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Oxidative coagulopathy
Oxidative
coagulopathy
A proposed pathogenetic mechanism for
environmental illness
Majid Ali
Capital University of Integrative Medicine, Washington, DC,
Institute of Preventive Medicine, New York, and
Columbia University, New York, USA
175
Received 11 December
1998
Accepted 4 May 1999
Keywords Environment, Oxidation, Health, Illness
Abstract Freshly prepared, unstained peripheral blood smears from 46 of 50 patients
with chronic environmental illness showed clear microscopic evidence of advanced oxidative
injury to all elements of circulating blood. As observed with high-resolution (15,000)
phase-contrast and darkfield microscopy, morphologic patterns of oxidative injury to
blood components have been designated oxidative coagulopathy, a state of circulating blood
comprising: structural abnormalities involving erythrocytes and granulocytes and zones
of congealed plasma in its early stages; fibrin clots and thread formation with
platelet entrapment in the intermediate stages; and microclot and microplaque formation
in late stages. Moderate to advanced changes of oxidative coagulopathy were seen in only two
of 15 healthy control subjects. Oxidative coagulopathy begins with oxidative activation of
plasma enzymes and leads to oxidative permutations of plasma lipids, proteins, and sugars,
and is not merely confined to oxidative activation of recognized coagulation pathways.
It is proposed that oxidative coagulopathy represents one of the core pathogenetic mechanisms
of homeostatic dysregulation seen in environmental illness and leads to oxidative injury
to intracellular matrix, cell membranes, and intracellular organelles such as mitochondria.
The observed cellular and plasma changes shed considerable light on many aspects
of the macroecologic toxicants and their cellular targets, as well as the microecologic
oxidants and their molecular targets. Oxidative coagulopathy is a powerful explanation of
the production of symptom-complexes characteristically encountered in environmental
illness.
Introduction
While clinical patterns of environmental illness are quite well recognized and
established among physicians who practice environmental medicine[1-8] this
subject remains controversial[9-12].
The primary reason for this is the nonlinear dynamics of clinical disease
caused by ecologic factors[13]. Thus, unlike chemical toxicity, chemical
sensitivity in most cases is not dose-related, and the range of susceptibility of
environmentally sensitive persons to ecologic chemicals is so wide as to make
the traditional approaches for establishing cause-and-effect relationships
exceedingly difficult.
Moreover, the lack of morphologic or biochemical abnormalities in the
results of commonly performed laboratory tests in environmental illness has
further hampered progress in understanding clinical ecologic illness.
During nearly two decades of the author's clinical work, he has investigated
redox dysregulation in patients with environmental illness with biochemical
Environmental Management and
Health, Vol. 11 No. 2, 2000,
pp. 175-191. # MCB University
Press, 0956-6163
EMH
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tests and high-resolution, phase-contrast microscopic studies. Specifically, he
has focused on the following:
.
the fundamental oxygen order of human biology[14];
.
spontaneity of oxidation in nature and its impact on pathogenesis of
illness[15];
.
oxidative injury to elements of circulating blood called oxidative
coagulopathy[16];
.
oxidative injury to intracellular matrix, cell membranes, and
mitochondria previously designated AA oxidopathy[17];
.
clinical consequences of anoxia, acidosis, and accumulation of toxic
organic acids[18];
.
oxidative regression to primordial cellular ecology (ORPEC) that favors
proliferation of anaerobes under primordial conditions[18]; and
.
clinical entities caused by, or associated with, oxidative coagulopathy,
AA oxidopathy, and the ORPEC state[19-22].
In this paper, morphologic evidence of accelerated oxidative injury to
circulating blood in environmental illness is presented as an extension of the
previous studies.
Patients and clinical diagnostic criteria for environmental illness
There were 31 females and 19 males in the study. The ages ranged from 15-67
years for females (average, 42.5) and from 17-61 years for males (average, 40.5).
For this study, the following clinical criteria for the diagnosis of environmental
illness were used:
.
no history of organic or psychiatric illness before the onset of
environmental illness;
.
persistence of symptoms for a minimum of 12 months; and
.
a clear pattern of clinical symptomatology characteristic of
environmental illness elicited by a physician experienced in the
diagnosis and management of environmental illness.
A total of 33 patients also met diagnostic criteria of chronic fatigue syndrome
(21), fibromyalgia (12), or both.
Peripheral blood morphology examined with high-resolution phase-contrast and
darkfield microscopy
Freshly prepared, unstained peripheral blood smears of patients were
examined with a high-resolution (15,000) microscope with phase-contrast and
darkfield optics (American Biologics, Chula Vista, CA). The procedural details
of such microscopy have been described[18]. The peripheral blood morphology
with such microscopy is distinctly different from that studied with ordinary
bright-light microscopy. The following brief comments about peripheral blood
morphology in healthy subjects are included here to provide a frame of
reference for presenting features and degrees of oxidative coagulopathy in
environmental illness. Erythrocytes appear as pliable round cells that readily
change their shape to ovoid, triangular, dumbbell, or irregular outlines to
squeeze past other erythrocytes in densely populated fields. Such cells resume
their regular rounded contour as soon as they find open space (Plate 1). Most
granulocytes were observed to show amoeboid movements, their locomotion
provided by streaming of their granules into little protrusions of cytoplasm
which grew in size to become the ``legs'' of the cells. Such cells continuously
changed their configurations as they appeared to explore their
microenvironment. Not uncommonly, active phagocytosis of bacteria and
cellular debris by some cells is observed. Lymphocytic details seen included
fine cytoplasmic granules and finer detail of the nuclear chromatin. The
platelets appear as dark round-to-ovoid poorly circumscribed bodies with
poorly visualized granules. Some fields show clumping. However, platelet
agglutination and degranulation is only infrequently seen. There is little
tendency toward plasma congealing in their vicinity. Indeed even when smears
are allowed to stand for 15-30 minutes, platelets remain discrete and do not
cause congealing of fields of plasma that surround them in the central portions
of the smears. The peripheral parts of the smear commonly show cellular
damage as a processing artifact.
Oxidative
coagulopathy
177
Plate 1.
Illustrates peripheral
blood morphology of a
healthy control subject
as seen in freshly
prepared, unstained
smears with a highresolution phasecontrast (15,000)
microscope. Note the
smooth outline of
erythrocytes and
irregular shape of four
polymorphonuclear cells
included in the field. The
plasma fields (open
spaces between cells) are
free of any zones of
congealing, microclots
or microplaques
EMH
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178
Morphologic patterns of oxidative coagulopathy
In previous studies of peripheral blood morphology in clinical entities
characterized by accelerated oxidative stress, the author and his colleague,
Omar Ali, have described the following salient morphologic features of
oxidative coagulopathy:
.
erythrocyte and leukocyte membrane deformities;
.
diaphanous congealing of plasma;
.
platelet aggregation and lysis;
.
filamentous coagulum (fibrin needles);
.
lumpy coagulum;
.
microclots; and
.
microplaques[17,18].
In the present study, the following observations were made in environmentally
sensitive patients.
