Advances in Bioscience and Biotechnology, 2012, 3, 459-503 ABB
http://dx.doi.org/10.4236/abb.2012.324065 Published Online August 2012 (http://www.SciRP.org/journal/abb/)
Stress repair mechanism activity explains inflammation
and apoptosis
Lewis S. Coleman
Barnes Dental Surgery Center, Visalia, USA
Received 28 June 2012; revised 28 July 2012; accepted 16 August 2012
ABSTRACT
A review of modern evidence using Internet resources
has identified the Stress Repair Mechanism (SRM)
postulated by Hans Selye in 1951. SRM activity regu-
lates thrombin generation to govern tissue mainte-
nance, tissue repair, hemodynamic physiology, in-
flammation, and apoptosis. Thrombin utilizes ATP to
energize coagulation, capillary hemostasis, chemo-
taxis, immune activity, mitosis, metabolism, angio-
genesis, and the release of chemokines, cytokines,
bradykinins, and prostaglandins that enable cell-to-
cell communications, promote perfusion, loosen cell
connections, and sensitize nociceptors during tissue
repair. The orchestration of these diverse activities by
the SRM explains the disparate elements of the in-
flammation syndrome, including dolor (pain), rubor
(redness), calor (heat), tumor (swelling), and Functio
laesa (loss of function). Inflammation resolves as tis-
sue repair nears completion and declining SRM ac-
tivity restores thrombin to maintenance levels. As
thrombin levels decline below a critical threshold, re-
pair cells undergo apoptosis and clots disintegrate.
Apoptosis shrinks granulation tissues to enable wound
closure. Apoptosis also facilitates embryological de-
velopment. Occult systemic SRM hyperactivity due to
sepsis, surgery, trauma, chemicals, pain, fear, and
emo-tional memories causes inflammatory effec ts tha t
manifest as the fever, edema, malignancy, organ dis-
ruption, eclampsia, Multi-System Organ Failure (MS-
OF), Systemic Inflammatory Response Syndrome (SI-
RS), Adult Respiratory Distress Syndrome (ARDS),
Disseminated Intravascular Coagulation (DIC) and
other pathologies.
Keywords: Selye; Stress; Inflammation; Atherosclerosis;
Tissue Repair; Hemodynamic
1. INTRODUCTION
Medicine remains an art based on experiment rather than
a true science based on theory that enables predictably
effective treatments. The nature of tissue repair is un-
known. Inflammation, apoptosis, and embryological de-
velopment remain mysterious. Hemodynamic physiology
is customarily attributed to direct autonomic innervation
that controls cardiac and arteriolar contractility, but this
explanation is notoriously weak. Smooth muscle con-
traction is energy intensive, short-lived, and followed by
obligatory vasodilation, so that it cannot explain sus-
tained hypertension. Sustained increases in cardiac work
cause congestive heart failure. These and other short-
comings in medical theory force physicians to base their
treatments on symptoms rather than causes, so that treat-
ments are often use l ess or even counterproductive.
Stress theory has represented the best hope for im-
proved medical theory in recent times. In 1951, Hans
Selye famously predicted that a single physiological me-
chanism maintains and repairs the vertebrate body. Se-
lye’s putative mechanism would theoretically enable a
“Universal Theory of Medicine” that explains hemody-
namic physiology, tissue repair, pathology, stress, and
their relationships. It would revolutionize medical treat-
ments and pharmaceutical development. Soon after Se-
lye’s prediction, the discovery of DNA inspired enor-
mous excitement in medicine and biology. Since the
DNA mechanism by itself does not explain how genetic
information is converted into structural development,
many expected that Selye’s mechanism would function
as a “companion mechanism” that works closely with
DNA to enable embryological development. The com-
panion mechanism would remain active to maintain ma-
ture structures and regulate hemodynamic physiology for
the duration of life, while DNA becomes quiescent once
embryological development is complete. These exciting
ideas inspired an intense but futile international search
for a testable mechanism that could confirm Selye’s the-
ory.
Stress researchers developed two important concepts
to help identify Selye’s mechanism. Capillary gate the-
ory postulates a submicroscopic mechanism that effi-

L. S. Coleman / Advances in Bioscience and Biotechnology 3 (2012) 459-503 460
ciently controls capillary flow. It theoretically explains
capillary hemostasis, hemodynamic physiology, and or-
gan function. Tissue repair theory postulates a single me-
chanism that governs tissue repair. It theoretically ex-
plains the orderly and predictable sequence of events that
occurs during tissue repair, including inflammation and
apoptosis [1].
Stress research lasted more than 30 years and con-
sumed hundreds of research careers, thousands of test
animals, and millions of dollars. Unfortunately, no test-
able mechanism was found that explains tissue repair or
hemodynamic physiology, let alone both. Furthermore,
capillary gate theory and tissue repair theory seemed
incompatible. Despite its promise, the frustrating failure
to find a testable stress mechanism caused stress theory
to fall into disrepute, and it has now been almost com-
pletely abandoned for more than 30 years. Prominent
experts have pronounced that no single mechanism could
possibly explain the bewildering multitude of stress and
disease manifestations [2,3]. However, that turns out not
to be the case.
Powerful scientific theories often appear long before
their time. They must await the death of critics and the
accumulation of supporting evidence before they are em-
braced, and the visionaries who contribute them seldom
outlast their critics1. Nearly thirty years after Selye’s
death, fresh evidence has finally enabled the first descri-
ption of the long sought “stress repair mechanism”
(SRM) that explains stress theory and enables it to be
tested and verified (Figure 1) [4]. The SRM was identi-
fied after compelling new information about coagulation
factor VIII insp ired an ex tensive review of scientific lite-
rature using Internet resources [5]. PubMed provided the
primary source of published medical research reports.
Computer search techniques made it possible to effi-
ciently evaluate thousands of research abstracts to iden-
tify pertinent papers, and obtain full copies via email.
Sophisticated “Endnote” software2 facilitated the man-
agement of hundreds of essential references. The distinc-
tive physical and enzymatic properties of factor VIII
served as a “Rosetta Stone” that deciphered SRM char-
acteristics and yielded a fresh explanation for coagula-
tion [6] that was soon followed by explanations of athe-
rosclerosis [7,8], capillary gate theory [9,10], and tissue
repair theory [11,12]. Finally, all of these seemingly dis-
parate mechanisms were comprehended as elements of
the SRM [4].
The SRM exceeds the expectations of earlier stress
researchers. As they anticipated, it explains both hemo-
dynamic physiology and tissue repair, and it enables Se-
lye’s Universal Theory of Medicine that explains physic-
ology, pathology, stress, and their relationships. In addi-
tion, it provides a new theory of anesthesia, analgesia,
allostasis, and surgical stress [13]. Its appearance ex-
plains the Cambrian Explosion. It provides unexpected
insights to vertebrate cell biology, embryology, evolution,
anatomy, apopto sis, behavior, intelligence, and taxon omy
that will be detailed in a future publication. It explains
the hitherto mysterious nature of inflammation and apo-
ptosis and their role in the tissue repair process, which is
the subject of this pap er.
It retrospect, it is not surprising that the SRM eluded
detection until now. It is complex and counterintuitive,
and it conflicts with entren ched medical beliefs, practices,
and assumptions. In retrospect, the previous generation
of stress researchers was amazingly insightful, and their
capillary gate and tissu e repair theories paved the path to
SRM discovery. The “coagulation cascade” concept that
appeared in their time was analogous to the SRM, but
critical information necessary to clarify the relationships
of coagulation enzymes to tissue repair was unavailable
until recently. Apoptosis was generally unknown before
1972 [14]. The dual autonomic innervation of the vascu-
lar endothelium was unclear [15]. Thrombin was re-
garded as a “coagulation enzyme” that was similar to
other enzymes in the coagulation cascade. The chimeric
nature of Factor VIII had yet to be clarified [5]. “Nitrer-
gic Neurogenic Vasodilation” was unknown [16]. Che-
mokines and cytokines were obscure [17]. Chemical tests
could not distinguish the physical properties of fibrino-
gen, soluble fibrin, and insoluble fibrin. These and other
important elements of SRM operation have been clarified
during the 30 years since stress theory was abandoned,
and this fresh information has finally enabled the first
crude description of the SRM.
2. THE STRESS REPAIR MECHANISM
Even though compelling evidence suggests an intimate
relationship between coagulation and tissue repair, medi-
cal education has traditionally treated hemostasis as an
independent phenomenon whose sole purpose is to stem
blood loss. Researchers and clinicians may therefore be
surprised to learn that coagulation is but one manifesta-
tion of the cohesive SRM mechanism that explains tissue
repair, hemodynamic physiology, pathology, and stress.
Detailed and fully referenced descriptions of the SRM
and its medical effects have already been published [4,
13] and are available from the author’s website3.
The SRM consists of the autonomic nervous system,
the vascular endothelium, and the enzymatic interaction
of blood-bor ne hepatic enzyme Factors VII, VIII, IX, and
X that generates thrombin, soluble fibrin, and insoluble
fibrin. The effects of these three products explain all SRM
manifestations, including inflammation and apoptosis.
1http://en.wikipedia.org/wiki/Alfred_Wegener
2http://www.endnote.com/enhome.asp 3www.stressmechanism.com

L. S. Coleman / Advances in Bioscience and Biotechnology 3 (2012) 459-503 461
Term Meaning
TFPI Tissue Factor Pathway Inhibitor
ATIII Stoichiometric ATIII
ATP Adenosine Tri-Phosphate
SVR Systemic vascular resistance
CO Cardiac output
HR Heart rate
DIC Disseminated Intrav asc ular Coagulation
HAPE High-Altitude Pulmonary Edema
ARDS Adult Respiratory Distress Syndrome
MSOF Multi-System Organ Failure
ARF Acute Renal Failure
TPA Tissue Plasminogen Activator
PAI Plasminogen Activator Inhibitor
Figure 1. The Stress Repair Mechanism (SRM). The SRM appears complex, but its underlying structure is simple and symmetrical.
Arrows represent the influence (direct and indirect) that one biological function or reaction brings to bear on another. The SRM is
analogous to the older “ co agulati on casc ade ” co nce pt, but i t com b ines m ore r ecen t research informa tion with c apillar y gat e th eo ry and
tissue repair theory to produce a cohesive explanation of capillary hemostasis, tissue repair, physiology, and pathology as well as
coagulation. The capillary gate component corresponds to the intrinsic pathway of the coagulation cascade. The tissue repair compo-
nent corresponds to the extrinsic pathway of the coagulation cascade. Both the SRM and the coagulation cascade generate thrombin,
and convert fibrinogen to soluble fibrin and thence to insoluble fibrin.

