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IMMUNE
SYSTEM ACTIVATION
of
COAGULATION (ISAC) THEORY
Recurrent
Miscarriages (HOPI Syndrome)1,
Chronic Fatigue5,
Chronic Pain,
Fibromyalgia5,
Osteonecrosis6,
BISS, GWS, & Other Syndromes
CELL SURFACES: Platelets & Endothelial Cells
1)
Platelets and Endothelial Cells (EC) express phosphatidylserine (PS) on
their surface. Normally, over 95% of PS is contained on the inner
membrane of the cell. There is both active and passive transport from the
inner membrane to the outer membrane and visa versa.
2)ß2GlycoProtein
I (ß2GP
I) and Annexin V [Placental Anticoagulant Protein I (PAP-I)] bind to PS
when exposed on the cell surface, serving as a protective anticoagulant
layer to the cell2.
APS INTERFERENCE:
1)
IgGs bind to negatively charged phospholipids, namely PE and PS. This begins
the APS (AntiPhospholipid antibody Syndrome) cycle (aPL IgG [antiPhosphoLipid
IgG]).
2)
IgG can either attack ß2GP
I directly or punch holes in the Annexin V protective layer3.
3)
This aPL inhibition of Annexin V allows some exposure of PS to circulating
blood proteins and macrophages. IgG bound to ß2GP
I will also bind macrophages.
4)
Exposed PS creates a negatively charged binding site for coagulation proteins
allowing inappropriate generation of thrombin on a local level.
PLATELET INVOLVEMENT & ASPIRIN:
1)
aPL antibodies decrease PGI2,
IL-3 and thrombomodulin production in endothelial cells.
2)
aPL antibodies increase thromboxane (TxA2) production in platelets, causing
vasoconstriction or reduce blood flow in any given localized area. Low
dose aspirin normalizes the thromboxane production without altering prostacyclin
production. This explains the benefit of low dose aspirin which is
consistent with clinical data.
3)
Aspirin's second beneficial effect is decreasing platelet activation.
4)
Heparin and aspirin increase EC production of IL-3, decreasing cell activation.
FIBRIN DEPOSITION:
1)
Thrombomodulin (TM) is normally expressed on the surface of endothelial
cells (EC) to create an anticoagulant environment. TM combines with thrombin,
forming a T/TM complex that activates Protein C to APC, which produces
an anticoagulant environment in vascular system.
2)
As IgG antibodies activate endothelial cells, TM is displaced from the
cell surface, which diminishes Protein C activation to APC, effectively
converting the anticoagulant environment to a procoagulant environment.
This change also activates the expression of Tissue Factor (TF) on EC.
3)
As IgG antibodies activate platelets and endothelial cells, these activated
surfaces provide PS exposure for binding of cascade factors, inducing activation
of the cascade, and leading to thrombin generation.
4)
If the normal mechanism of controlling thrombin generation is compromised
by the immune system, then more thrombin will be generated than can be
removed by Antithrombin III and the Protein C pathway. This leads
to Soluble Fibrin Monomer (SFM) formation.
5)
These
monomers may then deposit locally on capillary walls, creating a vasculopathy
and potential occlusion.
6)
Primary endothelial cell injury and/or thrombosis from SFM generation results
in starvation of cells, muscles, or organs around the vessels. This can
cause myalgia, trigger points in fibromyalgia, local pathology such as
osteonecrosis, increased blood viscosity, etc. This is the likely
pathogenesis for many hypercoagulable states in which there is no thrombosis4,5,6.
CONCLUSIONS:
Immune activation (IgG antibodies) induce anatomic, immunopathologic, leukotriene, and cytokine abnormalities in specific target tissues. Once the cycle is started from whatever the source (viral, bacterial, chemical, etc), IgG memory generation and future events create amnestic responses that create positive feedback generating more IgG antibodies. IgG antibodies can destroy protective proteins on EC surfaces and allow coagulation proteins to bind, generating thrombin inappropriately.
Laboratory testing of the ISAC (immune system activation of coagulation) includes: elevated Fibrinogen, increased Soluble Fibrin Monomer, elevated Prothrombin Fragment 1+2 and activation of platelets (positive PA Score). The laboratory detection of IgGs includes antiphospholipid antibodies (+/- antiPhosphatidylSerine or anti ß2GP I antibodies) and may include ANA screening. Since the levels of IgGs vary over time, they may or may not be elevated on a particular patient draw. Elevated IgGs are merely an indicator that the immune response is activated. Hereditary risk factors should be tested to rule out other contributing causes (double hit theory): Protein C, Protein S, APC Resistance, Antithrombin Activity and Factor II (Prothrombin gene mutation). Additionally, blood smear pathology may include elevated eosinophils and the presence of schistocytes.
Additional prospective studies are in progress and will be submitted for publication in 1999.
1
ASH Meeting, San Diego, Ca, Dec, 97: BLOOD, Vol 90, (10), #3206, p 111b.
2
7th International Symposium on Antiphospholipid Antibodies: Special Issue.
LUPUS, 5 (5),p 343- 558.
3
NEJM: v337, 7/17/97, p159
4
ASH Meeting, Orlando, Fl, Dec, 96: BLOOD, 88 (10) 1-804.
5
AACFS Meeting, Boston, MA, Oct, 98: Proceedings, p 62.
6
Glueck, et al: J Lab Clin Med, v130,#5, Nov, 97, p540-543.