Erythrocytic morphology in environmental illness
The most common abnormalities observed in environmental illness involved
erythrocytes and consisted of lack of erythrocyte membrane plasticity,
irregularities of its outlines, and clumping. Many erythrocytes showed surface
wrinkling, teardrop deformity, sharp angulations, and spike formations. In
later stages, zones of plasma congealing were seen around many erythrocytes.
In more advanced cases, an increasing number of erythrocytes showed
shrinkage and filamentous outgrowths extending from their membranes, such
filamentous outgrowths covering the entire surface of cells to produce a
Medusa-like appearance. Other cells appeared as ghost outlines. Zones of
congealed plasma surrounded many cells.
Granulocytic morphology in environmental illness
The earliest changes involving granulocytes were clumping and loss of
locomotion, with cells lying limp in pools of plasma with absence of granular
streaming and amoeboid cytoplasmic protrusions. In later stages, granulocyte
cytoplasm showed vacuolation, zones of increased density, and disintegrating
membranes. Congealed plasma surrounded ruptured cells. Clear evidence of
granulocytic phagocytic dysfunction was observed in the majority of smears.
Even when actively motile, phagocytic leukocytes failed to actively engulf and
digest primordial life forms (yeast-like organisms).
Interestingly, leukocytes in such situations were observed to approach
clusters of primordial organisms, shrink back, and move away. (For illustrated
details of such altered predator-prey dynamics of granulocytic phagocytes and
microbes in peripheral smears, see[18].)
Lymphocytic morphology in environmental illness
The dominant morphologic alteration of lymphocytes involved enlargement.
and lymphoblastic transformation. In mild to moderate degrees of oxidopathy,
lymphocyte nuclei lost their normal intense basophilic appearance and
exhibited pale blue staining. Cytoplasmic vacuolation was an uncommon
feature. In most advanced stages, up to 90 per cent of lymphocytes in most
smears showed abnormal cytologic characteristics with a majority of cells in
lymphoblastic transformation.
Platelet morphology in environmental illness
The earliest changes involving platelets were platelet clumping and loss of
membrane detail. Enlarged platelets were seen frequently. With increasing
intensity of coagulopathy, degranulation and lysis were common. Zones of
congealed plasma, the beginning of soft clots, were pronounced, and often
extended to erythrocytes and leukocytes in the vicinity. Fibrin deposits
occurred both as fibrin needles and amorphous masses surrounding lysed
platelets and other corpuscles.
Plasma morphology in environmental illness
Zones of congealed plasma in close vicinity of platelets, erythrocytes,
granulocytes, and lymphocytes, as described in the preceding paragraphs, were
encountered in all cases. Such zones of plasma solidification were also
commonly observed surrounding microbes (coccal and bacillary microbes as
well as primordial life forms described fully previously[18]); this phenomenon
was most pronounced in the vicinity of the latter. Congealed plasma also
surrounded microcrystals encountered in oxidative coagulopathy (presumably
composed of oxalates, urates, cholesterol and other substances precipitated by
acidosis associated with oxidative coagulopathy). While congealed areas were
small and discrete in mild cases, large and confluent areas of plasma
consolidation were seen in nearly every microscopic field in advanced cases.
Microclot and microplaque formation in the circulating blood in environmental
illness
In earlier descriptions of oxidative coagulopathy in ischemic coronary artery
disease, a microclot was defined as a discrete zone of clotting of plasma
components with entrapped blood corpuscles, with or without visible fibrin
crystals. Microclots seen in this study ranged from 20-150microns or larger.
Microclots were observed as loose (``soft'') with poorly delineated edges or as
firm (``hard'') with rather circumscribed boundaries. A microplaque in that
report was defined as a compacted microclot with a clearly definable inner
structure composed of fibrin needles, amorphous masses, and discrete layers of
thrombotic material. The morphology of microclots and microplaques is
illustrated in Plates 2-6.
Oxidative
coagulopathy
179
EMH
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180
Plate 2.
Shows radiating zones
of congealed plasma (an
early change of
oxidative coagulopathy)
spreading from the
periphery of
erythrocytes
Plate 3.
Shows three irregularly
shaped soft microclots
composed of plasma
coagulums with trapped
agglutinated and lysed
platelets. Some
erythrocytes show
crenated membranes
Oxidative
coagulopathy
181
Plate 4.
llustrates a transitional
stage between a
microclot and a soft
microplaque, and shows
early changes of
compaction. Some
erythrocytes stick to the
periphery of the
microclot
Plate 5.
Shows a well-formed,
hard microplaque with a
layered structure
(created by compaction
of a soft microplaque
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182
Plate 6.
Shows multiple wellformed microplaques in
the center field and
many dark shrunken
erythrocytes. Faintly
visible zones of
congealed plasma are
seen between 3 and 4
o'clock positions
Semiquantitative assessment of abnormal peripheral blood morphology in
environmental illness
In Table I, semiquantitative data for microscopic features observed in freshly
prepared peripheral blood smears of 50 patients with environmental illness are
compared with similar data for 15 apparently healthy subjects. Microscopy
was performed within five minutes of the preparation of smears. The
semiquantitative assessment of cellular and plasma abnormalities was done by
examination of a minimum of 100 microscopic fields in each case.
The scale of scoring abnormalities was as follows:
.
0 = abnormal feature absent;
.
1+ = abnormal features present in less than one in ten microscopic
fields;
.
2+ = abnormal features present in at least one in five fields;
.
3+ = abnormal features present in about one-half of fields; and
.
4+ = abnormal features present in nearly all fields.
Discussion
Environmental toxicants profoundly influence the physiologic processes of
humans[23-26]. The critical aspects of toxicant-cell dynamics are the following:
Morphologic characteristic
Rouleaux
RBC crenation/spikes
RBC membrane rupture
RBC lysis
Diminished WBC granules streaming
Diminished WBC motility
WBC membrane rupture
WBC lysis
Lymphocyte enlargement
Lymphoblastic transformation
Platelet agglutination
Platelet lysis
Congealed plasma
Filamentous coagulum
Lumpy coagulum
Microclots per 20 fields
Microplaques per 20 fields
Bacteria
Crystals per 20 fields
Oxidative coagulopathy
Overall score
Note:
a
Patient score
a
2.8
3.2
2.2
1.0
2.2
3.2
2.4
0.8
3.7
2.6
3.6
2.2
4.0
3.2
2.8
18
4
1+
6
2.8
0.4
0.6
0.2
0.3
0.6
0.8
0.3
0.1
1
0.4
0.6
0.2
0.8
0.3
0.5
2.4
0.3
Rare
1.1
0.3
See scale of scores in text
.
exposure to toxicant (concentration and route of entry);
.
uptake;
.
transport;
.
storage;
.
direct toxicity;
.
Control score
metabolism of toxicant (including Phase-I involving oxidation,
reduction, or hydrolysis and phase II involving various conjugation
reactions);
.
secondary and tertiary tissue responses; and
.
excretion.