L. S. Coleman / Advances in Bioscience and Biotechnology 3 (2012) 459-503 462
Thrombin is the “Universal Enzyme of Extracellular
Energy Transduction.” Though it is conventionally re-
garded as a “coagulation enzyme,” it energizes both he-
mostasis and tissue repair. It also energizes activity that
is not directly related to SRM operation, such as the
complement cascade and gelsolin [18,19]. It transforms
ATP energy into both cell and enzyme activities [20-32 ].
It affects all cell types thus far tested via their protease
activated receptors (PAR), which vary in type and num-
ber according to individual cell types [31,33-42]. It in-
creases intracellular Calcium levels and mitochondrial
activity via PAR-1 receptors [21,31,37,43-48]. Its acti-
vity requires Ca+, and parathyroid glands regulate ex-
tracellular Ca+ to optimize its activity [48-62]. Mg+
competitively inhibits Ca+ and mitigates thrombin acti-
vity [46,49,58,63-78].
All cells thus far tested possess PAR (thrombin) re-
ceptors that are present in various combinations that are
characteristic of specific cell types, and these combina-
tions determine how individual cell types react to throm-
bin [79,80]. PAR (thrombin) receptors are over-expressed
during both malignancy and normal tissue repair [25,81].
The SRM continuously generates thrombin in all tis-
sues to energize tissue maintenance [82,83]. It acceler-
ates thrombin generation to energize hemostasis immedi-
ately after injury [84]. It then maintains lesser thrombin
elevations to energize tissue repair [79]. As healing nears
completion, it returns thrombin to maintenance levels,
causing clot disintegration and apoptosis of repair cells
that facilitates wound closure [33,38]. Thrombin ener-
gizes and orchestrates all elements of tissue maintenan ce
and repair including the following:
 Chemotaxis of platelets, osteocytes, white blood cells,
and other tissue repair cells [53,79,80,85]
 Mitosis [42,53,82,86,87]
 Metabolism [53]
 Hypertrophy [53,80,88-91]
 Angiogenesis [21,45,92]
 Platelet activation, chemotaxis, and thromboxane re-
lease [20,93-96]
 Proliferation, spreading and gap formation in the vas-
cular endothelium [47,97]
 Release of chemokines, cytokines, interleukins, bra-
dykinins, caspases, and prostaglandins [35,85,90,98-
106]
 Production of bone, muscle, collagen and immune
activity by osteocytes, myocytes, fibroblasts, and im-
mune cells [17,28,33,43,5 1,80,86,89,91,97,107-116]
 Conversion of fibrinogen to soluble fibrin [56] that
facilitates tissue repair
 Conversion of fibrillar soluble fibrin to three-dimen-
sional insoluble fibrin [55,84,117-125] that enables
hemostasis and regulates tissue repair and hemody-
namic physiology
 Stabilization of insoluble fibrin via “Thrombin-Acti-
vated Fibrin ol y s i s Inhibitor” (TAFI) [122,12 6-129]
 Inflammation, which dissolves the “basement mem-
brane” that binds cells in tight formation with one an-
other and with the Vascular Endothelium to facilitate
chemotaxis [37,51]
 Proliferation of astrocytes and glial cells in brain tis-
sue [42,87].
 Activation of gelsolin that neutralizes Actin [18]
 Complement activation that attacks foreign antigens
[19]
 T-cell activation independent of an immune response
[39,109]
 Blast transformation in lymphocytes
 Increased macrophage phagocytic activity [39,45,48,
92,109,113,130]
 Activation of plasma (immune) cells and neutrophils
[113,124,131]
 Release of “Tumor Necrosis Factor” from microglial
cells [132]
 Tumor growth, malignancy, and fibrosis [29,33,34,38,
107,108,112,133,134]
 Inhibits apoptosis [31,34,40,41,135,136]
 Intracellular gap formation in the vascular endothe-
lium that increases permeability [47]
 Defects in Factors VII, X and Tissue Factor that dis-
rupt thrombin generation necessary for embryological
development and tissue repair are generally lethal
[137]
 Embryological development, tissue maintenance,
wound healing [24,44 ,82,83,138]
Thrombin energizes the conversion of fibrinogen to
soluble fibrin, and then energizes the conversion of solu-
ble fibrin to insoluble fibrin (see below). Older studies
have confused fibrinogen, soluble fibrin, and insoluble
fibrin, because they are nearly identical chemically [125,
139-142]. Their fluctuating equilib rium determin es bloo d
viscosity and co agulability (see “The capillary gate com-
ponent” below).
Fibrinogen is a structurally complex protein molecule
that exists in more than one form. It is the precursor of
both soluble and insoluble fibrin. The liver produces and
releases fibrinogen into the blood at steady rates. It can-
not escape the intact vasculature. It is not directly in-
volved in either tissue repair or hemostasis, but fibrino-
gen depletion causes defective insoluble fibrin produc-
tion [117,143]. Fibrinogen consists of alpha, beta and
gamma subunits that are connected by disulfide bonds
[125]. Thrombin disrupts the disulfide bonds and causes
the alpha, beta, and gamma fibrinogen subunits to poly-
merize into fibrillar (two-dimensional) strands of “solu-
ble fibrin” [47,56,123].
Soluble fibrin is the “Universal Protein of Tissue Re-
pair.” It is the precursor of insoluble fibrin, but it has no

L. S. Coleman / Advances in Bioscience and Biotechnology 3 (2012) 459-503 463
direct effect on blood viscosity and coag u lability. It is the
substance of pus, scabs, mucus, exudates, renal casts, and
hyaline deposits [144,145]. Thrombin-generated soluble
fibrin escapes from the vascular system through thrombin-
induced inflammatory gaps in the vascular endothelium
into thrombin-inflamed extravascular tissues to form a
structural matrix that facilitates the formation of granu la-
tion tissue that fills wound cavities [28 ,47,56 ,8 6,122,1 24,
144]. Excessive soluble fibrin generation causes tissue
edema and disrupts organ function. For example, soluble
fibrin causes proteinuria and hyaline casts. It disrupts
pulmonary function by flooding alveoli in pneumonia
and influenza, and narrowing airway passages in asthma
[139,144,146,147]. Soluble fibrin deposits promote col-
lagen production, fibrosis, sclerosis, adhesions, and scar
formation [116,140,141,148-159]. For example, perito-
neal soluble fibrin deposits produce peritoneal adhesions
after surgery and infection, and alveolar soluble fibrin
evolves into pulmonary fibrosis in the aftermath of
ARDS, chronic asthma, and prolonged pulmonary infec-
tion. Thrombin inhibitio n mitigates so luble fibrin gen era-
tion and collagen production [108], but most anticoagu-
lants have minimal effect on soluble fibrin deposits and
collagen scars once they have formed [160].
Insoluble fibrin is the “Universal Polymer of Hemo-
stasis”. It cannot escape the intact vascular system. It
binds red cells and platelets together, and this produces
several seemingly unrelated effects. It increases blood
viscosity and coagulability, accelerates atherosclerosis,
activates capillary hemostasis, and forms viscoelastic
clots that stem blood loss and then regulate tissue repair
[123,161-170]. The generation and disintegration of in-
soluble fibrin explains viscoelastic clot formation, capil-
lary hemostasis, hemodynamic physiology, organ regula-
tion, tissue repair regulation, atherosclerosis acceleration,
infarction, and the effects of anticoagulants and “vasoac-
tive” drugs [171].
The conversion of soluble fibrin to insoluble fibrin
occurs in a series of complex enzymatic interactions.
Factor VIII accelerates thrombin generation to energize
its enzymatic conversion of Factor X to Factor XIII [163,
168,169]. Factor XIII adds plasminogen and fibronectin
cross-links to fibrillar soluble fibrin to generate three-
dimensional insoluble fibrin that spontaneously polyme-
rizes into strands that bind red cells and platelets together
[165,170,172]. The plasminogen cross-links spontane-
ously deteriorate into plasmin that disintegrates insoluble
fibrin into inert fibrin sp lit products (FSP, or d-Dimer)—
unless plasminogen is continuously stabilized by throm-
bin via Thrombin Activated Fibrinolysis Inhibitor (TAFI)
[122,126-129]. Parasympathetic Nervous System (PNS)
activity stimulates the release of nitric oxide, which
binds avidly to Ca+, inactivates thrombin, and acceler-
ates the disintegration of insoluble fibrin [49]. The ef-
fects of insoluble fibrin are thus readily reversible, and
this explains the fluctuations of blood viscosity, tissue
perfusion, and organ regulation in accord with autonomic
balance.
Hemophilia and von Willebrand Disease Coagulo-
pathies illustrate the difference between soluble fibrin
and insoluble fibrin. Both conditions paralyze Factor
VIII, which impairs the ability to convert soluble fibrin
to insoluble fibrin for hemostasis. Afflicted patients re-
tain the normal ability to generate solub le fibrin to repair
tissues and produce pus, scabs, exudates, soluble fibrin
deposits, fibrosis, scars, and adhesions [173,174]. Like
normal patients, they produce excessive quantities of so-
luble fibrin in accord with pneumonia, influenza, ARDS,
MOFS, asthma, and eclampsia [146,147,155-157,175].
However, their inability to produce Factor VIII in normal
quality and/or quantity inhibits their ability to accelerate
thrombin generation to activate platelets, energize the
enzymatic conversion of soluble fibrin to insoluble fibrin,
and stabilize the insoluble fibrin molecule via “Thrombin-
Activated Fibrinolysis Inhibitor” (TAFI) [93,126,170,
176-182]. This explains why they exhibit abnormally low
blood viscosity and coagulability, retarded atherosclero-
sis, and reduced incidence of heart disease, as well as
defective coagulation and capillary hemostasis [183-185 ].
Defects or deficiencies in Factor XIII also disrupt the
conversion of soluble fibrin to insoluble fibrin by inhibi-
ting the installation of plasminogen and fibronectin
cross-links in the insoluble fibrin structure, but these
Coagulopathies do not impair thrombin generation and
platelet activation and are usually less severe [186-188].
Insoluble fibrin elevations cause increased viscosity
and coagulability that pre-disposes to Disseminated In-
travascular Coagulation (DIC), thrombophlebitis, pulmo-
nary embolus, and accelerated atherosclerosis [189-194].
Insoluble fibrin generation also closes the capillary gate
and disrupts perfusion and oxygenation in organs and
tissues (see “Capillary Gate Component” below). This
causes stroke [195,196], mental disturbances [197,198],
myocardial infarction [195,199-202], renal dysfunction
[145], bowel infarction, bowel ileus, and increased vas-
cular resistance.
3. THE DYNAMIC ENZYMATIC
INTERACTION OF FACTORS VII, VIII,
IX, AND X
The interaction of hepatic Factors VII, VIII, IX, and X
generates thrombin, soluble fibrin, and insoluble fibrin.
Tissue factor activates Factor VII to initiate the interact-
tion [54,121,158,203-213]. Factor VII slowly penetrates
the vascular endothelium to enter extravascular tissues,
where tissue factor activates it to generate small amounts
of thrombin sufficient to energize tissue maintenance [83,
214], but insufficient for hemostasis or tissue repair

