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Davidson first hematology 2015

3rdInternational Conference on Hematology & Blood Disorders

November 2-4, 2015 Atlanta, Georgia USA

Biophysical Aspects of the

Sanarelli-Shwartzman Phenomenon

Robert M. Davidson M.D. Ph.D. FAIS*

Ann Lauritzen, Stephanie Seneff,

Stephen D. Kette, Glyn Wainwright,

Anthony Samsel, and Sydney J. Bush

*Fellow, The American Institute of Stress

Physician and Medical Researcher, Kilgore, Texas, USA

Email: [email protected]

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Davidson first hematology 2015

DEFINITION:

UNIVERSAL NON-SPECIFIC MESENCHYMAL

REACTION (UNMR)

• The UNMR refers to the different causes of an

acceleration of metabolism of connective tissue of blood

vessels as well as that of all organs studied [Hauss et al.

1962].

• Selye (1966) described a local or general intravascular

coagulation that occurs in response to certain toxins or

systemic stress [Selye, Thrombohemorrhagic Phenomena,

1966].

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Davidson first hematology 2015

DEFINITION:

Sanarelli-Shwartzman Phenomenon (SSP), a.k.a.

Generalized Shwartzman Reaction (GSR)

• Activation of the coagulation system is thought to be the primary

event in a clinical syndrome involving disseminated intravascular

coagulation (DIC), a consumptive coagulopathy of the

microvasculature, which can be localized or generalized, acute,

subacute, or chronic.

• Fibrinolysis, if it occurs, is thought to be a secondary protective

phenomenon [Bang et al. Thrombosis and Bleeding Disorders, 2014]

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Davidson first hematology 2015

The Major “Players" in Our Passion Play

Acid mucopolysaccharides

Serine proteases

Aryl sulfatases

Transition metals

Inflammatory stress

Interfacial water stress

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Davidson first hematology 2015

TIME IS OF THE ESSENCE

A prompt response is often required: there’s not much time for de

novo protein synthesis and diffusion of substrates

• In the setting of acute bleeding: to achieve hemostasis and maintain organ

perfusion

• In the setting of critical care medicine: associated with inflammatory stress,

e.g., ARDS, DIC syndrome, severe trauma, acute coronary and

neurovascular syndromes

• In the setting severe infectious disease, e.g. septicemia, Purpura

fulminans, Hemorrhagic Fever viruses (Dengue, Ebola, etc.)

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Davidson first hematology 2015

Purpura Fulminans

“a rare syndrome of intravascular thrombosis and hemorrhagic

infarction of the skin that is rapidly progressive and is

accompanied by vascular collapse and disseminated intravascular

coagulation. It may be classified as (1) neonatal, (2) idiopathic, or

(3) acute infectious.”

The 4 primary features of acute infectious purpura fulminans are

as follows:

• Large purpuric skin lesions

• Fever

• Hypotension

• Disseminated intravascular coagulation (DIC)

SOURCE: http://emedicine.medscape.com/article/2202749-overview

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Davidson first hematology 2015

THE INITIAL COMMON PATHWAY

Exogenous Interfacial Water Stress (EIWS)

Davidson, Robert M.; Seneff, Stephanie. 2012.

Entropy 14, no. 8: 1399-1442.

Inflammation

Davidson, R.M.; Lauritzen, A.; Seneff, S. 2013.

Entropy 15, 3822-3876.

Disease

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Davidson first hematology 2015

Two Important Characteristics

of Inflammatory States

Low pH: 4.7 - 5.7 Tsai, et al (2014)

cardiac ischemia

cancer

septicemia

trauma (fractures, hematomas)

High oxidative stress: Khansari et al (2009);

Reuter et al (2010); Kim et al (2013)

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Davidson first hematology 2015

The Redox Potential of Water is

pH Dependent

“The redox potential increases as the pH decreases

(increasing [H+])”. --- Martin Chaplin

http://www1.lsbu.ac.uk/water/water_redox.html

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Davidson first hematology 2015

Our Proposal for pH Dependent e(aq) Speciation

Mizuse, K. and Fujii, A. (2013). Characterization of a Solvent-Separated Ion-Radical Pair in Cationized Water Networks: Infrared

Photodissociation and Ar-Attachment Experiments for Water Cluster Radical Cations (H2O)n+ (n = 3–8). The Journal of Physical

Chemistry A, 117, 929-938.

Larsen, R.E., Glover, W.J. and Schwartz, B.J. (2010). Does the hydrated electron occupy a cavity? Science, 329, 65-69.

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Davidson first hematology 2015

ATP and PAPS are unstable in the setting

of Inflammation

• pH instability of ATP in low pH range

“…but is rapidly hydrolysed at extreme pH.”

• pH instability of PAPS in low pH range

“…should be made up in pH 8.0 buffer and stored aliquoted at -70o

C.”

• Sulfotransferase (SULT) pH optima are typically neutral pH range

to slightly alkaline

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Davidson first hematology 2015

Need for a Universal Sulfurylation Factor

in Inflamed Tissue

• A prompt response is required for the GSP/SSP,

DIC, Purpura Fulminans

• There is not enough time for de novo protein

synthesis and diffusion of substrates, and/or

• To rescue PAPS and ATP from a "hydrolytic fate“

or a recycling, proofreading “mistake”

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Davidson first hematology 2015

Our Proposal for a Universal Sulfurylation

Factor

WE PROPOSE: 2-O-sulfate L-ascorbate radical plays a central role in the

"universal nonspecific mesenchymal reaction", which has also been referred to as

the Sanarelli-Shwartzman phenomenon.