All of the above are complex issues. For instance, uptake of the toxicant by the
cells involves complex dynamics between the cell membrane and the
xenobiotics, including:
.
.
.
passive diffusion through spores or relevant spaces of lipid-proteinsugar bilayers;
facilitated transport that requires water-soluble substances ``carried'' by
fat-soluble moities; and
lipophility of the toxicant.
Oxidative
coagulopathy
183
Table I.
Semiquantitative
scores of morphologic
abnormalities observed
in oxidative
coagulopathy in
50 patients with
environmental illness
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184
Moreover, each of the above elements is profoundly influenced by the
concentration and tension of oxygen, pH, temperature, humidity, light, and the
availability (as well as lack) of redox-active nutrients. While many advances in
our understanding of the above factors have been made in plant and animal
models[26-28], little, if any, progress has been made in this field as regards
human ecologic illness. The primary reason is that plant and animal ecotoxicity
experiments are designed to culminate in sacrifice of the living organisms,
which, of course, cannot be planned for human subjects. To such difficulties
must be added the previously noted lack of biochemical and morphologic
abnormalities in the traditional diagnostic laboratory tests in clinical
environmental illness. It is in this context that the changes of oxidative
coagulopathy observed in the present study not only open up the possibility of
an expedient laboratory method of assessing the degree of oxidative stress in
environmental illness but also provide valuable insight into the pathogenesis of
its symptom-complexes.
To provide a framework for considering the role of oxidative coagulopathy
in the pathogenesis of symptom-complexes of environmental illness, brief
comments about the following aspects of human redox regulation seem
necessary: spontaneity of oxidation and disease; clotting-unclotting
dysequilibrium in environmental illness; redox dynamics of oxidative
coagulopathy; primary pathologic processes triggered or perpetuated by
oxidative coagulopathy; and oxidative injury to matrix, membranes, and
mitochondria.
Spontaneity of oxidation and disease
In 1983, the author proposed that spontaneity of oxidation in nature is the core
pathogenetic mechanism of the aging process and all diseases[15]. That one
basic mechanism should be the basis of molecular injury in all diseases seems
implausible at first blush. However, extensive review fails to provide any
evidence to the contrary[15-19]. Specifically, in 1988, the author proposed that
spontaneity of oxidation provides the molecular basis of environmental illness
in the sense that all agents causing environmental illness are oxidizing in
nature and that oxidizing injury once initiated perpetuates itself. (Spontaneity
of oxidation, then, becomes the essential mechanism that flames the oxidative
fires and perpetuates molecular injury.) In 1990, following the study of
peripheral blood morphology of several hundred patients with chronic fatigue
syndrome, the oxidative nature of the erythrocyte abnormalities observed in
patients with chronic fatigue syndrome was established by demonstrating the
reversibility of changes by ascorbic acid[18]. In 1991, the author established the
oxidative nature of platelet aggregation and clot formation by the addition of
ascorbic acid and ethylenediaminetetraacetic acid (EDTA) to platelet
aggregates induced by oxidizing agents such as collagen, epinephrine, ADP,
and ristocetin. Both ascorbic acid and EDTA can readily break up platelet
aggregates formed by addition of various aggregating agents[19]. In 1995,
accelerated oxidative molecular injury was recognized as the core pathogenetic
mechanism of chronic fatigue syndrome[20]. In 1997, oxidative coagulopathy
was proposed as the core pathogenetic mechanism of ischemic coronary artery
disease[10].
Abnormal coagulative phenomena within the circulating blood occur in
diverse clinicopathologic entities such as eclampsia, anaphylaxis, localized and
generalized Shwartzman reactions, hemorrhagic diathesis in clinical and
experimental acute viral in fections, bacterial endotoxic shock and others[21].
However, until recently, intravascular clotting was regarded as a homeostatic
dysregulation of interest only in life-threatening acute illnesses. The essential
role of such homeostatic dysregulation in chronic illness has only recently been
recognized[23-26].
Clotting-unclotting dysequilibrium (CUD) in environmental illness
Clotting-unclotting equilibrium (CUE) is, in the author's view, the second most
critical homeostatic requirement in health, the first being the redox equilibrium.
The present study adds to the author's previously published evidence for this
view. Notable in those investigations are the studies documenting reversibility
of the early changes of oxidative coagulopathy by antioxidants such as
ascorbic acid[29,30] vitamin E, taurine and others[31]. Accelerated oxidative
molecular injury, regardless of its origin, disrupts the CUE of health and causes
CUD of disease[18]. It is noteworthy that all oxidants operant on the circulating
blood contribute to oxidative coagulopathy.
Human external and internal ecosystems are under increasing oxidative
stress. The oxidizing capacity of the planet earth is increasing[31,32]. The
ozone layer is thinning and is oxidizing[33]. Global anoxia is increasing and is
oxidizing[34]. Ever-increasing levels of fossil fuel burning are increasing
oxidant stress. Industrial pollution is increasing, and most pollutants are
oxidizing. Ten thousand years ago, the estimated average temperature of Earth
was 50oF[35] and it has been steadily rising. From January to July 1998,
average monthly temperatures consistently broke previous monthly records,
with temperatures rising to 124oF in India, claiming 3,000 lives[36]. The
greenhouse effect is oxidizing. All of the above natural and anthropogenic
oxidizing elements contributing to the increasing oxidizing burden on human
ecosystems have increased enormously in recent decades.
As for the various body organ ecosystems in environmental medicine,
oxygen transport and utilization in chemical sensitivity is impaired, as
evidenced by increased urinary excretion of toxic organic acids such as tartaric
acid that inhibit the Krebs' cycle[37]. Clinical evidence for that is furnished by
the pervasive sense of ``air hunger'' among patients with environmental illness
and clinical benefits of oxygenative therapies for such patients[18]. The bowel
ecology disrupted by massive sugar overload and extended antibiotic use
(which feeds yeast and primordial flora) is oxidizing[18]. Lactic acidosis and
dehydration, almost invariably seen in advanced environmental illness, is
Oxidative
coagulopathy
185
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186
oxidizing by interfering with the Krebs' cycle as well as hepatic enzyme
detoxification pathways. This subject has been recently discussed at
length[18].
Redox dynamics of oxidative coagulopathy in environmental illness
Not unexpectedly, erythrocytes were found to be more vulnerable to oxidative
injury than other blood corpuscles since such cells transport oxygen, the most
important oxidizer in the body. Furthermore, unlike the leukocyte cell
membrane which is sturdy and uniquely equipped with enzymatic antioxidant
defenses against oxidative stresses of microbial invaders, the erythrocyte
membrane is more permeable to oxygen (to facilitate uptake and delivery of
oxygen). Erythrocyte lysis leads to the release of free hemoglobin in plasma.
Free hemoglobin has been considered a dangerous protein ± a biological Fenton
catalyst[38]. It rapidly quenches free radicals in a highly oxidizing environment
and becomes oxidized, thus turning into a potent oxidant. It is readily degraded
by H2O2 to release free iron, which initiates and propagates several free radical
reactions[39,40]. Hemoglobin reacts with H2O2 to produce a protein-bound
oxidizing species capable of causing lipid peroxidation[41]. Free hemoglobin
also avidly binds with nitric oxide radicals and induces vasospasm, triggering
yet other oxidizing events which, in turn, feed the oxidative fires of AA
oxidopathy.