L. S. Coleman / Advances in Bioscience and Biotechnology 3 (2012) 459-503 464
[121]. In the immediate aftermath of injury, Factor VIII
interacts with Factors VII, IX, X and tissue factor to ac-
celerate thrombin generation to very high levels neces-
sary to energize insoluble fibrin production for coagula-
tion [123,162-170]. The viscoelastic clot then regulates
contact between blood enzymes and damaged tissues. It
is impermeable to Factor VIII, but it allows Factors VII,
IX and X to enter damaged tissues, where Factors IX and
X interact with Factor VII and tissue factor to amplify
thrombin generation to levels sufficient to energize cel-
lular repair activities [121,215].
The priority of tissue development, maintenance, and
repair is illustrated by teratogenic and potentially lethal
anticoagulants and defects that affect Factors VII, X and
tissue factor [32,52,82,83,108,216,217]. Defects in he-
mostasis Factors VIII, IX and XIII are non-teratogenic
and survivable [173]. Heparin does not disturb tissue
maintenance and is non-teratogenic because it inhibits
only Factor VIII.
4. THE CENTRAL ROLE OF THE
VASCULAR ENDOTHELIUM
The vascular endothelium is a ubiquitous, diaphanous,
selectively permeable layer of cells, one cell thick, that
lines all blood vessels and is the sole constituent of cap-
illary walls. It controls the dynamic interaction of enzy-
matic Factors VII, VIII, IX and X. The vascular endothe-
lium secretes tissue factor into extravascular tissues and
then insulates it from the Factor VII flowing freely in
blood, so that tissue damage exposes tissue factor to
blood-borne Factor VII and initiates tissue repair com-
ponent activity (see “Tissue Repair Component” below)
[203,210,212,218-221].
The vascular endothelium also functions as a neuro-
endocrine organ that releases nitric oxide hormone and
von Willebrand Factor hormone into blood in accord
with autonomic balance to regulate the capillary gate
component (see “Capillary Gate Component” below) [15,
222-226]. Endothelial cells respond to their immediate
surroundings and communicate with one another via ele-
ctrical signals. Endothelial cells also produce fibronectin
[165], tissue factor pathway inhibitor (TFPI) [220], pro-
tein C [227], and tissue plasminogen activator (TPA)
[144,228].
5. THE SRM SUB-COMPONENTS
The SRM consists of two semi-independent sub-com-
ponents. The tissue repair component regulates Factor
VII activity to maintain and repair extravascular tissues.
The capillary gate component regulates Factor VIII ac-
tivity to govern hemodynamic physiology. These two
sub-components share the enzymatic interaction of Fac-
tors VII, VIII, IX, and X, so that the activity of each ex-
aggerates that of the other. This enables the SRM to ge-
nerate positive feedb ack and focus its powerful effects to
repair damaged tissues. It also explains the bewildering
variety of SRM manifestations in health and disease.
6. THE CAPILLARY GATE COMPONENT
The capillary gate component consists of Factors VII,
VIIIC, IX and X, the autonomic nervous system, the
vascular endothelium, von Willebrand Factor, and nitric
oxide. It generates and disintegrates insoluble fibrin in
accord with autonomic balance to simultaneously govern
a capillary gate mechanism (see page 9) that regulates
tissue perfusion, capillary hemostasis, and o rgan function
and a turbulence mechanism (see page 10) that regulates
turbulent viscosity in arterial blood flow [222,229-231].
The capillary gate component explains why von Wille-
brand Factor, Factor VIII, insoluble fibrin, d-Dimer (Fi-
brin Split Products), blood v iscosity, b lood coagulability,
blood pressure, cardiac output, heart rate, capillary he-
mostasis, tissue perfusion, tissue oxygenation, athero-
sclerosis, and organ function all fluctuate in accord with
autonomic balance [15,222,231-246]. Its acute hyperac-
tivation causes infarction, pulmonary embolus, throm-
bophlebitis, and high altitude pulmonary edema (HAPE)
[189,190,195,199,247-266]. Its chronic hyperactivation
accelerates atherosclerosis and capillary senescence that
causes diabetes, hypertension, and congestive heart fail-
ure [225,231,232,257,267-279].
The Factor VIII complex links the sympathetic nervous
system to the enzymatic interaction of Factors VII, VIIIC,
IX and X. Factor VIII consists of von Willebrand Factor
produced by the vascular endothelium and Factor VIIIC
produced by the liver. These bind together to circulate
and exert their effects in concert. Sympathetic nervous
system activity releases von Willebrand Factor hormone
from the vascular endothelium to stabilize enzymatic
Factor VIIIC and thereby regulate the activity and half-
life of Factor VIII. Factor VIII then interacts with Factors
VII, IX and X to accelerate thrombin generation to ener-
gize its conversion of Factor X to Factor XIII. Factor
XIII adds “cross-links” of fibronectin and plasminogen
to soluble fibrin to generate insoluble fibrin in capillaries
and flowing blood [224,280-286]. Continued Factor VIII
activity inhibits the spontaneous disintegration of insolu-
ble fibrin into inert fibrin split products via thrombin
activated fibrinolysis inhibitor (TAFI) [118,126,170,179,
234].
Parasympathetic nervous system activity disintegrates
insoluble fibrin by releasing nitric oxide from the vascu-
lar endothelium. Nitric oxide is a ubiquitous gaseous
signaling molecule that bind s avidly to Ca+, which inac-
tivates thrombin, and thereby accelerates the spontaneous
disintegration of in soluble fibrin [16,226,246,287-296].

L. S. Coleman / Advances in Bioscience and Biotechnology 3 (2012) 459-503 465
Capillary gate component operation requires the con-
tinuous “leakage” of tissue factor from extravascular
tissues into blood circulation to activate Factor VII,
without which Factors VIII, IX and X remain inert. The
vascular endothelium releases Stoichiometric ATIII, tis-
sue factor pathway inhibitor (TFPI), and protein C hor-
mones into blood to quench excessive Factor VII activity
lest Factors VIII, IX and X interact with activated Factor
VII to harmfully exaggerate thrombin generation in
flowing blood [121,129,201,207,212,215,220,227,297-
301].
7. THE CAPILLARY GATE MECHANISM
Capillary perfusion is the essence of hemodynamic
physiology. Athletic conditioning induces angiogenesis
that enhances tissue perfusion and oxygenation, mitigates
flow resistance, reduces blood pressure, and enhances
ejection fraction, which slows heart rate via the Starling
mechanism [24,270,302-317]. Allostatic load accelerates
capillary senescence [318-320] that increases vascular
resistance, impairs tissue and organ perfusion, inhibits
glucose uptake, and causes diabetes and essential hyper-
tension [142,192,231,232,267,273,276,277,279,321-327].
The capillary gate is a sub-microscopic, molecular
mechanism that governs capillary flow, tissue perfusion,
organ function, and capillary hemostasis—despite the
absence of contractile musculature in capillaries. [15,254,
288,289,328,329] It operates efficiently, because capil-
lary flow, pressure, and turbulence are minimal, and cap-
illary surface area is greater than that of all other vessels
combined. The capillary gate explains hemodynamic
physiology and “vasoactive” drug effects in terms of fib-
rinogenesis and fibrinolysis (the generation and disinter-
gration of insoluble fibrin) as opposed to “vasoconstric-
tion,” “vasodilation,” and “stiffness” of muscular arteri-
oles that become rapidly exhau sted [66,171,229, 236,237,
242,251,254,280,330-334].
Sympathetic nervous system activity “closes” the cap-
illary gate by causing the vascular endothelium cells of
the capillary walls to release von Willebrand Factor [278,
282,283,285,286]. This release activates Factor VIIIC,
which converts fibrinogen and fibronectin at adjacent
binding sites into polymerizin g strands of insoluble fibrin
that bind to passing red cells and halt capillary flow [161,
165,186,273,335,336].
Nitrergic neurogenic vasodilation “opens” the capil-
lary gate by releasing nitric oxide from the vascular en-
dothelium in visceral organs, including eye, brain, lung,
GI tract, urinary tract, and pancreas via direct parasym-
pathetic innervation [16,226,246,287-290,337]. Parasym-
pathetic stimulation also releases insulin, which indi-
rectly mobilizes nitric oxide in the capillaries of skeletal
muscle and other peripheral tissues where parasympa-
thetic innervation is absent [331,338-348]. This explains
why insulin prolongs bleeding time, reduces systemic
vascular resistance, increases cardiac index, aggravates
angina, and counteracts “vasopressor” (fibrinogenic) drugs
[307,314,315,332,343,349-352]; why allostatic load in-
hibits insulin effects [353]; and why diabetes and hyper-
tension are closely-related [225,231,232,268-271,273,
276-279,315-317,321-323,348,354-363].
The vascular endoth elium additionally regulates capil-
lary flow via TPA (tissue plasminogen activator) that dis-
integrates insoluble fibrin, and its rapid inhibitor, plas-
minogen activator inhibitor (PAI-1) [187,228,364,365].
Astrocytes proliferate when exposed to thrombin and
release TPA to ensure brain perfusion [87,228]. Their
anticoagulant effects necessitate abundant tissue factor,
which explains the exaggerated morbidity of brain injury
[107,140,210].
Coagulopathies reveal capillary gate characteristics.
Capillary structural integrity requires von Willebrand
Factor, so that chronic von Willebrand Factor deficien-
cies cause flow-related capillary damage called angio-
dysplasia [366-374]. Sudden von Willebrand Factor de-
struction disrupts capillary gate structure, causing ana-
phylaxis (angioneurotic edema), wherein vascular resis-
tance and blood pressure drop sharply as blood shifts
from larger vessels into capillaries, causing lethal airway
edema, while coagulation enzymes and cardiac output
remain unaffected [375-377]. Defective VIIIC (true he-
mophilia) paralyzes capillary gate regulatio n, causing ex-
ercise intolerance, but capillary gate structure and ana-
phylaxis susceptibility remain intact [378-380].
8. THE TURBULENCE MECHANISM
Red cell mass exceeds oxygen requirements, and hemo-
globin encapsulation does not enhance oxygen delivery.
However, the physical characteristics of red cells alter
blood turbulence, and thereby beneficially affect blood
viscosity, coagulability, atherosclerosis, and hemody-
namic efficiency [381-385].
In pipes, turbulence causes viscosity (flow resistance)
to increase exponentially with velocity in “Newtonian”
fluids such as water and oil (Figure 2) [386]. Mamma-
lian blood, however, is a “non-Newtonian” fluid that
exhibits exponential declines in viscosity with in creasing
velocity. This is because bi-concave mammalian red cells
spontaneously form highly efficient, self-organizing
“aggregate” flow structures that suppress systolic turbu-
lence to optimize blood acceleration, cardiac output, and
peak end-systolic velocity [292,387-393]. Mammalian
arterial blood flow during systolic ejection might thus be
compared to electrical “superconductivity”. The resulting
hemodynamic efficiency explains the mammalian heart
accelerates blood from 0 to 125 cm/s in a tenth of a se-
cond (Figure 3) and why the hearts of both elephant and

