activation of the coagulation system in Gulf War Illness: a potential
pathophysiologic link with chronic fatigue syndrome, a laboratory
approach to diagnosis
by
KL Hannan, D E Berg, W. Baumzweiger, HH Harrison, L H Berg, R Ramirez,
and D. Nichols
The symptoms of Gulf War illness(GWI) are similar to Chronic Fatigue
Syndrome(CFS and or Fibromyalgia). We investigated whether these
symptoms are associated with an activated coagulation system as has been
reported in
some cases of . coagulation assays include activation markers of the
cascade, platlet activation and hereditary risk factors. Our findings show
activation of the coagulation system in GWI. The evidence of a
hypercoagulable
state suggests that symptoms may be due to poor blood flow and, therefore, a
basis for the potential utility of anticoagulant therapy.
Introduction
The existence of Gulf War Illness has been controversial. It has been
difficult to diagnosis because no definite etiological agent has been
isolated or a biochemical process defined. GWI is responsible for
physiological and mental stress symptoms that have required medical
therapy.
In many, it is a medical entity with neurological symptoms caused by
sequential insults to the brain. Because some of the symptoms and
chronicity of GWI are similar to those of the Chronic Fatigue
Syndrome/Fibromyalgia(CFS/FM) complex, and because immune system
activation of coagulation has been observed in CFS/FM, we investigated
coagulation
and platlet activation in veterans with a diagnosis of GWI. The sensitive
new markers of coagulation activation assays included: fibrinogen,
prothrombin fragment 1+2, thrombin/anti-thrombin complexes, soluble fibrin
monomer
and platelet activity index(PA) by flow cytometry using CD 62P( with and
without adenosine diphosphate (ADP) stimulation). Predisposing heredaitary
factors include, in part plasminogen activator inhibitor, factor II activity
screening for the prothrombin gene mutation, antithrombin activity,
protein C activity, protein S(PS) activity, APC resistance screening for
factor V
Leiden mutation, liproprotein (a), homocysteine and anti-B2GPI antibodies
MODEL
We propose that GWI may be due, at least in part, to an intense immune
response to viral, bacterial, chemical, and/or biological warfare
antigens, following exposure to either intact pathogens or vaccines. This
immune
response may activate the coagulation system by the cross-reaction of
antibodies against certain cell surface antithrombotic proteins. We
hypothesize that the binding of anti B2-GPI or anti-annexin-V
antibiodies to their corresponding proteins on the endothelial cell (EC)
surfaces
exposes phosphatidylserine, a potent thrombogenic phospholipid, on the EC
surfaces. Inflamatory responses, which include cytokine down regulation of
the
antithrombotic environment(thromobomodulin and tPA) causes EC
expression of prothrombotic tissue factor(TF) on the EC surface. TF and
exposed PS
allow binding of the coagulation tenase and prothrombinase complexes,
resulting in thrombin generation.
Fibrinogen is then cleaved by thrombin, forming soluble fibrin
monomer(SFM).
SFM forms dimer complexes, increasing blood viscosity, and is deposited
on the affected EC surfaces. This fibrin deposition could create local
ischemia and pathology by blocking nutrient passage and oxygen delivery in
the
microcirculation. Cross-linked fibrin and full-scale clot formation do not
occur in this model because the amount of thrombin formation is less than
the
amount needed for factor XIII activation.
This process may also decrease the local antithrombotic environment by
inhibiting EC ability to express heparans, thrombomodulin and annexin
II(in hibition of plasminogen activation). This process may be documented as
below normal thrombin-antithrombin complex values in the circulating plasma.
Using this model, the administration of anticoagulants(heparin or Coumadin)
to GWI patients should decrease the coagulation activation, with potential
relief of symptoms related to poor blood flow, fibin deposition and /or this
activated coagulation or hypercoagulable state.