Not unexpectedly, granulocytes also play critical roles in the initiation and
perpetuation of oxidative coagulopathy.[42,43]. In health, such cells produce
bursts of oxidizing species for microbial killing as well as for oxidative
neutralization of toxins. In oxidative coagulopathy, granulocytes are activated
by increasing oxidant stress and, in turn, feed the oxidative flames by their
own increased generation of toxic oxidative species that degrade other
intracellular and extracellular molecular species, inflict peroxidative injury to
cytoplasmic and organelle membranes, enhance polymorphonuclear leukocyteendothelial adhesion, and increase microvascular permeability[44,45].
Evidently, all of those factors can initiate, perpetuate and intensify oxidative
phenomena in environmental illness. Some oxidizing molecular species
elaborated by granulocytes increase capillary permeability and enhance
granulocyte-endothelial adhesiveness[46,47]. The cytoplasmic granules of
human granulocytes are rich in many enzymes, including proteases such as
elastase, which is capable of degrading proteins in intracellular as well as
extracellular fluids[48]. Oxidative cell membrane injury may be expected to
result in escape of proteases from granulocytes into the circulating blood. The
destructive capacity of granulocytes represents an exaggerated physiologic
response in which bursts of potent oxidative molecular species are produced
during inflammatory and repair responses. Specifically, hydroxyl radicals (OH)
derived from superoxide radicals (O2±) produced by granulocytes are a major
cause of cellular injury. Granulocytic myeloperoxidase generates hypochlorite
radicals when exposed to H2O2 following phagocytic activation[49].
Hypochlorite, in turn, oxidizes protease inhibitors, thus leading to increased
proteolytic tissue damage.
Primary pathologic processes initiated or perpetuated by oxidative coagulopathy
Oxidative coagulopathy initiates and perpetuates the following seven primary
pathologic processes that feed upon each other and serve as core pathogenetic
mechanisms for various symptom-complexes of environmental illness:
(1) impaired perfusion;
(2) increased free radical activity;
(3) anoxia;
(4) acidosis;
(5) impaired enzymatic functions;
(6) matrix, membrane, and mitochondria dysfunctions; and
(7) autoimmune injury.
It is proposed that oxidative coagulopathy triggers all of the recognized
symptom-complexes of environmental illness.
Oxidative coagulopathy impairs perfusion by the following mechanisms:
.
increased viscosity and impaired rheology of the blood;
.
vasospasm induced by increased free radical activity;
.
occlusion of capillaries and arterioles by microclots and microplaques;
.
diminished antithrombotic characteristics of the endothelium.
Clear evidence for all of those factors is vasodilation by intravenous infusion of
EDTA, which arrests oxidative coagulopathy and increases perfusion[50].
Oxidative coagulopathy, initially triggered by oxidative stress, is known to
facilitate free radical generation by all known mechanisms operant in the
circulating blood[17]. Specifically, it causes lysis of erythrocytes and releases
into the plasma free autoxidation of glucose, oxidatively damages plasma
proteins, and accelerates activation of myriads of redox-active enzyme systems.
Oxidative coagulopathy causes anoxia, both by impaired perfusion and
increased free radical activity. Anoxia, in turn, leads to yet greater free radical
activity, as is amply demonstrated by reperfusion studies[51,52], and further
fires the oxidative flames of coagulopathy. Thus, perfusion deficits, increased
free radical activity, and anoxia feed upon each other, setting off reverberating
cycles of coagulative stresses.
Oxidative coagulopathy causes acidosis by the following mechanisms:
.
accumulation of lactic acid due to impaired tissue perfusion;
.
accumulation of other organic acids due to accumulated oxyradicals;
and
Oxidative
coagulopathy
187
EMH
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188
.
anoxia. Intracellular acidosis results in compensatory alkalosis in
peripheral blood, which further impairs oxygen transport to tissues by
shifting to the right the oxygen dissociation curve.
Oxidative coagulopathy, if allowed to persist, leads to autoimmune injury by
all of the mechanisms that cause impaired tissue perfusion, increased free
radical activity, anoxia, and acidosis.
Clinical significance of oxidative coagulopathy in environmental illness
The symptom-complexes of environmental illnesses have been delineated in
numerous clinical studies[1-6,53-54]. One or more of the seven primary
pathologic processes of oxidative coagulopathy listed above trigger or
perpetuate almost all of the molecular mechanisms that underlie such
symptom-complexes. Many of those mechanisms have been recently
reviewed[55]. However, the precise initial molecular events that render patients
exquisitely sensitive to minute amounts of chemicals that do not cause
symptoms in subjects without chemical sensitivity have not been fully
elucidated. Notwithstanding, the phenomenon of oxidative coagulopathy
illuminates well the pathogenesis of the following symptom-complexes:
.
Absorptive/digestive
dysfunctions,
including
indigestion,
malabsorption, abdominal bloating and cramps, and cycles of
constipation and diarrhea.
.
Activity disorders including easy fatiguability, diminished endurance,
and, in advanced cases, disabling fatigue.
.
Autonomic dysfunction, including temperature dysregulation,
palpitations, cardiac arrythmias, and vasculitis.
.
Adrenal, thyroid, and pancreas functional disorders, including cold
sensitivity, dry skin, rapid hyperglycemic-hypoglycemic shifts, and
hyperadrenergic episodes. Clear laboratory evidence of such
dysfunctions was seen in the majority of patients in this study.
.
Allergic diasthessis, asthma, bronchospastic episodes, and air hunger.
.
Arthralgia, myalgia, and soft tissue pain syndromes.
.
Amennorrhea, PMS, lack of libido, and related dysregulation of sex
hormones, pituitary-hypothalamus axis, and the limbic system. The
common disorders of mood, memory and mentation in environmental
illness are also included in this category.
It is noteworthy that accelerated oxidative injury (which triggers, and is fed by,
oxidative coagulopathy) is the common denominator in all pathophysiologic
derangements that underlie the pathogenesis of clinical symptom-complexes in
environmental illness. Why some symptom-complexes predominate in some
patients while other symptoms predominate in others, is in the author's view, is
a matter of genetic predisposition.
Conclusion
Occurrence and intensity of oxidative coagulopathy in 50 chemically-sensitive
patients are described. Such coagulopathy is recognized as the core
homeostatic dysregulation in environmental illness. It is triggered by oxidative
stressors operant in our internal and external environments. Seven major
pathologic processes triggered and perpetuated by oxidative coagulopathy are
highlighted and are shown to cause all of the established symptom-complexes
of environmental illness. High-resolution phase-contrast microscopy is
identified as a useful laboratory method for assessing the degree of oxidative
stress in environmental illness as well as for monitoring the efficacy of
therapies employed in the recently described model of integrative
medicine[56,57].