L. S. Coleman / Advances in Bioscience and Biotechnology 3 (2012) 459-503 466
Figure 2. Newtonian pipe flow turbulence [386] turbulent for-
ward flow appears as fast-moving “jet streams” (shown in red)
that form along the inner walls of pipes and force slow-moving
fluid to the center, where it moves backward (shown in blue),
causing increased viscosity (flow resistance). (a), (c) and (e) are
laser photographs that show “fast (a), faster (c) and fastest (e)”
flow acceleration that produce “small (a), medium (c) and large
(e)” increases in turbulent intensity. (b), (d) and F are computer
simulations that predicted the experimental re- sults shown by
(a), (c) and (e). Similar arterial turbulence dur- ing diastole
mobilizes particulate deposits from arterial walls to prevent
atherosclerosis. It also genera tes lateral forces that press on the
inner walls of the vessel, which explains blood pressure and the
palpable pulse.
mouse weigh only 0.6% of their body weight [394]. Dia-
stolic deceleration disrupts the aggregates, and sud-
denly converts their kinetic energy into Newtonian tur-
bulence that dissipates in a traveling pulse wave. The
pulse wave periodically increases viscosity, halts flow,
generates turbulent mixing that inhibits coagulation and
atherosclerosis, and induces turbulent lateral forces that
explain blood pressure and the palpable pulse [395,396].
Diastolic turbulence is inversely related to red cell
mass. Polycythemia accelerates atherosclerosis and in-
creases coagulability. An emia progressively retards athe-
rosclerosis and paralyses coagulation [176,397-403].
Oil must flow through a pipeline at high rates to gene-
rate enough turbulence to prevent sludge deposits [404].
Similarly, pulsatile arterial flow operates at the threshold
of peak diastolic turbulence to prevent atherosclerosis.
The vascular endothelium adjusts arterial diameter via
neuromuscular control to optimize diastolic turbulent
mixing, which mobilizes particulate deposits from arte-
rial walls [236,405-407]. Without adequate turbulence,
deposits form on the inner walls of arteries, and this ac-
tivates the tissue repair component, causing thrombin
and soluble fibrin generation, inflammation, tissue factor
accumulation, fibrosis, and cholesterol trapping that forms
atherosclerotic p laque [196,221,222,327,408-416].
The washing machine demonstrates how shear stress
induces turbulence, and how viscosity exponentially in-
hibits turbulence even though it has no effect on shear
Figure 3. Turbulence and velocity in pulsatile blood flow in a
dog. Mammalian red blood cells spontaneously form aggre-
gates that suppress turbulence during systole to enable rapid
and efficient blood acceleration. Diastolic deceleration disrupts
the aggregates and converts laminar systolic flow into diastolic
turbulence that halts net forward flow [395]. In humans, the
brief flow reversal in the distal aorta inhibits turbulent clean-
sing and accelerates atherosclerosis relative to the proximal
aorta [408].
stress. The rotor mechanism of the washing machine
corresponds to the heart. The mixture of so ap, water, and
dirty clothes corresponds to blood. Like the heart, the
rotor mechanism of the washing machine generates con-
sistent work with each cycle. The force induced by the
rotor corresponds to shear stress. Each times the rotor
changes direction, it causes a burst of turbulent mixing
that exponentially increases contact between soap, clo-
thes, dirt, and water to enhance the ability of soap to
clean clothes. The clothing load corresponds to blood
viscosity. With reasonable clothing loads, turbulent mix-
ing is optimized, and cleaning proceeds efficiently. If the

L. S. Coleman / Advances in Bioscience and Biotechnology 3 (2012) 459-503 467
machine is overloaded, the rotor energy is shifted in fa-
vor of turbulent lateral forces at the expense of turbulent
mixing, and the clothes are not cleaned properly. Simi-
larly, increased blood viscosity alters diastolic pulsatile
blood turbulence in favor of turbulent lateral forces that
increase blood pressure at the expense of turbulent mix-
ing forces that inhibi t at her os cl e rosis.
Atherosclerosis begins on the greater curvatures of ar-
teries, where shear stress and systolic velocity decline
and turbulence decreases exponentially [405-407,417-
421]. Diastolic turbulence increases exponentially with
end-systolic velocity. Exercise increases cardiac contrac-
tility, elevates peak end-systolic velocity, exaggerates
diastolic pulsatile turbulence, and inh ibits atherosclerosis.
Myxedema, congestive heart failure, and sedentary life
style reduce cardiac contractility, retard peak end -systolic
velocity, decrease diastolic cleansing turbulence, and
accelerate atherosclerosis [305,306,422-431].
Like ultrasound, diastolic turbulence inhibits coagula-
tion [432]. Thrombosis is rare in arteries, where turbu-
lence is intense, but thrombophlebitis is common in veins,
where turbulence is sluggish [433]. Insoluble fibrin fluc-
tuates in blood in accord with sympathetic nervous sys-
tem activity, which is increased by allostatic load. In-
soluble fibrin entangles red cells and disrupts aggregate
patterns, which induces systo lic turbulence that increases
viscosity, decreases Ejection Fraction, and increases heart
rate via the Starling mechanism [161,268,304,392,434].
Insoluble fibrin elevations disrupt red cell aggregates and
induce turbulence during systolic acceleration that strains
and collapses structurally defective red cells, causing
sickle-cell anemia crisis [435-440]. Systolic turbulence
also retards peak end-systolic blood velocity, which ex-
aggerates diastolic turbulent lateral forces at the expense
of turbulent mixing, elevates blood pressure, increases
blood coagulability, and accelerates atherosclerosis [118,
183,185,196,268,385,396,424,432,441-451]. Insoluble fi-
brin binds red cells into a clot after it reduces turbulent
mixing belo w a threshold [161, 43 2, 4 52].
Blood turbulence normally occurs below the threshold
of hearing. Blood pressure cuff inflation constricts arte-
rial diameter, increases flow velocity, and alters the tur-
bulent pulse wave so as to elevate diastolic turbulent
frequencies above audible levels at the distal edge of the
cuff to produce Korotkoff sounds that are analogous to
bruit sounds [453]. The blood pressure cuff measures
diastolic turbulent lateral forces in arteries, as opposed to
the forward force imparted by cardiac contraction that
induces laminar systolic blood flow, so that blood pres-
sure is not directly related to perfusion. Blood pressure is
similar among most mammalian species because red
cells and body temperature are nearly identical, and car-
diac power generation is proportional to body size [394].
Hemodynamic relationships usually appear linear be-
cause turbulent variables are maintained within narrow
ranges. However, hemodynamic parameters are affected
by complex fluctuating exponential interactions of ino-
tropy, chronotropy, temperature, and viscosity that can
produce non-linear perturbations. This explains why
blood pressure and cardiac ou tput are not linearly related
[454,455].
Reptilian red cells enhance systolic turbulence at the
expense of cardiac output to prevent atherosclerosis
caused by lipoprotein solidification at cool temperatures
that exaggerates blood viscosity [456,457]. This limits
reptile cardiac output and constrains the ability of rep-
tiles to deliver oxygen to peripheral tissues, so that they
must rely on anaerobic metabolism to sustain vigorous
activity [458]. This explains why reptiles have limited
exercise capacity. Reptiles thus thrive in warm environ-
ments and their activity is sluggish at low temperatures.
Mammals achieve superior exercise tolerance and domi-
nate cold environments by maintaining their body tem-
perature above the level of fat liquefaction, which en-
ables their bi-concave red cells to simultaneously opti-
mize hemodynamic efficiency and atherosclerosis resis-
tance, but this necessitates substantially greater caloric
intake [456,457,459,460].
9. THE TISSUE REPAIR COMPONENT,
INFLAMMA TION, AND APOPT OSIS
The tissue repair component continuously maintains and
repairs tissues by elevating thrombin levels in injured
tissues. It consists of the vascular endothelium, tissue
factor hormone, and the enzymatic interaction of Factors
VII, VIII, IX, and X. Its activity explains all aspects of
the inflammation syndrome, including rubor, calor, dolor,
edema, and loss of function.
The selectively permeable vascular endothelium al-
lows the slow, continuous penetration of Factor VII from
blood into healthy extravascular tissues, where tissue
factor activates it to generate small amounts of thrombin
that energize fibroblast mitosis and collagen production
to maintain tissues [83,108,159].
Trauma disrupts the fragile vascular endothelium and
directly exposes tissue factor to blood enzymes [88, 210,
212]. Factor VII activation by tissue factor initiates the
enzymatic interaction and determines its magnitude and
location [208,209,212]. Factors IX and X amplify Factor
VII thrombin production to mod erate levels that energize
tissue repair [27,121,215]. Factor VIII then accelerates
thrombin production to high levels to generate insoluble
fibrin for hemostasis [30,93,94,121,182,410,461]. Pulsa-
tile blood flow thrusts platelets into damaged tissues
[462], where thrombin chemotaxis attracts them and in-
soluble fibrin binds them into a short-lived “white clot”
[94]. Thrombin-activated platelets release thromboxane