Chiral

Paramagnetic

Quasi-aromatic

• Takebayashi, J., Kaji, H., Ichiyama, K., Makino, K., Gohda, E., Yamamoto, I. and Tai, A. (2007). Inhibition of free radical-induced erythrocyte

hemolysis by 2-O-substituted ascorbic acid derivatives. Free Radical Biology and Medicine, 43, 1156-1164.

• Verlangieri, A.J. and Mumma, R.O. (1973). In vivo sulfation of cholesterol by ascorbic acid 2-sulfate. Atherosclerosis,17, 37-48.

• Cabral, J., Haake, P. and Kessler, K. (1998). Rearrangement of 3-Acyl Derivatives of L-Ascorbic Acid. Journal of Carbohydrate Chemistry, 17, 1321-1329.

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Davidson first hematology 2015

Need for a Universal Phosphorylation

Factor in Inflamed Tissue

• A great need also exists for an ultimate

phosphorylation factor in inflamed tissue to

(a) rescue ATP from a "hydrolytic fate“, and

(b) rescue DNA/RNA from proofreading

"errors".

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Davidson first hematology 2015

Proposed TBP TS for sulfuryl and phosphoryl

group transfer by Ascorbate derivative radicals

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Davidson first hematology 2015

“Flattening” the Free Energy Landscape

for Biological Group Transfers, generally

• Having proposed chemical biological means by which

the Ascorbate radical can catalyze sulfuryl and

phosphoryl group transfer, under conditions of

inflammatory stress, it soon became apparent that:

• Similar chemical biological means might exist by

which the Ascorbate radical can also catalyze

nitrosyl, acyl, and glycosyl group transfer, under

conditions of inflammatory stress

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Davidson first hematology 2015

Copper-Ascorbate Complex

Source:

L. Amudat, Ph.D.

Dissertation, 2010

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Davidson first hematology 2015

A NEW PARADIGM FOR

HYPOTHESIS TESTING:

• Null hypothesis: The Cu1+ Ascorbate radical complex does

NOT directly modulate miRNA synthesis by RNA polymerase III

in human patients with cancer, i.e. under conditions of

inflammatory stress (low pH and high oxidative stress).

• Application: Disproving the null hypothesis would allow us to

assert that the Cu1+ Ascorbate radical complex directly

modulates miRNA synthesis by RNA polymerase III in humans

with cancer, perhaps as a sequela of a proofreading "error" or

a sequela of dysregulating of a mesenchymal stem cell, under

conditions of inflammatory stress.

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Davidson first hematology 2015

Fractones, Defined:

Fractones have been referred to as stem cell “niches” and they are thought to regulate

cytoskeletal assembly and organize the ECM of the heart, gut, brain, and bone

marrow/RES. They have complex cytoarchitectures consisting of stem cells, progenitor

cells, supporting cells, and laminin-rich basement membranes (Hochman-Mendez et al

2014).

Frederic Mercier and his associates have studied neural stem cell niches and described

fractones as:

“particulate extracellular matrix structures that I previously characterized in both the

developing and adult brain”. --- F. Mercier (personal statement)

“In the neural stem cell niche of the adult brain, I have demonstrated that fractone-

associated heparan sulfate proteoglycans serve as captors and activators of growth

factors to regulate neural stem cell proliferation.”

Mercier, F., Kitasako, J.T. and Hatton, G.I. (2002). Anatomy of the brain neurogenic zones revisited: fractones and the

fibroblast/macrophage network. J Comp Neurol, 451, 170-188.

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Davidson first hematology 2015

CNS Fractones Need Sulfur

• GAGs and HSPGs need a UNIVERSAL SULFURYLATION

FACTOR, e.g. 2-O-sulfate-L-ascorbate radical might

preempt and supercede PAPS/SULTS

• CNS fractones need BOTH ascorbate and sulfur

• HSPGs have been shown to be low in sulfur at autopsy of

CNS fractones in Autism

Corley et al (2012); Mercier et al (2012); Meyza et al (2012); Pearson et al (2013); Mercier

et al (2011)

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Davidson first hematology 2015

High-dose Intravenous Ascorbate

in Critical Care Medicine

• High Dose Intravenous Ascorbate has become

mainstream

• Evidence now exists to suggest an important role

in both the prevention and management of

critical care disease characterized by endothelial

dysfunction [Oudemans-van Straaten, 2014;

Rodemeister, 2014].

http://www.ccforum.com/content/18/4/460

http://www.ccforum.com/content/18/4/461

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Davidson first hematology 2015

Early Reversal of Endothelial Dysfunction

SOURCE: Oudemans-van Straaten, H.M., Spoelstra-de Man, A.M. and de Waard, M.C. (2014). Vitamin C revisited. Critical

care (London, England), 18, 460.

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Davidson first hematology 2015

Conclusion:

Ascorbate radical and putative 2-O-substituted L-

Ascorbate derivative radicals,

(a) catalyze group transfer

reactions, and

(b) modulate redox kinetics.

The catalysis and modulation function for Vitamin C has

supramolecular, epigenetic, biophysically-pleiotropic

implications which apply to all aspects of medicine.

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Davidson first hematology 2015

THANK YOU !

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