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191
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Oxidative coagulopathy
Oxidative
coagulopathy
A proposed pathogenetic mechanism for
environmental illness
Majid Ali
Capital University of Integrative Medicine, Washington, DC,
Institute of Preventive Medicine, New York, and
Columbia University, New York, USA
175
Received 11 December
1998
Accepted 4 May 1999
Keywords Environment, Oxidation, Health, Illness
Abstract Freshly prepared, unstained peripheral blood smears from 46 of 50 patients
with chronic environmental illness showed clear microscopic evidence of advanced oxidative
injury to all elements of circulating blood. As observed with high-resolution (15,000)
phase-contrast and darkfield microscopy, morphologic patterns of oxidative injury to
blood components have been designated oxidative coagulopathy, a state of circulating blood
comprising: structural abnormalities involving erythrocytes and granulocytes and zones
of congealed plasma in its early stages; fibrin clots and thread formation with
platelet entrapment in the intermediate stages; and microclot and microplaque formation
in late stages. Moderate to advanced changes of oxidative coagulopathy were seen in only two
of 15 healthy control subjects. Oxidative coagulopathy begins with oxidative activation of
plasma enzymes and leads to oxidative permutations of plasma lipids, proteins, and sugars,
and is not merely confined to oxidative activation of recognized coagulation pathways.
It is proposed that oxidative coagulopathy represents one of the core pathogenetic mechanisms
of homeostatic dysregulation seen in environmental illness and leads to oxidative injury
to intracellular matrix, cell membranes, and intracellular organelles such as mitochondria.
The observed cellular and plasma changes shed considerable light on many aspects
of the macroecologic toxicants and their cellular targets, as well as the microecologic
oxidants and their molecular targets. Oxidative coagulopathy is a powerful explanation of
the production of symptom-complexes characteristically encountered in environmental
illness.
Introduction
While clinical patterns of environmental illness are quite well recognized and
established among physicians who practice environmental medicine[1-8] this
subject remains controversial[9-12].
The primary reason for this is the nonlinear dynamics of clinical disease
caused by ecologic factors[13]. Thus, unlike chemical toxicity, chemical
sensitivity in most cases is not dose-related, and the range of susceptibility of
environmentally sensitive persons to ecologic chemicals is so wide as to make
the traditional approaches for establishing cause-and-effect relationships
exceedingly difficult.
Moreover, the lack of morphologic or biochemical abnormalities in the
results of commonly performed laboratory tests in environmental illness has
further hampered progress in understanding clinical ecologic illness.
During nearly two decades of the author's clinical work, he has investigated
redox dysregulation in patients with environmental illness with biochemical
Environmental Management and
Health, Vol. 11 No. 2, 2000,
pp. 175-191. # MCB University
Press, 0956-6163
EMH
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tests and high-resolution, phase-contrast microscopic studies. Specifically, he
has focused on the following:
.
the fundamental oxygen order of human biology[14];
.
spontaneity of oxidation in nature and its impact on pathogenesis of
illness[15];
.
oxidative injury to elements of circulating blood called oxidative
coagulopathy[16];
.
oxidative injury to intracellular matrix, cell membranes, and
mitochondria previously designated AA oxidopathy[17];
.
clinical consequences of anoxia, acidosis, and accumulation of toxic
organic acids[18];
.
oxidative regression to primordial cellular ecology (ORPEC) that favors
proliferation of anaerobes under primordial conditions[18]; and
.
clinical entities caused by, or associated with, oxidative coagulopathy,
AA oxidopathy, and the ORPEC state[19-22].
In this paper, morphologic evidence of accelerated oxidative injury to
circulating blood in environmental illness is presented as an extension of the
previous studies.
Patients and clinical diagnostic criteria for environmental illness
There were 31 females and 19 males in the study. The ages ranged from 15-67
years for females (average, 42.5) and from 17-61 years for males (average, 40.5).
For this study, the following clinical criteria for the diagnosis of environmental
illness were used:
.
no history of organic or psychiatric illness before the onset of
environmental illness;
.
persistence of symptoms for a minimum of 12 months; and
.
a clear pattern of clinical symptomatology characteristic of
environmental illness elicited by a physician experienced in the
diagnosis and management of environmental illness.
A total of 33 patients also met diagnostic criteria of chronic fatigue syndrome
(21), fibromyalgia (12), or both.
Peripheral blood morphology examined with high-resolution phase-contrast and
darkfield microscopy
Freshly prepared, unstained peripheral blood smears of patients were
examined with a high-resolution (15,000) microscope with phase-contrast and
darkfield optics (American Biologics, Chula Vista, CA). The procedural details
of such microscopy have been described[18]. The peripheral blood morphology
with such microscopy is distinctly different from that studied with ordinary
bright-light microscopy. The following brief comments about peripheral blood
morphology in healthy subjects are included here to provide a frame of
reference for presenting features and degrees of oxidative coagulopathy in
environmental illness. Erythrocytes appear as pliable round cells that readily
change their shape to ovoid, triangular, dumbbell, or irregular outlines to
squeeze past other erythrocytes in densely populated fields. Such cells resume
their regular rounded contour as soon as they find open space (Plate 1). Most
granulocytes were observed to show amoeboid movements, their locomotion
provided by streaming of their granules into little protrusions of cytoplasm
which grew in size to become the ``legs'' of the cells. Such cells continuously
changed their configurations as they appeared to explore their
microenvironment. Not uncommonly, active phagocytosis of bacteria and
cellular debris by some cells is observed. Lymphocytic details seen included
fine cytoplasmic granules and finer detail of the nuclear chromatin. The
platelets appear as dark round-to-ovoid poorly circumscribed bodies with
poorly visualized granules. Some fields show clumping. However, platelet
agglutination and degranulation is only infrequently seen. There is little
tendency toward plasma congealing in their vicinity. Indeed even when smears
are allowed to stand for 15-30 minutes, platelets remain discrete and do not
cause congealing of fields of plasma that surround them in the central portions
of the smears. The peripheral parts of the smear commonly show cellular
damage as a processing artifact.
Oxidative
coagulopathy
177
Plate 1.
Illustrates peripheral
blood morphology of a
healthy control subject
as seen in freshly
prepared, unstained
smears with a highresolution phasecontrast (15,000)
microscope. Note the
smooth outline of
erythrocytes and
irregular shape of four
polymorphonuclear cells
included in the field. The
plasma fields (open
spaces between cells) are
free of any zones of
congealing, microclots
or microplaques
EMH
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178
Morphologic patterns of oxidative coagulopathy
In previous studies of peripheral blood morphology in clinical entities
characterized by accelerated oxidative stress, the author and his colleague,
Omar Ali, have described the following salient morphologic features of
oxidative coagulopathy:
.
erythrocyte and leukocyte membrane deformities;
.
diaphanous congealing of plasma;
.
platelet aggregation and lysis;
.
filamentous coagulum (fibrin needles);
.
lumpy coagulum;
.
microclots; and
.
microplaques[17,18].
In the present study, the following observations were made in environmentally
sensitive patients.