L. S. Coleman / Advances in Bioscience and Biotechnology 3 (2012) 459-503 468
that induces local vasoconstriction to temporarily reduce
flow and turbulence, which increases coagulability. Ris-
ing levels of insoluble fibrin increase local blood visco-
sity to reduce pulsatile turbulent mixing below a thres-
hold (see “turbulence mechanism” on page 10), where-
upon insoluble fibrin binds red cells into a durable, vis-
coelastic, selectively permeable “red clot” that substi-
tutes for the damaged vascular endothelium by isolating
damaged tissues from flowing blood [84,161,169,432,
452]. The enormous molecular size of Factor VIII pre-
vents it from penetrating the clot and interacting with the
other enzymes, so that clot formation is self-limiting.
The red clot regulates thrombin in damaged tissues
[463,464]. Factors VII, IX, and X penetrate the clot and
interact with tissue factor to generate thrombin, which
reduces clot permeability and constrains thrombin pro-
duction [29,126,212,463-465]. Tissue repair then pro-
ceeds in predictable stages, energized by optimized
thrombin levels [135]. Thrombin elevations in damaged
tissues cause cells to release bradykinins, caspases, pros-
taglandins, chemokines, cytokines, and interleukins. These
induce inflammation and enable cell-to-cell communica-
tions that coordinate cell repair activities and determine
the stages of wound healing [1,466-469]. Inflammation
loosens cell con nections to facilitate the entry and move-
ment of soluble fibrin and repair cells [47]. Thrombin-
generated soluble fibrin moves from blood through in-
flammatory gaps in the vascular endothelium to enter
damaged tissues, where it creates a structural matrix that
facilitates repair cell activity [149]. Thrombin elevation
in damaged tissues attracts fibroblasts, myoblasts, os-
teocytes, and immune cells via chemotaxis, and these
cells move through inflamed tissues into damaged tissues,
where they proliferate and produce collagen, muscle,
bone, and immune activity to fill empty spaces, replace
damaged tissues, inhibit infection, and remove debris and
foreign substances [108,109,159]. Thrombin-energized
angiogenesis p e rf uses p rol i fe r a ti ng r epair tissues. Throm-
bin-energized increases in cell metabolism cause tem-
perature elevation in healing tissues. [133] As the repair
process nears completion, proliferation and spreading of
the vascular endothelium restores the normal barrier be-
tween blood enzymes and tissue factor in extravascular
tissues, which reduces thrombin generation to mainte-
nance levels. This undermines clot integrity and repair
cell viability, so that the clot disintegrates, apoptosis fa-
cilitates wound closure by actomyosin, and structural
integrity is restor ed [34,38,470,471 ].
The tissue repair component automatically forms ab-
scesses, furuncles, and fistulas. Fibroblasts produce col-
lagen to form barriers that isolate bacteria and foreign
materials, and inflammation weaken s surrounding tissues
to create passages that expel them from the body. Trauma,
burns, toxic chemicals, sepsis, and radiation disrupt the
vascular endothelium, activate the tissue repair compo-
nent, and release inflammatory substances that sensitize
nociceptors and activate the capillary gate component.
The delay between tissue damage and nociceptor sensi-
tization explains the delayed onset of pain caused by
radiation [213].
10. ANESTHESIA, ANALGESIA,
ALLOSTASIS, AND THE THREE
PATHWAYS OF SRM ACTIVATION
Three independent pathways activate the SRM and focus
its powerful effects: the spinal pathway, the cognitive
pathway, and the tissue pathway. Individual stressors and
combinations of stressors activate these synergistic path-
ways in various magnitudes, locations, intervals, and
combinations, so that the manifestations of SRM activity
appear chaotic and confusing. Analgesia inhibits the spi-
nal pathway, and anesthesia inhibits the cognitive path-
way. There are no clinically available means to inhibit
the tissue pathway.
11. THE SPINAL PATHWAY
The spinal pathway consists of peripheral nociceptors in
the skin and internal organs that detect noxious stimuli
and activate the SNS via peripheral nerves and spinal
cord internuncial pathways. Nociceptors detect vibration,
temperature, inflammation and tissue disruption, but are
insensitive to radiatio n, sepsis, and many toxic chemicals
[472]. Spinal pathway activity is called nociception. De-
scending cortical pathways inhibit nociception, so that
their absence exaggerates nociception [473]. Analgesic
agents inhibit nociception by disrupting spinal pathway
activity. Cyclo-oxygenase (COX) inhibitors prevent in-
flammation that activates nociceptors. Opioids inhibit
spinal cord nociception pathways. Lidocaine, marcaine,
and other local analgesics block the function of periph-
eral nerves, spinal cord pathways, and autonomic nerve
endings that conduct nociception signals. The following
examples illustrate spinal pathway function:
1) Spinal Pathway nociception resists anesthesia in
safe and practical doses [153,4 74-479]. This explains the
release of stress hormones (VWF, cortisol, epinephrine,
glucagon, etc.) during surgery despite dangerously deep
levels of anesthesia. It also explains spinal cord “wind-
up” syndrome that causes problematic muscle tension
and unexpected muscular movements during surgery des-
pite deep levels of anesthesia.
2) Spinal cord damage at or above the level of T5
causes autonomic dysreflexia. The cognitive pathway no
longer responds to nociception , so that pain is eliminated,
but spinal pathway nociception, freed from descending
cortical inhibition, causes harmful SNS hyperactivity that
is little affected by anesthesia [473,480].

L. S. Coleman / Advances in Bioscience and Biotechnology 3 (2012) 459-503 469
3) Cortical inhibition remains intact in spinal cord
damage below the level of T5, and it inhibits spinal cord
nociception pathways and synergizes the effects of gene-
ral anesthetic agents in a manner analogous to analgesia
[481-483].
4) Analgesia prevents both nociception and pain and
thereby reduces surgical morbidity and mortality more
effectively than anesthesia, which prevents only pain,
fear, and apprehension (see Cognitive Pathway below)
[153,479,481,484-504].
5) Pediatric anesthetic methods such as th e once popu-
lar “Liverpool technique” that rely on inhalation agent
supplemented by muscle relaxants do not adequately
control stress. Fetuses and newborn babies cannot under-
stand language and perceive danger, but their nociception
pathways are fully functional so that they require analge-
sia as well as anesthesia for surgical safety [234,505-
510].
6) I hypothesize that cortical damage sometimes im-
pairs descending inhib ition of spinal cord activity, so that
spinal cord nociception pathway activity is exaggerated
in the manner of autonomic dysreflexia (see #2 above). I
further hypothesize that general anesthesia without sup-
plemental analgesia exaggerates nociception by inhibit-
ing cortical activity that is essential for descending path-
way inhibition.
7) Nociceptors are not directly sensitive to radiation
and some toxic chemicals, but they are indirectly and
belatedly activated by inflammation that is induced by
these forms of stress. For example, sunburn is initially
painless, but becomes painful the day after sun exposure
due to the inflammatory effects of radiation damage.
12. THE COGNITIVE PATHWAY
The cognitive pathway consists of conscious awareness
generated by corticofugal mechanisms that assesses en-
vironmental hazards via sensory input including sight,
smell, sound, vibration, and nociception. It activates the
SNS and the HPA axis via hypothalamic pathways that
are independent of the spinal pathway [191,250,511-514].
The cognitive pathway also inhibits spinal pathway no-
ciception via descending pathways from the brain to the
spinal cord [473]. Conscious awareness interprets no-
ciception as pain [515,516]. Inhalation anesthetics are
hypnotic agents that obtund consciousness. Even moder-
ate inhibition of conscious awareness by hypnotic agents
can eliminate pain, but hypnotic agents have little effect
on nociception. The benefits of hypnotic inhalation an-
esthetic agents such as ether, halothane, chloroform,
Ethrane, Isoforane, Desflurane and Sevoflurane are equi-
valent to those of intravenous hypnotic agents such as
benzodiazepines, barbiturates, Propofol, ketamine, Eto-
midate, Althesin, V iadril, and alcohol.
Emotional mechanisms modulate cognitive pathway
activity. This explains allostasis, which is the subcon-
scious alteration of behavior and physiology in accord
with prior experience. Hyperthymestic Syndrome dem-
onstrates that the brain automatically records permanent
audiovisual memories of all waking moments throughout
life, and that these normally suppressed memories acti-
vate emotions and SNS activity [517,518]. Sleep halts
the recording process while the emotional mechanism
engages in the process of dreaming, wherein it automati-
cally compares and contrasts previously stored memories
to identify threatening circumstances [266,511,512,519].
This enables the pre-emptive perception of danger,
whereupon emotional mechanisms automatically gene-
rate anx iet y, rage, fear and app reh ens ion, a nd a ctiv ate th e
SNS and the HPA axis to facilitate “fight or flight” [520,
521]. This activates capillary hemostasis, and, increases
blood viscosity [522], which limits blood loss in the
event of subsequent injury. It also concentrates blood
flow in critical organs such as heart, lung, and brain,
whose tissues resist capillary hemostasis. The HPA axis
simultaneously releases epinephrine, glucagon, cortisol,
and other stress hormones. These combined effects ex-
plain the tachycardia, hypertension, and hyperglycemia,
other reactions associated with acute and chronic allosta-
sis, and how these reactions are progressively altered by
accumulating memories and their ongoing manipulation
by emotional mechanisms [523].
The emotional mechanism plays an important surviv al
role in animals, which often face life or death confronta-
tions and lack the reason ing ab ility o f h umans. Idiopathic
Insomnia demonstrates that sleep and dreaming are not
essential in humans [230,522,524-526]. However, occult
allostasis explains neurosis in humans. It also explains
how emotions alter the perception of pain and danger,
which suggests new treatments for chronic pain and
neurosis [527].
The following examples illustrate cognitive pathway
activity:
1) The cognitive pathway activates the SNS despite
the absence of nociception. One may not sense the pain
of a dentist’s drill, but one can still perceive vibration,
pressure, the noise of the drill, and the comments of the
dentist and his staff. One anticipates pain and danger
consciously, even if none is present, and this activates the
SNS [230,524-526,528-531].
2) The cognitive pathway resists analgesia in clinically
practical doses, because sight, smell, vibration, and sound
perception remain intact. Spinal and epidural analgesia,
analgesic block techniques, and high-dose opioid analge-
sia for cardiac surgery often require supplementation
with hypnotic agents to prevent sharp increases in blood
pressure, pulse rate and muscle activity caused by frigh-
tening sounds and sensations, even though nociception