Methods
The test group consisted of 33 veterans, comprising 27 military
personnel activated and deployed during the Gulf War, three veterans
activated
but not deployed(and), and three veterans activated and deployed to the Gulf
after the war(ADA). This was compared with 33 age and sex matched healthy
controls. The ill veterans participating in this study satisfied the
diagnosis of
GWI.
Blood samples were drawn according to specific laboratory protocols and
transported to laboratory for testing. Assays included: platlet activity
index by flow cytometry using CD62P(Becton Dickinson, San Jose
California,USA) (with and without ADP stimulation); fibrinogen, clauss
method(reference range 180-310 mg/dl)(Dade Behring, Marburg, Germany);
prothrombin fragment 1+2 (F1+2), Enzygnost F1+2 (reference range)(Dade
Behring); thrombin-antithrombin complexes (TAT), enzygnost
TAT(1.0-4.1ug/l)(Dade Behring),SFM, Berichron FM (0-17mg/l)(Dade
Behring); plasminogen activator inhibitor (PAI-1), Chromolize PAI1 (0-15.5
U/ml)(Biopool Int,.Ventura, California,USA 0; factor II activity,
ThromboScreen II Deficient Plasma (60-120%)(Pacific Hemostasis,
Middletown,Virginia,USA); antithrombin activity(AT),Berichrom AT III
(75-125%)(Dade Behring); protein C activity(PC), Staclot
PC(60-140%)(Diagnostica Stago,Asnieres,France); PS activity, Staclot PS
(65-150%) (Diagnostica Stago); APC Resistance, Coatest APC Resistance
V(Chromogenix,Milano,Italy); Liproprotein(a)(Lp(a)), TintElise LP(a)
(0-30mg/dl)(Biopool,Int); homocysteine, IMX System(0-13umol/l)(Abbott
Diagnostics, Deerfield,Illinois,USA): and anti B2GPI antibiodies,Reaads
B2GPI
(0-20 G,A or M units)(Corgenix Inc, Westminister, Colorado,USA).
Students tests were calculated for test and control groups, and indicated
different populations (based on one SD) due to some very high values beyond
the
reference ranges in the study groups. Statistical P values were then
determined using 2X2 chi-square analysis for each assay.
Results
Results for the 33 veterans are reported as a qualitative score of
coagulation activation tests in the Immune system Activation of
Coagulation
(ISAC) panel as previously reported in this journal. In addition, eight
hereditary thrombosis risk factors were evaluated. An
age-matched/sex-matched
control group was tested for the same markers of coagulation
activation. The
average age of the patient group was 40 years versus 41 years in the
control
group. The ISAC Panel results are summarized in Tables 1-3.
As previously reported by Berg et al, the laboratory criteron for
activation
of coagulation in CFS/FM is two or more positive results on the ISAC
panel.
In this study, 22/23 or 67% of the GWI patient group scored positive in
two
out of five or more tests. Ten of the military subjects were positive
in only
one out of five tests, and one was negative for all five. In the
veteran
group that scored one out of five test postivity, eight out of 10(80%)
had
positive hereditary thrombosis risk factors and six out of the 10(60%)
had
compensatory anticoagulation mechanisms, manifested as either elevated
antithrombin, protein C or protein S levels. In contrast, the control
group
had no samples that were positive for two or more of five tests, and
only 10
of the 33 had one positive test. The rest of the controls were negative
in
all tests. The veteran that scored negative had taken numerous
antibiotics
for several years.
The hereditary risk factors of hypercoagulability can be divided into
two
groups based on the model of Glueck and Triplett and coworkers;
thrombophilia
and hypofibrinolysis. Thrombophilia patients respond more favorably to
anticoagulation than hypofibrinolysis patients. These categories may be
useful in predicting treatment responses. Out of the 33 veterans,
20(61%) had
positive hereditary defects. Eight out of 33 (24%) were positive
thrombophilia risk factors and seven of 33 (21%) of the patients were
positive for hypofibrinolysis. Five out of 33 patients(15%) had a risk
factor
in each group. This last combination was either increased Lp(a) and/or
PAI-1
with increased factor II levels. One patient had a homocysteine level
of
20.9(reference range 0-13).