Erythrocytic morphology in environmental illness
The most common abnormalities observed in environmental illness involved
erythrocytes and consisted of lack of erythrocyte membrane plasticity,
irregularities of its outlines, and clumping. Many erythrocytes showed surface
wrinkling, teardrop deformity, sharp angulations, and spike formations. In
later stages, zones of plasma congealing were seen around many erythrocytes.
In more advanced cases, an increasing number of erythrocytes showed
shrinkage and filamentous outgrowths extending from their membranes, such
filamentous outgrowths covering the entire surface of cells to produce a
Medusa-like appearance. Other cells appeared as ghost outlines. Zones of
congealed plasma surrounded many cells.
Granulocytic morphology in environmental illness
The earliest changes involving granulocytes were clumping and loss of
locomotion, with cells lying limp in pools of plasma with absence of granular
streaming and amoeboid cytoplasmic protrusions. In later stages, granulocyte
cytoplasm showed vacuolation, zones of increased density, and disintegrating
membranes. Congealed plasma surrounded ruptured cells. Clear evidence of
granulocytic phagocytic dysfunction was observed in the majority of smears.
Even when actively motile, phagocytic leukocytes failed to actively engulf and
digest primordial life forms (yeast-like organisms).
Interestingly, leukocytes in such situations were observed to approach
clusters of primordial organisms, shrink back, and move away. (For illustrated
details of such altered predator-prey dynamics of granulocytic phagocytes and
microbes in peripheral smears, see[18].)
Lymphocytic morphology in environmental illness
The dominant morphologic alteration of lymphocytes involved enlargement.
and lymphoblastic transformation. In mild to moderate degrees of oxidopathy,
lymphocyte nuclei lost their normal intense basophilic appearance and
exhibited pale blue staining. Cytoplasmic vacuolation was an uncommon
feature. In most advanced stages, up to 90 per cent of lymphocytes in most
smears showed abnormal cytologic characteristics with a majority of cells in
lymphoblastic transformation.
Platelet morphology in environmental illness
The earliest changes involving platelets were platelet clumping and loss of
membrane detail. Enlarged platelets were seen frequently. With increasing
intensity of coagulopathy, degranulation and lysis were common. Zones of
congealed plasma, the beginning of soft clots, were pronounced, and often
extended to erythrocytes and leukocytes in the vicinity. Fibrin deposits
occurred both as fibrin needles and amorphous masses surrounding lysed
platelets and other corpuscles.
Plasma morphology in environmental illness
Zones of congealed plasma in close vicinity of platelets, erythrocytes,
granulocytes, and lymphocytes, as described in the preceding paragraphs, were
encountered in all cases. Such zones of plasma solidification were also
commonly observed surrounding microbes (coccal and bacillary microbes as
well as primordial life forms described fully previously[18]); this phenomenon
was most pronounced in the vicinity of the latter. Congealed plasma also
surrounded microcrystals encountered in oxidative coagulopathy (presumably
composed of oxalates, urates, cholesterol and other substances precipitated by
acidosis associated with oxidative coagulopathy). While congealed areas were
small and discrete in mild cases, large and confluent areas of plasma
consolidation were seen in nearly every microscopic field in advanced cases.
Microclot and microplaque formation in the circulating blood in environmental
illness
In earlier descriptions of oxidative coagulopathy in ischemic coronary artery
disease, a microclot was defined as a discrete zone of clotting of plasma
components with entrapped blood corpuscles, with or without visible fibrin
crystals. Microclots seen in this study ranged from 20-150microns or larger.
Microclots were observed as loose (``soft'') with poorly delineated edges or as
firm (``hard'') with rather circumscribed boundaries. A microplaque in that
report was defined as a compacted microclot with a clearly definable inner
structure composed of fibrin needles, amorphous masses, and discrete layers of
thrombotic material. The morphology of microclots and microplaques is
illustrated in Plates 2-6.
Oxidative
coagulopathy
179
EMH
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180
Plate 2.
Shows radiating zones
of congealed plasma (an
early change of
oxidative coagulopathy)
spreading from the
periphery of
erythrocytes
Plate 3.
Shows three irregularly
shaped soft microclots
composed of plasma
coagulums with trapped
agglutinated and lysed
platelets. Some
erythrocytes show
crenated membranes
Oxidative
coagulopathy
181
Plate 4.
llustrates a transitional
stage between a
microclot and a soft
microplaque, and shows
early changes of
compaction. Some
erythrocytes stick to the
periphery of the
microclot
Plate 5.
Shows a well-formed,
hard microplaque with a
layered structure
(created by compaction
of a soft microplaque
EMH
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182
Plate 6.
Shows multiple wellformed microplaques in
the center field and
many dark shrunken
erythrocytes. Faintly
visible zones of
congealed plasma are
seen between 3 and 4
o'clock positions
Semiquantitative assessment of abnormal peripheral blood morphology in
environmental illness
In Table I, semiquantitative data for microscopic features observed in freshly
prepared peripheral blood smears of 50 patients with environmental illness are
compared with similar data for 15 apparently healthy subjects. Microscopy
was performed within five minutes of the preparation of smears. The
semiquantitative assessment of cellular and plasma abnormalities was done by
examination of a minimum of 100 microscopic fields in each case.
The scale of scoring abnormalities was as follows:
.
0 = abnormal feature absent;
.
1+ = abnormal features present in less than one in ten microscopic
fields;
.
2+ = abnormal features present in at least one in five fields;
.
3+ = abnormal features present in about one-half of fields; and
.
4+ = abnormal features present in nearly all fields.
Discussion
Environmental toxicants profoundly influence the physiologic processes of
humans[23-26]. The critical aspects of toxicant-cell dynamics are the following:
Morphologic characteristic
Rouleaux
RBC crenation/spikes
RBC membrane rupture
RBC lysis
Diminished WBC granules streaming
Diminished WBC motility
WBC membrane rupture
WBC lysis
Lymphocyte enlargement
Lymphoblastic transformation
Platelet agglutination
Platelet lysis
Congealed plasma
Filamentous coagulum
Lumpy coagulum
Microclots per 20 fields
Microplaques per 20 fields
Bacteria
Crystals per 20 fields
Oxidative coagulopathy
Overall score
Note:
a
Patient score
a
2.8
3.2
2.2
1.0
2.2
3.2
2.4
0.8
3.7
2.6
3.6
2.2
4.0
3.2
2.8
18
4
1+
6
2.8
0.4
0.6
0.2
0.3
0.6
0.8
0.3
0.1
1
0.4
0.6
0.2
0.8
0.3
0.5
2.4
0.3
Rare
1.1
0.3
See scale of scores in text
.
exposure to toxicant (concentration and route of entry);
.
uptake;
.
transport;
.
storage;
.
direct toxicity;
.
Control score
metabolism of toxicant (including Phase-I involving oxidation,
reduction, or hydrolysis and phase II involving various conjugation
reactions);
.
secondary and tertiary tissue responses; and
.
excretion.