L. S. Coleman / Advances in Bioscience and Biotechnology 3 (2012) 459-503 470
and pain are absent [15 3,474-478,532,533].
3) Anesthesia increases surgical safety by abolishing
consciousness, fear, apprehension, and pain, but it cannot
prevent harmful spinal pathway nociception in clinically
practical doses [250,266,522,528,534-542].
4) Acute allostatic load, such as occurs in uninjured
earthquake victims, activates the cognitive pathway and
causes acute and residual elevations of VWF, Factor VIII
activity, blood viscosity, blood coagulability, myocardial
infarction, stroke, heart rate and blood pressure in accord
with the severity of fear. This explains how people are
sometimes frightened to death [441].
5) Chronic emotional allostatic load, such as job diffi-
culties, elevates VWF and Factor VIII activity, acceler-
ates atherosclerosis, and shortens life span [191,230,514,
520,529-531,543,544].
6) Moderate alcohol consumption inhibits conscious-
ness and mitigates emotional distress, which reduces
SNS activity, thus explaining its ability to prevent heart
disease and enhance longevity [532,545,546].
7) Analgesia prevents infarction during anesthetic
emergence, when the sudden restoration of cognitive
pathway function and the ability to perceive pain and
danger synergizes with spinal pathway nociception to
harmfully exaggerate capillary gate component activity
[210].
13. THE TISSUE PATHWAY
The tissue pathway consists of the vascular endothelium,
tissue factor, and Factor VII. The vascular endothelium
manufactures tissue factor, excretes it into extravascular
tissues, and insulates it from flowing blood. Tissue dam-
age disrupts the vascular endothelium and exposes tissu e
factor to Factor VII in flowing blood, which activates
Factor VII and initiates tissue repair. The tissue pathway
activates the tissue repair component in accord with the
magnitude and location of injurious forces that disrupt
the vascular endothelium, expose tissue factor to Factor
VII in blood, and release tissue factor into blood circula-
tion with systemic consequences.
Brain, lung, nerves, autonomic ganglia, cervix, blood
vessel adventitia, epithelium, mucosa, glomeruli, and
placenta are rich in tissue factor [139,144,210,213,301,
547,548]. This explains why these tissues are “targets”
for positive feedback in stress-related conditions. For
example, severe brain and burn injuries release tissue
factor into systemic circulation and ex aggerate morbidity
and mortality. Lung tissue reacts violently to microbes,
antigens, and chemicals, causing lethal overproduction of
soluble fibrin that floods alveolar spaces and airway
passages and disrupts gas exchange in asthma, pneumo-
nia, influenza, and poison gas exposure. Brain, lung, kid-
ney, nerves, skin, cervix, and peri-arterial tissues are
more likely to develop malignancies or be the site of
metastasis than other tissues. Placenta, brain, kidney and
lung function are primary targets in eclampsia. Adult Re-
spiratory Distress Syndrome (ARDS) is usually the first
manifestation of Multi-Organ Failure Syndrome (MOFS)
that primarily affects lung, brain, and kidney.
The following examples illustrate tissue pathway ac-
tivity:
1) Pneumonia and influenza insensibly disrupt the vas-
cular endothelium in lung tissues that are rich in tissue
factor, causing profuse soluble fibrin exudates that flood
alveolar spaces, disrupt gas exchange, and promote col-
lagen generati o n (fi b rosis) [146, 147,549].
2) Inhaled antigens imperceptibly deposit on airway
passages and induce soluble fibrin generation on their
inner walls. This has minor effect during inhalation,
when airway diameters are increased, but inhibits airflow
during exhalation, when airway diameters are reduced,
causing asthma [47,141,149,213,281,550,551].
3) Bacterial products that enter the bloodstream cause
sepsis by insensibly increasing the permeability of the
vascular endothelium and releasing tissue factor into the
blood, causing po sitive feedback that exaggerates throm-
bin and soluble fibrin generation. Thrombin energizes
inflammatory changes that enable soluble fibrin to enter
extravascular tissues, causing tissue edema and organ
dysfunctio n [ 1 40 ,5 52].
4) Brain and burn injuries release large amounts of tis-
sue factor into blood circulation, causing abnormal sys-
temic Factor VII activation that overwhelms inhibitory
mechanisms and induces SRM hyperactivity and positive
feedback that exaggerates morbidity and mortality [21 3].
5) Radiation does not directly activate peripheral no-
ciceptors, but it damages the vascular endothelium, caus-
ing thrombin generation and positive feedback that ener-
gizes the release of inflammatory substances that activate
nociceptors, causing belated pain. For example, skin da-
mage due to sun exposure is initially painless and invisi-
ble, but the gradual onset of inflammatory effects caused
by radiation damage produces a delayed painful reaction.
6) Site-inactivated tissue factor neutralizes the tissue
pathway and inhibits the effects of sepsis [553-555].
7) Amniotic fluid is rich in tissue factor. Amniotic fluid
embolus suddenly introduces large amounts of tissue fac-
tor into circulation, which activates Factor VII and in-
duces capillary gate component hyperactivity that trig-
gers spontaneous systemic coagulation activity that de-
pletes coagulation precursors such as fibrinogen and fi-
bronectin, causing defective coagulation activity known
as Disseminated Intravascular Coagulation (DIC) (see
below) [184].
14. POSITIVE AND NEGATIVE
FEEDBACK
The tissue repair pathway activates the tissue repair

L. S. Coleman / Advances in Bioscience and Biotechnology 3 (2012) 459-503 471
component in accord with the magnitude and location of
injurious forces that affect the vascular endothelium. For
example, invasive surgery releases greater amounts of
tissue factor into circulation than minor surgery, thereby
exaggerating morbidity and mortality [454]. The semi-
independent and synergistic spinal and cognitive path-
ways both activate the capillary gate component, in ac-
cord with combinations of sight, sound, smell, vibration,
and nociception. Combinations of anesthesia and analge-
sia synergistically inhibit sympathetic nervous system
activity and control capillary gate component activity.
The tissue repair component activates Factor VII, am-
plifies thrombin production, and generates soluble fibrin
[177,368]. The capillary gate component activates Factor
VIII, accelerates thrombin production, and generates in-
soluble fibrin [82,140 ,141,556-558]. Th e activity of each
component exaggerates that of the other in a “chaotic”
manner [454], because both share the enzymatic interact-
tion of Factors VII, VIII, IX and X [297]. The simulta-
neous, synergistic activation of both components induces
“positive feedback” so that peak SRM activity occurs
several hours after injury [129]. The constantly fluctuat-
ing activities of the three synergistic pathways enable the
SRM to focus its powerful effects and generate an infi-
nite variety of manifestations [281,284,502-504,536,559-
563].
As stressors subside, “negative feedback” restores
homeostasis via clot formation and tissue repair that pro-
gressively reduces thrombin production to maintenance
levels. Likewise, parasympathetic activity, Stoichiomet-
ric ATIII, TFPI, TPA and protein C mobilization [141,
148,281,564-566] restores homeostasis by inhibiting
Factor VII and Factor VIII activity and accelerating the
spontaneous disintegration of insoluble fibrin [116,141,
281,519,550,567-572]. However, prolonged Factor VIII
half-life and spinal cord “wind up” can cause residual
capillary gate component hyperactivity to linger long
after stressors subside [139,144,148,157,210,573-575].
15. THE INFLAMMATION SYNDROME
AND THE SRM
SRM activity explains the nature of disease, disease
symptoms, and the relationships of physiology, patho-
logy and stress[4]. Radiation, surgery, trauma, chemicals,
sepsis, obesity, allergic reactions, myopathy, peritonitis,
atherosclerosis, rheumatoid diseases, diabetes, exercise,
malignancy, and other forms of stress cause systemic
SRM positive feedback and hyperactivity that elevates
thrombin generation and produces local or systemic in-
flammatory changes that can be either visible or occult.
Inflammation is a medical syndrome that is classically
described as a combination of dolor (pain), rubor (red-
ness), calor (heat), tumor (edema), and Functio laesa
(loss of function). The simultaneous appearance and
resolution of these seemingly unrelated visible symptoms
remains unexplained. SRM activity explains all aspects
of inflammation. It is most easily understood in terms of
tissue repair. Coagulation is the first event in tissue repair.
It stems blood loss and then governs thrombin generation
in damaged tissues. Thrombin energizes the cellular re-
lease of chemokines, cytokines, prostaglandins, and bra-
dykinins. These increase capillary perfusion, which causes
redness (rubor); sensitize nociceptors, which causes pain
(dolor); loosen cell connections, which enables chemo-
taxis; and enable cell-to-cell communicatio ns that govern
the orderly sequence of cell activities during the repair
process. Thrombin converts fibrinogen to soluble fibrin,
which escapes from blood through inflammatory gaps in
the vascular endothelium and diffuses into inflamed and
damaged tissues. This causes tissue swelling and edema
(tumor). Repair cells multiply and differentiate to in-
crease immune activity and generate granulation tissue
that fills wound cavities and replaces damaged tissues.
This intense metabolic activity generates heat and ele-
vates tissue temperature (calor). Pain and swelling im-
mobilizes inflamed joints and tissues, causing loss of
function (Functio laesa). The integrity of the vascular
endothelium is restored as tissue repair nears completion,
and this causes thro mbin generation and inflammation to
subside to maintenance levels. Thrombin starvation then
undermines clot integrity, shrinks granulation tissues and
draws wound edges together via apoptosis, and resolves
the tissue repair process.
16. INFLAMMATION AND
ATHEROSCLEROSIS
The SRM explains why inflammation is involved in
atheroma formation. Atherosclerosis is a complex phe-
nomenon that is explained by a combination of inade-
quate blood turbulence that causes particulate deposits to
accumulate on the inner surfaces of arteries, and SRM
activity that generates inflammation and plaque forma-
tion in response to these deposits.
Inadequate blood turbulence explains why atheroscle-
rosis begins on the greater curvatures of arteries, where
shear stress and systolic velocity decline and diastolic
turbulence decreases exponentially [405-407,417-421].
High flow rates are necessary to generate turbulence that
prevents sludge d eposits in oil pipelines [404]. Similarly,
pulsatile arterial flow operates at the threshold of peak
diastolic turbulence to prevent particulate deposits on the
inner walls of arteries that are the initial cause of athe-
roma formation. The vascular endothelium adjusts arte-
rial diameter via neuromuscular control to optimize tur-
bulent cleansing [236,405-407].
Arterial deposits activate the tissue repair component