Sixteen out of 33 (48%) had evidence of activation of anticoagulation
pathways as demonstrated by elevated protein C, protein S and/or
antithrombin
activity. This is probably a compensatory response that attempts to
downregulate the hypercoagulable state that results from significantly
increased fibrinolysis inhibitors or thrombophilia factors. This has
also
been observed in CSF/FM patients.
Thirteen of the veterans (27%) had normal protein levels in the
hereditary
risk factors screened. Nevertheless, 11 of these 13 patients(85%) had
two or
more activated coagulation markers (positive ISAC panel results). Three
out
of this group of 11 had increased protein C or protein S levels to
compensate
for the activated coagulation system. Two patients (6%) that had no
detectable protein abnormalities had platlet activation. It is possible
that
these patients may have had other protein abnormalities, such as
heparin
cofactor II, C4b binding protein, plasminogen, histadine-rich
glycoprotein,
factor XII, soluble thrombomodulin, dysfibrinogen, and /or tissue
factor.
Discussion
Control Group
Civilian controls were selected instead of military controls for
several
reasons related to vaccination policy and other military environmental
exposures. A soldier who received the recent anthrax vaccination and
developed fibromyalgia tested 1/5 positive in this study. We also
tested a
civilian who received only a squalene injection. This person tested 2/5
positive in a preliminary study. Squalene antibodies were present in
the Gulf
War veterans and there is speculation that squalene is the adjuvant in
the
recent anthrax vaccinations. The series of anthrax is mandatory for all
soldiers. Therefore, the appropriate controls for the anticoagulant
study are
civilians until these issues are resolved.
Patient information
All the veterans diagnosed with GWI in this study satisfied the
diagnosis of
Gulf War Syndrome by the Merck manual according to their physicians' or
medical records elsewhere. An in-depth survey of all medications,
prescriptive
or over the counter, was not attempted because some of the patients had
participated in experimental Gulf War protocols that involve placebos.
The
number of positive tests in some patients who actively sought treatment
was
less than the untreated patients, implying beneficial responses from
prescription medicines that could ameliorate the coagulation
activation.
Coagulation and cellular anatomy
Exposure to viral, bacterial, chemical, biological warfare pathogens
and/or
vaccine adjuvants induces an immune response. Normal immunoglobulin
(Ig)M and
IgG antibody formation leads to protection against such pathogens. IgA
antibiodies are formed from interaction of lymphoid elements in the
mucosal
membranes with the pathogens. We postulate that this is the case with
exposures of the veterans in this study. Of the veterans who were
tested for
anti-B2-GPI antibidies(n=5), those who had positive platelet activation
had
positive anti-B2-GPI IgA antibioties(n=3) while those who had normal
platelet
activation had negative IgA antibodies(n=3). In a previous study of
antiphospholipid antibodies in Gulf War Veterans, there was no
significant
positivity for either lupus anticoagulant or antiphosphatidylscrine
antibodies. Anti-B2-GPI antibodies were tested, but only for the IgG
type.
Further studies of IgA positivity may yield better data about the
concept of
an air-borne pathogen or mucosal membrane exposure in these veterans.
The EC is a connecting point between pathogen activated inflammation
and the
coagulation system, and is part of the defensive host response. During
inflammation, cytokines modulate the coagulation system by
downregulating the
expression of thrombomodulin on EC surfaces and eliminating the
anticoagulant
environment by blocking the activation of protein C. At the same time,
these
cytokines induce expression of TF on the EC surfaces, which promotes a
procoagulant environment. Thus, both TF and PS promote the binding of
the
tenase and prothrombinase complexes for the local generation of
thrombin. TF
expression can also decrease local fibrinolysis by inducing EC to
produce
PAi-I instead of tPA. This leads to fibrin build up instead of fibrin
removal. Another result of fibrin deposition is the effect of
diminishing
capilllary size, which may compromise erythrocyte integrity or impair
the
rate of delivery of oxygen and nutrients to the surrounding tissues.