All of the above are complex issues. For instance, uptake of the toxicant by the
cells involves complex dynamics between the cell membrane and the
xenobiotics, including:
.
.
.
passive diffusion through spores or relevant spaces of lipid-proteinsugar bilayers;
facilitated transport that requires water-soluble substances ``carried'' by
fat-soluble moities; and
lipophility of the toxicant.
Oxidative
coagulopathy
183
Table I.
Semiquantitative
scores of morphologic
abnormalities observed
in oxidative
coagulopathy in
50 patients with
environmental illness
EMH
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184
Moreover, each of the above elements is profoundly influenced by the
concentration and tension of oxygen, pH, temperature, humidity, light, and the
availability (as well as lack) of redox-active nutrients. While many advances in
our understanding of the above factors have been made in plant and animal
models[26-28], little, if any, progress has been made in this field as regards
human ecologic illness. The primary reason is that plant and animal ecotoxicity
experiments are designed to culminate in sacrifice of the living organisms,
which, of course, cannot be planned for human subjects. To such difficulties
must be added the previously noted lack of biochemical and morphologic
abnormalities in the traditional diagnostic laboratory tests in clinical
environmental illness. It is in this context that the changes of oxidative
coagulopathy observed in the present study not only open up the possibility of
an expedient laboratory method of assessing the degree of oxidative stress in
environmental illness but also provide valuable insight into the pathogenesis of
its symptom-complexes.
To provide a framework for considering the role of oxidative coagulopathy
in the pathogenesis of symptom-complexes of environmental illness, brief
comments about the following aspects of human redox regulation seem
necessary: spontaneity of oxidation and disease; clotting-unclotting
dysequilibrium in environmental illness; redox dynamics of oxidative
coagulopathy; primary pathologic processes triggered or perpetuated by
oxidative coagulopathy; and oxidative injury to matrix, membranes, and
mitochondria.
Spontaneity of oxidation and disease
In 1983, the author proposed that spontaneity of oxidation in nature is the core
pathogenetic mechanism of the aging process and all diseases[15]. That one
basic mechanism should be the basis of molecular injury in all diseases seems
implausible at first blush. However, extensive review fails to provide any
evidence to the contrary[15-19]. Specifically, in 1988, the author proposed that
spontaneity of oxidation provides the molecular basis of environmental illness
in the sense that all agents causing environmental illness are oxidizing in
nature and that oxidizing injury once initiated perpetuates itself. (Spontaneity
of oxidation, then, becomes the essential mechanism that flames the oxidative
fires and perpetuates molecular injury.) In 1990, following the study of
peripheral blood morphology of several hundred patients with chronic fatigue
syndrome, the oxidative nature of the erythrocyte abnormalities observed in
patients with chronic fatigue syndrome was established by demonstrating the
reversibility of changes by ascorbic acid[18]. In 1991, the author established the
oxidative nature of platelet aggregation and clot formation by the addition of
ascorbic acid and ethylenediaminetetraacetic acid (EDTA) to platelet
aggregates induced by oxidizing agents such as collagen, epinephrine, ADP,
and ristocetin. Both ascorbic acid and EDTA can readily break up platelet
aggregates formed by addition of various aggregating agents[19]. In 1995,
accelerated oxidative molecular injury was recognized as the core pathogenetic
mechanism of chronic fatigue syndrome[20]. In 1997, oxidative coagulopathy
was proposed as the core pathogenetic mechanism of ischemic coronary artery
disease[10].
Abnormal coagulative phenomena within the circulating blood occur in
diverse clinicopathologic entities such as eclampsia, anaphylaxis, localized and
generalized Shwartzman reactions, hemorrhagic diathesis in clinical and
experimental acute viral in fections, bacterial endotoxic shock and others[21].
However, until recently, intravascular clotting was regarded as a homeostatic
dysregulation of interest only in life-threatening acute illnesses. The essential
role of such homeostatic dysregulation in chronic illness has only recently been
recognized[23-26].
Clotting-unclotting dysequilibrium (CUD) in environmental illness
Clotting-unclotting equilibrium (CUE) is, in the author's view, the second most
critical homeostatic requirement in health, the first being the redox equilibrium.
The present study adds to the author's previously published evidence for this
view. Notable in those investigations are the studies documenting reversibility
of the early changes of oxidative coagulopathy by antioxidants such as
ascorbic acid[29,30] vitamin E, taurine and others[31]. Accelerated oxidative
molecular injury, regardless of its origin, disrupts the CUE of health and causes
CUD of disease[18]. It is noteworthy that all oxidants operant on the circulating
blood contribute to oxidative coagulopathy.
Human external and internal ecosystems are under increasing oxidative
stress. The oxidizing capacity of the planet earth is increasing[31,32]. The
ozone layer is thinning and is oxidizing[33]. Global anoxia is increasing and is
oxidizing[34]. Ever-increasing levels of fossil fuel burning are increasing
oxidant stress. Industrial pollution is increasing, and most pollutants are
oxidizing. Ten thousand years ago, the estimated average temperature of Earth
was 50oF[35] and it has been steadily rising. From January to July 1998,
average monthly temperatures consistently broke previous monthly records,
with temperatures rising to 124oF in India, claiming 3,000 lives[36]. The
greenhouse effect is oxidizing. All of the above natural and anthropogenic
oxidizing elements contributing to the increasing oxidizing burden on human
ecosystems have increased enormously in recent decades.
As for the various body organ ecosystems in environmental medicine,
oxygen transport and utilization in chemical sensitivity is impaired, as
evidenced by increased urinary excretion of toxic organic acids such as tartaric
acid that inhibit the Krebs' cycle[37]. Clinical evidence for that is furnished by
the pervasive sense of ``air hunger'' among patients with environmental illness
and clinical benefits of oxygenative therapies for such patients[18]. The bowel
ecology disrupted by massive sugar overload and extended antibiotic use
(which feeds yeast and primordial flora) is oxidizing[18]. Lactic acidosis and
dehydration, almost invariably seen in advanced environmental illness, is
Oxidative
coagulopathy
185
EMH
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186
oxidizing by interfering with the Krebs' cycle as well as hepatic enzyme
detoxification pathways. This subject has been recently discussed at
length[18].
Redox dynamics of oxidative coagulopathy in environmental illness
Not unexpectedly, erythrocytes were found to be more vulnerable to oxidative
injury than other blood corpuscles since such cells transport oxygen, the most
important oxidizer in the body. Furthermore, unlike the leukocyte cell
membrane which is sturdy and uniquely equipped with enzymatic antioxidant
defenses against oxidative stresses of microbial invaders, the erythrocyte
membrane is more permeable to oxygen (to facilitate uptake and delivery of
oxygen). Erythrocyte lysis leads to the release of free hemoglobin in plasma.
Free hemoglobin has been considered a dangerous protein ± a biological Fenton
catalyst[38]. It rapidly quenches free radicals in a highly oxidizing environment
and becomes oxidized, thus turning into a potent oxidant. It is readily degraded
by H2O2 to release free iron, which initiates and propagates several free radical
reactions[39,40]. Hemoglobin reacts with H2O2 to produce a protein-bound
oxidizing species capable of causing lipid peroxidation[41]. Free hemoglobin
also avidly binds with nitric oxide radicals and induces vasospasm, triggering
yet other oxidizing events which, in turn, feed the oxidative fires of AA
oxidopathy.