L. S. Coleman / Advances in Bioscience and Biotechnology 3 (2012) 459-503 472
[415]. Tissue repair component activity then causes
thrombus formation, inflammation, tissue factor accumu-
lation, fibrosis, and cholesterol trapping that produces
atherosclerotic p laque [196,221,222,327,408-416].
Diastolic turbulence increases exponentially with end-
systolic velocity. Exercise increases cardiac contractility,
elevates peak end-systolic velocity, exaggerates diastolic
pulsatile turbulence, and inhibits atherosclerosis. Myxe-
dema, congestive heart failure, and sedentary life style
reduce cardiac contractility, retard peak end-systolic ve-
locity, decrease diastolic cleansing turbulence, and ac-
celerate atherosclerosis [305,306,422-431]. The natural
decline in cardiac index with advancing age accelerates
atherosclerosis and explains its prevalence in old age.
Shear stress and viscosity both affect turbulence, but
viscosity has no effect on shear stress and vice-versa.
This explains why shear stress cannot explain athero-
sclerosis resistance in Down’s Syndrome [576,577], he-
mophilia, von Willebrand coagulopathy [578], and pa-
tients treated with anticoagulants.
17. INFLAMMATION, APOPTOSIS, AND
MALIGNANCY
The SRM provides a cohesive explanation of inflamma-
tion, apoptosis, and malignancy. The simplest explana-
tion of apoptosis is thrombin starvation of repair cells.
This normally occurs during tissue repair resolution . The
SRM continuously governs thrombin levels in all tissues
to energize, and thereby regulate, tissue repair. SRM hy-
peractivity generates thrombin elevations that induce
repair cell hyperactivity that cau ses inflammation, which
loosens cell connections to enable cellular repair active-
ties. As tissue repair nears conclusion, declining SRM
activity restores thrombin to maintenance levels, which
causes thrombin-dependent repair cells to undergo apop-
tosis. This shrinks granulation tissues in wound cavities
and enables wound closure.
Cellular thrombin receptor configurations become al-
tered during both embryological development and tissue
repair, and exaggerated repair cell mitosis and metabo-
lism during normal tissue repair causes abnormal chro-
mosome morphology, so that the microscopic appearance
of normal repair cell hyperactivity cannot be distin-
guished from malignancy [204,579-592]. Malignancy is
an abnormal manifestation of tissue repair activity that
occurs when prolonged and exaggerated positive feed-
back causes SRM repair hyperactivity to become self-
sustaining [204,210,593]. Malignant cells invade normal
tissues, release tissue factor, activate nervous sensors,
and cause a “vicious cycle” of positive feedback that
sustains abnormal thrombin elevations that inhibit the
apoptosis and resolution that normally occurs at the con-
clusion of the tissue repair process [29,82,216,217,594-
597]. For example, uncontrolled osteomyelitis sometimes
evolves into osteosarcoma. Malignancy induces systemic
SRM hyperactivity that causes systemic inflammatory
effects and increases blood viscosity and coagulability.
This increases the risk of infarction and metastasis. Brain,
nerve, retina, ovary, placenta, lung, artery, and cervix
tissues are rich in tissue factor and therefore especially
vulnerable to both primary malignancy and metastasis
[210,552,556,557,598-600]. SRM activity thus explains
the close association of malignancy with chronic disease,
environmental stress, inflammation, elevated Factor VII
and Factor VIII activity, increased blood viscosity and
coagulability, accelerated atherosclerosis, and seemingly
unrelated forms of maligna ncy [556-558,566 ,601-605].
The SRM indicates an effective strategy for cancer
prevention and treatment. Combinations of analgesia that
inhibits the spinal pathway, anesthesia that inhibits the
cognitive pathway, and treatments that inhibit the tissue
pathway can mitigate positive feedback reduce the risk
of malignancy, and induce apoptosis to cure malignancy
[505-507,606,607].
The currently prevailing belief that defective DNA
causes cancer is unfounded, and treatments based on this
concept are notoriously ineffective. “The Secret History
of the War on Cancer” by Devra Davis explains how
current cancer beliefs and treatments became entrenched
[592]. Drs. Goodman and Gilman of pharmacology text-
book fame demonstrated that toxic war gases reduce
white blood cell counts in leukemia, which they assumed
was beneficial. Then they tested their toxic treatment on
a mouse with a solid tumor, whereupon the tumor shrank
dramatically. Though subsequent experiments produced
unimpressive results, they assumed that they had disco-
vered an effective cancer treatment strategy. Soon there-
after, the discovery of DNA provided the seemingly rea-
sonable rationale that DNA damage causes cancer, which
implies that killing cancer cells cures cancer. Thus che-
motherapy seeks to induce apoptosis (programmed cell
death) in malignant cells [608], while surgery and radia-
tion therapy seek to extirpate and destroy them. Unfor-
tunately, these conventional cancer treatments are harm-
ful and unreliable. Surgery, radiation, and toxic chemi-
cals all increase SRM activity, which explains why con-
ventional treatments are accompanied by increased risk
of cancer and cardiovascular disease [552,556,557,598-
600]. They are plagued by toxic side effects and physical
disfiguration, bedeviled by the subsequent appearance of
other, seemingly unrelated, forms of cancer, and they
increase morbidity and mortality from atherosclerosis,
infarction, and pulmonary embolus [582]. They some-
times succeed, but only because hyperactive repair cells
are more vulnerable to radiation and toxic chemicals than
quiescent cells, and spontaneous apoptosis sometimes
occurs despite the treatments. Conventional cancer treat-
ments are comparable to fighting fire with oil. This can

L. S. Coleman / Advances in Bioscience and Biotechnology 3 (2012) 459-503 473
succeed, but only if enough oil is poured fast enough to
smother the fire. Otherwise, the oil may accelerate the
fire, and residual oil increases the risk of subsequent
fires.
18. INFLAMMATION AND SURGICAL
STRESS
Surgery simultaneously activates all three SRM path-
ways, causing positiv e feedback in accord with the dura-
tion and degree of sympathetic nervous system activation
and tissue factor released into systemic circulation by
surgical tissue disruption [505-507,606,607]. This mani-
fests as symptoms distant from the location and time of
surgery that are known as the surgical stress syndrome
[238,239,328,474,475,482,487,505,506,510,532,533,546,
561,609-628]. Analgesia controls nociception, and pre-
vents SNS activation via spinal cord pathways. Anesthe-
sia controls conscious awareness, and prevents SNS ac-
tivation via hypothalamic pathways that are independent
of spinal cord n ociception pathways. Either anesthesia or
analgesia can independently reduce positive feedback
and surgical stress to the point that most patients survive
surgery [13,132], but outcome is further enhanced if
synergistic combinations of anesthesia and analgesia are
maintained continuously throughout surgery [233,238,
243,328,465,533,610,621,629-648]. Such combinations
beneficially prevent thrombin acceleration, inhibit throm-
bin-induced immune activity and inflammatory effects
[601], and reduce blood viscosity an d coagulability. This
improves tissue perfusion and oxygenation, protects or-
gan function, maintains cardiac output, reduces blood
pressure, increases ejection fraction, slows heart rate via
the Starling Mechanism, and reduces the risk of malign-
nancy and heart disease in the distant aftermath of sur-
gery [201,210,213,479,508,551,649]. Theoretically, the
additional neutralization of tissue factor released into
blood during surgery should abolish the surgical stress
syndrome.
19. INFLAMMATION AND SEPSIS
The thrombin-energized complement cascade attacks
bacteria that enter the bloodstream [19]. Bacterial pro-
ducts cause inflammatory gaps to form in the vascular
endothelium that allow soluble fibrin to diffuse from the
bloodstream into extravascular tissues and organs, which
causes tissue edema and disrupts organ function [47,141,
144,218,281,550,551]. Gaps in the vascular endothelium
also allow tissue factor to escape into flowing blood,
which activates Factor VII, which then interacts with
Factors VIII, IX, and X to generate insoluble fibrin, in-
crease blood viscosity and coagulability, and induce
positive feedback in the SRM [213,281]. SRM hyperac-
tivity thus explains the devastating inflammatory effects
of sepsis.
20. SYSTEMIC INFLAMMATORY
SYNDROMES
Eclampsia, amniotic fluid embolism, Disseminated In-
travascular Coagulation (DIC), Multi-Organ Failure Syn-
drome (MOFS), and Adult Respiratory Distress Syn-
drome (ARDS) are all closely related. Combinations of
stressful forces and stressful stimuli cause these patholo-
gies by inducing severe systemic SRM hyperactivity and
positive feedback, causing syste mic inflammatory effects
that disrupt organ function [139,144,148,157,210, 573-
575].
MSOF commonly occurs after severe trauma, which
causes nociception, pain, and fear and releases tissue
factor into blood circulation. Trauma is often compli-
cated by sepsis, cold, and other stresses that exaggerate
the risk and sev erity of SRM hyperactivity [145,155,156 ,
175,307,650-660]. ARDS is typically the first manifesta-
tion of MSOF, because lung tissue possesses more tissue
factor than other organs and is therefore affected sooner
[661]. Inflammatory effects in the lung cause excessive
soluble fibrin production that interferes with gas ex-
change. Pulmonary exudates in ARDS are similar to
those in pneumonia and influenza, except that bacterial
and viral invasion of the lung trigg ers SRM hyperactivity
via direct lung tissue effects [4].
21. ECLAMPSIA AND AMNIOTIC FLUID
EMBOLUS
Eclampsia is analogous to MSOF, except that it occurs in
pregnant women. Pregnancy is a stressful condition cha-
racterized by SRM hyperactivity that elevates blood le-
vels of Factor VIII, generates insoluble fibrin, and in-
creases blood viscosity and coagulability [156,175,194,
657,658,662,663]. This is partially offset by Hemodilu-
tion anemia during pregnancy that increases blood tur-
bulence and inhibits atherosclerosis [7,8]. Additional
stress due to diabetes, obesity, and sepsis (commonly
caused by occult urinary tract infections during preg-
nancy) exaggerates SRM hyperactivity and increases the
risk and severity of eclampsia [51,81,112,113,133,138,200,
285,552-555,587,596,664-673]. The tranquilizing effects
of smoking mitigate the severity of eclampsia [21,81,130,
673,674].
Eclampsia increases the risk of DIC, especially in the
presence of amniotic fluid embolus. The developing fetus
sheds tissue factor into amniotic fluid throughout preg-
nancy, so that amniotic fluid contains increasing concen-
trations of tissue factor as the pregnancy progresses. If
amniotic fluid enters systemic circulation, it drastically
increases Factor VII activity [193,200,554,555]. Factor
VII then interacts with Factors VIII, IX, and X, which
cause blood viscosity and coagulability to suddenly rise