GWI, CFS and FM
There appears to be significant overlap in the symptoms of Gulf War
Illness,
CFS and Fibromyalgia. Perhaps FM is the peripheral manifestation of the
clotting cascade activation with SFM generation and fibrin deposit on
blocking oxygen and nutrient passage to the muscles, nerves, and
tendons. The
CFS may be the central nervous system manifestation of the clotting
activation creating lack of blood flow to the brain due to hyperviscous
blood, and, therefore, disturbance of the chemicals and hormones within
the
brain. Here the causes could be viral, bacterial, chemical, toxin
related or
lymphocytic transference. It is possible that the lymphocytes or
antibodies
found in bodily fluids could influence another person's immune system
by
transference. Live infectious vaccines have been developed that can
transfer
immunity from one individual to another. An injected live vaccine, such
as
smallpox or polio, could possibly be activated if the patient were
immunocompromised. The injection of an experimental adjuvant can
immuonocompromise or immunonstimulate, depending on factors such as the
doseage. The toxins or contaminants within the anthrax or other
vaccines
could possibly be an infectious etiology.
GWI and genetics
Uronvitz et al have found that Chromosome 22q11 genes rearrange
themselves
when exposed to toxins and infection, and that this rearrangement may
be the
cause for many of the neurological problems in GWI. The gene for the
coagulation protein heparin cofactor II(HCII) is also located on
chromsome
22Q11. The same gene rearrangement on C22 has been recently reported to
cause
low levels of HCII in the plasma. HCII is a protein that cause
inactivate
fibrin-bound thrombin, whereas AT is ineffective against fibrin- bound
thrombin. Thrombin may be bound to endothelial cells where there is
fibrin
deposition on capillary walls. Thispotential HCII defect may well
explain the
hypercoagulable state in patients where no protein defects have been
found to
date.
Conclusion
The symptoms of CFS/FM and GWI are very similar. The positive ISAC
testing of
the GWI patients parallels the results seen in CFS/FM patients. The
hereditary risk profile is also positive in both. GWI may be a unique
subset
of CFS/FM. The recent study by Zhang et al indicates the immune
function
tests of lymphocyte subpopulation as well as cytokines of the ill
veterans
differ from the immune panel of CFS/FM pateints. The pathophysiology
remains
constant; cytokines activating antibodies that bind to the EC and
activate
platelets and the coagulation cascade.
Vaccines may be the cause of the hypercoagulable state in the AND and
ADA
groups of veterans. There is nost likely a genetic predisposition to
developing adverse reactions towards vaccinations since over 60% of the
ill
Gulf War veterans in our study have positive hereditary risk factors.
There
may also be other contributing factors to the Gulf War Illness that may
have
caused the illness or worsened the pre exisiting disease. Activation of
coagulation may be a final common endpoint for differing etiologies of
GWI or
CFS.
Coagulation activation is the central focus of the GWI, in diagnosis
and
probably the target for treatment. Further research into the cause of
platlet
activation is needed to determine if there is an infectious etiology.
An in
depth study of the anti-B2GPI-IgA antibody in the GW veterans and their
families needs to be addressed.
Acknowledgements
The authors wish to thank Maggie Eklund, CNMT, Meryl Nass,MD., Jacob
Teitelbaum MD, Les Simpson ,phd, Elllen Sands and Marie Miller for
their
assistanc in this study. To the veterans and their families who
participated
in this study, the authors are most appreciative. They would also like
to
thank the doctors, the labs who made this study possible. In memory of
Jason
Whitcomb, Barbara Radomski and Daniel Steele.
Additional Note:
Reason for getting this out rapidly to all veteran!
References and Tables will be provided as requested. Please note this
paper
was very important and drs and researchers and most of all the veterans
needed this paper to read and discuss in order to promote more research
towards finding treatment but it is also possibly the key I feel to
saving
some lives from the early cardiac deaths and rare spleen ruptures that
have
occurred in Gulf War Veterans. My position has always been to save
lives of
my veterans, my patients I served with and had the duty in theater to
save
lives and care for the wounded. The duty just has not ended and it is a
long
road.
