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 HOPI SYNDROME THEORY
Hypercoagulability Of Pregnancy & Infertility
(Immune Activation of the Coagulation System) FERTILIZATION:

As the gamete is fertilized, the trophoblast expresses phosphatidylserine (PS) on its surface for binding purposes into the endometrial surface.
Annexin V [Placental Anticoagulant Protein I (PAP-I)] binds to PS on trophoblast as a protective anticoagulant mechanism in the normal embryo.
If there is a genetic defect with the embryo and a spontaneous abortion, then apoptosis expresses more PS on the cell surfaces, marking the embryo for destruction through immune IgG formation. This starts the immune system memory function.
 

APS INTERFERENCE:

Memory IgGs bind to negatively charged phospholipids, namely PE and PS. This begins the APS (AntiPhospholipid antibody Syndrome) cycle (aPL IgG [antiPhosphoLipid IgG]). The next pregnancy now carries a 70% risk of loss due to immune formation that recognizes exposed PS on the trophoblast. The normally present Annexin V protein must now compete with the aPL IgG for the exposed PS on the trophoblast. This aPL inhibition of Annexin V allows some aPL to bind to the embryo, blocking implantation and/or creating damage to the embryo and placenta. aPL antibodies (in the mouse model) usually cause fetal resorptions. This evidence suggests that aPLs are pathogenic.
 

ASPIRIN INVOLVEMENT:

aPL antibodies decrease IL-3 production in the placenta. aPL antibodies increase thromboxane (TxA2) production from human placental cultures. This mechanism then could reduce placental blood flow in vivo. 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. Aspirin's second beneficial effect may be due to increased production of IL-3, which is essential for maintenance of normal pregnancy, because it functions as a trophoblast growth factor. Heparin also increases production of IL-3. Thus, heparin and aspirin counteract two of the mechanisms of fetal loss in aPL (increased thromboxane and reduced   IL-3).
 

FIBRIN DEPOSITION:

Thrombomodulin (TM) is normally expressed on the surface of endothelial cells (EC) to create an anticoagulant environment. TM also binds to the outside of the microvilli EC of the embryo keeping the vascular system open. As aPL 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. As aPL 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. If the normal mechanism of controlling thrombin generation is compromised by aPL, 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. These monomers may then deposit on placental vessels, creating a placental vasculopathy and occlusion. Primary endothelial cell injury and/or thrombosis from SFM generation results in fetal starvation due to compromised maternal blood flow. This is the likely pathogenesis for fetal loss.
 

CONCLUSIONS:

aPL antibodies induce anatomic, immunopathologic, leukotriene, and cytokine abnormalities in specific target tissues. Once the
cycle is started, IgG memory generation and future events create amnestic responses that create positive feedback generating
more aPL antibodies. Thus, a woman becomes infertile over time and several abortions, spontaneous or induced. 2,3
 

Laboratory testing of the HOPI Syndrome (immune activation of coagulation) includes: elevated Fibrinogen, increased Soluble Fibrin Monomer, elevated Sonoclot Rate and activation of platelets (positive PA Score).
The laboratory detection of IgGs includes antiphospholipid antibodies, including antiPhosphatidylSerine, 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 and AT III. Additionally, blood smear pathology may include elevated
eosinophils and the presence of schistocytes (localized DIC).

Additional prospective studies are in progress and will be submitted for publication in 1998.

REFERENCES

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.     ASH Meeting, Orlando, Fl, Dec, 96: BLOOD, 88 (10) 1-804.