Not unexpectedly, granulocytes also play critical roles in the initiation and
perpetuation of oxidative coagulopathy.[42,43]. In health, such cells produce
bursts of oxidizing species for microbial killing as well as for oxidative
neutralization of toxins. In oxidative coagulopathy, granulocytes are activated
by increasing oxidant stress and, in turn, feed the oxidative flames by their
own increased generation of toxic oxidative species that degrade other
intracellular and extracellular molecular species, inflict peroxidative injury to
cytoplasmic and organelle membranes, enhance polymorphonuclear leukocyteendothelial adhesion, and increase microvascular permeability[44,45].
Evidently, all of those factors can initiate, perpetuate and intensify oxidative
phenomena in environmental illness. Some oxidizing molecular species
elaborated by granulocytes increase capillary permeability and enhance
granulocyte-endothelial adhesiveness[46,47]. The cytoplasmic granules of
human granulocytes are rich in many enzymes, including proteases such as
elastase, which is capable of degrading proteins in intracellular as well as
extracellular fluids[48]. Oxidative cell membrane injury may be expected to
result in escape of proteases from granulocytes into the circulating blood. The
destructive capacity of granulocytes represents an exaggerated physiologic
response in which bursts of potent oxidative molecular species are produced
during inflammatory and repair responses. Specifically, hydroxyl radicals (OH)
derived from superoxide radicals (O2±) produced by granulocytes are a major
cause of cellular injury. Granulocytic myeloperoxidase generates hypochlorite
radicals when exposed to H2O2 following phagocytic activation[49].
Hypochlorite, in turn, oxidizes protease inhibitors, thus leading to increased
proteolytic tissue damage.
Primary pathologic processes initiated or perpetuated by oxidative coagulopathy
Oxidative coagulopathy initiates and perpetuates the following seven primary
pathologic processes that feed upon each other and serve as core pathogenetic
mechanisms for various symptom-complexes of environmental illness:
(1) impaired perfusion;
(2) increased free radical activity;
(3) anoxia;
(4) acidosis;
(5) impaired enzymatic functions;
(6) matrix, membrane, and mitochondria dysfunctions; and
(7) autoimmune injury.
It is proposed that oxidative coagulopathy triggers all of the recognized
symptom-complexes of environmental illness.
Oxidative coagulopathy impairs perfusion by the following mechanisms:
.
increased viscosity and impaired rheology of the blood;
.
vasospasm induced by increased free radical activity;
.
occlusion of capillaries and arterioles by microclots and microplaques;
.
diminished antithrombotic characteristics of the endothelium.
Clear evidence for all of those factors is vasodilation by intravenous infusion of
EDTA, which arrests oxidative coagulopathy and increases perfusion[50].
Oxidative coagulopathy, initially triggered by oxidative stress, is known to
facilitate free radical generation by all known mechanisms operant in the
circulating blood[17]. Specifically, it causes lysis of erythrocytes and releases
into the plasma free autoxidation of glucose, oxidatively damages plasma
proteins, and accelerates activation of myriads of redox-active enzyme systems.
Oxidative coagulopathy causes anoxia, both by impaired perfusion and
increased free radical activity. Anoxia, in turn, leads to yet greater free radical
activity, as is amply demonstrated by reperfusion studies[51,52], and further
fires the oxidative flames of coagulopathy. Thus, perfusion deficits, increased
free radical activity, and anoxia feed upon each other, setting off reverberating
cycles of coagulative stresses.
Oxidative coagulopathy causes acidosis by the following mechanisms:
.
accumulation of lactic acid due to impaired tissue perfusion;
.
accumulation of other organic acids due to accumulated oxyradicals;
and
Oxidative
coagulopathy
187
EMH
11,2
188
.
anoxia. Intracellular acidosis results in compensatory alkalosis in
peripheral blood, which further impairs oxygen transport to tissues by
shifting to the right the oxygen dissociation curve.
Oxidative coagulopathy, if allowed to persist, leads to autoimmune injury by
all of the mechanisms that cause impaired tissue perfusion, increased free
radical activity, anoxia, and acidosis.
Clinical significance of oxidative coagulopathy in environmental illness
The symptom-complexes of environmental illnesses have been delineated in
numerous clinical studies[1-6,53-54]. One or more of the seven primary
pathologic processes of oxidative coagulopathy listed above trigger or
perpetuate almost all of the molecular mechanisms that underlie such
symptom-complexes. Many of those mechanisms have been recently
reviewed[55]. However, the precise initial molecular events that render patients
exquisitely sensitive to minute amounts of chemicals that do not cause
symptoms in subjects without chemical sensitivity have not been fully
elucidated. Notwithstanding, the phenomenon of oxidative coagulopathy
illuminates well the pathogenesis of the following symptom-complexes:
.
Absorptive/digestive
dysfunctions,
including
indigestion,
malabsorption, abdominal bloating and cramps, and cycles of
constipation and diarrhea.
.
Activity disorders including easy fatiguability, diminished endurance,
and, in advanced cases, disabling fatigue.
.
Autonomic dysfunction, including temperature dysregulation,
palpitations, cardiac arrythmias, and vasculitis.
.
Adrenal, thyroid, and pancreas functional disorders, including cold
sensitivity, dry skin, rapid hyperglycemic-hypoglycemic shifts, and
hyperadrenergic episodes. Clear laboratory evidence of such
dysfunctions was seen in the majority of patients in this study.
.
Allergic diasthessis, asthma, bronchospastic episodes, and air hunger.
.
Arthralgia, myalgia, and soft tissue pain syndromes.
.
Amennorrhea, PMS, lack of libido, and related dysregulation of sex
hormones, pituitary-hypothalamus axis, and the limbic system. The
common disorders of mood, memory and mentation in environmental
illness are also included in this category.
It is noteworthy that accelerated oxidative injury (which triggers, and is fed by,
oxidative coagulopathy) is the common denominator in all pathophysiologic
derangements that underlie the pathogenesis of clinical symptom-complexes in
environmental illness. Why some symptom-complexes predominate in some
patients while other symptoms predominate in others, is in the author's view, is
a matter of genetic predisposition.
Conclusion
Occurrence and intensity of oxidative coagulopathy in 50 chemically-sensitive
patients are described. Such coagulopathy is recognized as the core
homeostatic dysregulation in environmental illness. It is triggered by oxidative
stressors operant in our internal and external environments. Seven major
pathologic processes triggered and perpetuated by oxidative coagulopathy are
highlighted and are shown to cause all of the established symptom-complexes
of environmental illness. High-resolution phase-contrast microscopy is
identified as a useful laboratory method for assessing the degree of oxidative
stress in environmental illness as well as for monitoring the efficacy of
therapies employed in the recently described model of integrative
medicine[56,57].
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