--
Kansas Veterans Home Page
http://www.geocities.com/kansasvet
Don Thompson
--
Don Thompson
Another Thompson Scion
"Sand-man" <pgw...@sandbox.com> wrote in message
news:Kz%67.50004$Uu3.3...@typhoon.kc.rr.com...
Hans Wienhold
types are doing their best to squeel like pigs at the nanny government
and demand their welfare handouts.
Get off my back you lazy worthless bastards
"Sand-man" <pgw...@sandbox.com> wrote in message news:<Kz%67.50004$Uu3.3...@typhoon.kc.rr.com>...
> Gulf War Illness
> Activation of the coagulation system in Gulf War Illness: a potential
> pathophysiologic link with chronic fatigue syndrome, a laboratory
> approach to diagnosis
--------------
Money is the only true God - Vote Libertarian
http://members.tripod.com/wiendog/index.html
oldgoat
where they are today.
As they came home many Nam vets took it upon them selves to help them
out.
They still have a long way to go before they get any thing done that
will help them.
"Don Thompson" <flas...@ix.netcom.comghost> wrote in message news:<9jiog0$9l1$1...@slb7.atl.mindspring.net>...
Sand-man
--
Kansas Veterans Home Page
http://www.geocities.com/kansasvet
"Hans Wienhold" <ha...@freewebemail.com> wrote in message
news:4fe7896e.01072...@posting.google.com...
Hans Wienhold
they have been caught with their hands in the till.
Vetrans are just another group of money grubbing welfare slime
demanding handouts from an evil thieving state.
Get off my back you lazy worthless slime.
---
Do you love Liberty? Think Libertarian.
Visit the Freedom Website - Raybo.com
"Sand-man" <pgw...@sandbox.com> wrote in message news:<Pbj77.46180$k33.4...@typhoon.kc.rr.com>...
> well in to the kill file with you ass hole
> "Hans Wienhold" <ha...@freewebemail.com> wrote in message
retired fart
If it was not for the men that served you would not have your freedom.
ha...@freewebemail.com (Hans Wienhold) wrote in message news:<4fe7896e.01072...@posting.google.com>...
Hans Wienhold
> One more nut running around i see.
>
> If it was not for the men that served you would not have your freedom.
Like I said, money grubbing welfare slime. I see the slack jawed
"retiree" thief (social security) is providing proof of the assertion.
Social Security is nothing more than an illegal ponsi scheme.
---
Those who can not provide for themselves, deserve death.
retired fart
Does you momma know you are playing on the computer again?
Go live in China for a while and you will learn to love that the
veterans did to keep your sorry ass free.
Social security for those retired is not welfare. We paid into a
retirement plan( by force) and now we draw it back. Muck like a any
other retirement plan, but with far less growth.
Hans Wienhold
Welcome to the real world pinko. We who love freedom are rapidly
pulling squeeling liberal parasites from our backs.
What rock you crawl under of what boot you have to lick to survive
is your concern, not mine.
> Go live in China for a while and you will learn to love that the
> veterans did to keep your sorry ass free.
Why don't you go to China? Your self imposed work is not completed.
Maybe you can get them to pay your bills.
Don't ask we Freemen, we are tired of you putting your money
grubbing hands into our pockets.
> Social security for those retired is not welfare.
It's welfare. Even Trent Lott has recognized it as welfare. And
welfare is the state sanctioned theft of money, and therefore the life
of others. Those who steal life are parasites and murderers.
> We paid into a retirement plan( by force) and now we draw it back.
Wrong again Commie. Your money was spent by the state. And you paid
only a fraction of what you receive. The bulk is stolen from me and
my fellow freemen who work our asses off to keep you parasites living
in luxury.
> Muck like a any other retirement plan, but with far less growth.
Communism always has far less growth.