L. S. Coleman / Advances in Bioscience and Biotechnology 3 (2012) 459-503 474
above a critical threshold where spontaneous systemic
coagulation (D IC ) begins [675-6 79].
22. DISSEMINATED INTRAVASCULAR
COAGULATION (DIC)
The conversion of fibrinogen to soluble and insoluble
fibrin is a complex process that invo lves several en zymes
and precursors. Disseminated Intravascular Coagulation
(DIC) illustrates how this process can go awry in several
ways. DIC is usually caused by the abnormal entry of
tissue factor into systemic blood circulation due to sur-
gery, trauma, sepsis, and amniotic fluid embolus. This
activates Factor VII, overwhelms inhibitory mechanisms
(Protein C, TFPI, and ATIII), and initiates excessive in-
travascular generation of thrombin, soluble fibrin, and
insoluble fibrin. The risk and severity of DIC is exagger-
ated by sensory stresses that activate Factor VIII. Insolu-
ble fibrin exaggerates blood viscosity, which reduces
blood turbulence below a threshold, whereupon sponta-
neous systemic coagulation suddenly begins [193,552,
680,681]. This rapidly consumes and depletes coagula-
tion enzymes and precursors and distorts the coagulation
process. Thrombin converts fibrinogen to soluble fibrin,
which depletes fibrinogen [194,682]. Exaggerated Factor
VIII activity converts Factor X to Factor XIII to convert
soluble fibrin to insoluble fibrin, but this depletes Factor
VIII and Factor X [163,172,188,194 ]. Factor XIII installs
“cross-links” of fibronectin and plasminogen to soluble
fibrin to generate insoluble fibrin, and this consumes
both Factor XIII and fibronectin [680,681]. Shortages of
Factor XIII and fibronectin cause soluble fibrin to accu-
mulate to excessive blood levels [169]. Fibronectin ex-
haustion also causes Factor XIII to produce defective
forms of insoluble fibrin with inadequate fibronectin
“cross-links” [160]. These imbalances cause soluble fi-
brin to form abnormal attachments to the pathological
clots to produce “microthrombi”. Soluble fibrin also de-
posits on arterial walls [197,198,683]. The abnormal
coagulation activity reduces circulating red cell mass,
which exaggerates blood turbulence and further inhibits
effective coagulation. These abnormalities and imbal-
ances cause the generalized failure of hemostasis that
characterizes DIC [401,460,684].
DIC often occurs in patients who undergo extensive
surgical intervention in the immediate aftermath of major
trauma and massive blood loss [11,200,568]. Trauma and
surgery both release tissue factor into systemic circula-
tion and increase Factor VII activity, causing SRM hy-
peractivity and positive feedback [116,184,194,286,460,
542,660,684-686]. In addition, trauma patients are typi-
cally subjected to starvation, sepsis, hypothermia, fear,
pain, hypoxia, and iatrogenic hyperoxia, and these addi-
tional forms of stress exaggerate positive feedback and
SRM hyperactivity.
Misguided treatments can confuse and aggravate DIC.
Crystalloids, colloids, and starch solutions briefly dilute
coagulation precursors and enzymes, alter blood turbu-
lence, and exaggerate blood pressure, which conveys the
misleading impression that they improve cardiac output
[384,687,688]. DIC removes red cells from circulation,
causing anemia that exaggerates blood turbulence and
inhibits coagulation [457]. Blood transfusion corrects the
anemia, reduces blood turbulence, and restores blood
coagulability, but excessive transfusion with washed,
packed red cells can reduce blood turbulence below a
critical threshold and aggravate the problem. Reduction
of body temperature even slightly below normal mam-
malian body temperatures causes lipoprotein solidifica-
tion, which harmfully increases blood viscosity [660].
Cold stress activates the SRM and increases blood levels
of insoluble fibrin, which also increases blood viscosity
[401]. Severe hypothermia impairs SRM enzymes, and
inhibits hemostasis [459]. Metabolic acidosis and hypo-
thermia synergistically impair hemostasis [657].
23. EMBRYOLOGY, APOPTOSIS, AND
THE SRM
As expected by the previous generation of stress theorists
and researchers, the SRM explains the mysteries of em-
bryological development. Cell proliferation and differen-
tiation occurs faster during embryological development
than at any other time of life. Symmetrical and asymmet-
rical structural development occurs in three dimensions.
Ancient structures and organ systems such as the noto-
chord and primitive renal systems appear and then or
coalesce via apoptosis. The DNA mechanism by itself
cannot explain these phenomena, because it does not
explain how genetic information controls cell prolifera-
tion, cell maintenance, cell differentiation, and apoptosis.
Most presently available DNA information derives
from prokaryotes, because these are easy to study. Pro-
karyotic (bacterial) cells employ their outer membrane
for respiration, which limits them to single-cell existence,
small size, and a few shapes that optimize surface area.
They have simple internal structures and only one type of
DNA that floats freely in the cytoplasm and transmits its
genetic information via a straightforward mechanism that
employs RNA templates to generate proteins. Unfortu-
nately, the eukaryotic cells in complex animal are con-
siderably more complex than prokaryotic cells, so that
prokaryote information is often irrelevant to animal bi-
ology. Eukaryotic cells are believed to have originated
when a “parent” cell somehow engulfed other types of
previously free-living single-cell organisms (mitochon-
dria, Golgi apparatus, endoplasmic reticulum, etc.) that
subsequently became symbiotic organelles. The DNA of
the “parent” cell exists in the form of chromosomes that
are enclosed within a nuclear membrane that isolates

L. S. Coleman / Advances in Bioscience and Biotechnology 3 (2012) 459-503 475
them from the cytoplasm. The engulfed organisms persist
in the form of cytoplasmic “organelles” including mito-
chondria, endoplasmic reticulum, Golgi apparatus, and
vacuoles. These possess DNA that replicates and func-
tions independent of chromosome DNA in the nucleus.
Eukaryotic cells utilize the mitochondria for aerobic res-
piration, which enables them to be come much larger than
prokaryotes, assume diverse shapes, engage in locomo-
tion, and build multicellular life forms [689].
Unlike the DNA of prokaryotes, the nuclear DNA of
eukaryotic cells transmits its genetic information via
mechanisms that are not yet understood. Eukaryotic nu-
clear DNA consists of short protein-encoding segments
that are interspersed with large sections of “junk” DNA
that remains inert in the mature individual. “Junk” DNA
was originally assumed to lack function, but recent re-
search reveals that it consists at least in part of “introns”
that control embryological development. However, in-
trons do not produce proteins in the manner of DNA in
prokaryotic cells. Modern researchers therefore suspect
that introns control embryological development via a
cytoplasmic mechanism that is different from prokaryote
DNA mechanisms [31,690-692].
The previous generation of researchers expected that
Selye’s mechanism would function as a “companion
mechanism” that works closely with DNA to convert
genetic information into embryological structures. They
postulated that DNA becomes quiescent once embryo-
logical development is complete, while the “companion”,
mechanism remains active throughout life to maintain
and repair mature structures.
Both viewpoints may be correct. Thrombin receptors
are present on the outer surface of all animal cells thus
far tested, and they determine how cells respond to
thrombin elevations. Mature animal cells have stable
thrombin receptor configurations that characterize cell
types, but cells alter these configurations during tissue
repair and malignancy, and they can presumably alter
them during embryological development as well [25,81,
693]. Animal cells also possess precise timing mecha-
nisms that are critical to embryological development
[694]. The simplest explanation is that introns control
embryological cell proliferation, differentiation, and apo-
ptosis by releasing tissue factor and altering thrombin
receptor configurations in specific locations at precise
time intervals. Thrombin receptor configurations control
cell function, and tissue factor activates the SRM to ge-
nerate thrombin that energizes cell activity. Such a me-
chanism would explain how introns govern embryologi-
cal development in three dimensions. For example, it
would explain how both right and left thumb develop-
ment proceeds simultaneously, even though there is no
direct communication between the two sets of tissues.
This mechanism would explain how embryological cell
differentiation and proliferation occurs faster during em-
bryological development than at any other time of life,
why introns do not generate proteins, and why defects in
Factors VII, X and tissue factor disrupt embryological
development, while defects in Factors VIII, IX, and XIII
do not.
24. CONCLUSIONS
There is growing frustration with the lack of theoretical
progress in biological and medical science [695,696].
The DNA paradigm has dominated research since stress
theory was abandoned. DNA has revolutionized genetics
and criminal justice, but it has failed to explain either
embryological development or adult biology. The Ge-
nome Project illustrates this failure. It cost billions of
dollars and it promised to revolutionize medicine, but it
failed to produce a single treatment [695]. Scien tific his-
tory suggests that the DNA paradigm must soon be re-
placed or reinvigorated by a new paradigm that will
re-inspire scientific research [697].
Meanwhile, Selye’s theory has never been refuted, and
its virility remains undiminished. The SRM corroborates
stress theory, complements and extends DNA theory, and
exceeds the previous predictions of stress researchers.
Inflammation and apoptosis illustrate the power of stress
theory. Apoptosis explains key aspects of tissue repair,
embryology, and malignancy. Inflammation appears in
diverse circumstances and causes disparate symptoms
(pain, swelling, heat, redness, and loss of function) that
can now be understood as manifestations of SRM hy-
peractivity. In flammation plays an essential ro le in tissue
repair, but it can be harmful or even lethal when exces-
sive, so that control of SRM hyperactivity confers im-
proved outcome.
The SRM explains far more than inflammation and
apoptosis. It provides fresh insights to embryology, evo-
lution, taxonomy, anatomy, behavior, intelligence, phar-
macology, physiology, pathology, stress, and their rela-
tionships. It enables Selye’s Universal Theory of Medi-
cine, which promises to elevate medicine from an art
based on experiment to a science founded on theory.
Stress theory is thus poised to complement and rejuve-
nate the DNA paradigm, and inspire productive research
and pharmaceutical development. It portends a new era
of health, longevity, productivity, and freedom from the
eternal scourge of disease.
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