Increased Anti-Protein Z and Protein S Antibodies in Patients with Anti-Phospholipid Antibodies and/or Lupus Inhibitor.
Authors: Arkel Yale S. , Ku De-Hui W. , Ku Evelyn Y. , Birnbaum Jeffrey , Lam Xuam 
Published: April 2020

Abstract
Protein S (PS) and protein Z (PZ) are natural coagulation inhibitors that function as cofactors in mechanisms that decrease the generation of thrombin. Antibodies to PZ (aPZ) and PS (aPS) have been reported to be associated with adverse pregnancy outcomes (APO) and thrombosis (THRM). They have also been described in association with antiphospholipid antibodies (APLA) and the APLA syndrome (APLAS). We previously reported, ASH 2005, that there was an increase in aPZ and aPS in patients (pts) with serological and coagulation markers for APLA and lupus inhibitor (LI). In the current study we correlated the presence of aPZ and aPS in pts with APLA & LI with a THRM positive (+) or negative (−) history. We were not able to address the APO issue. The study group consisted of 26 male and 60 female, with ages ranging from 25 to 90, and mean age of 56. 33 pts are positive only for APLA (group 1) with 24 of them THRM(+), 16 pts are positive for LI only (group 2) with 7 of them THRM(+), and 37 pts are positive for both APLA and LI (group 3) with 21 of them THRM(+). The data was compared with 49 normal APLA/LI negative donors. We considered pts who have moderate to high levels of anticardiolipin and/or anti-β2 glycoprotein I (aB2GPI) as APLA positive. We define LI positive as pts with prolonged LI sensitive PTT, and positive for at least two of the confirmatory tests (Hexagonal phase assay, platelet neutralization procedure, and diluted Russel Viper Venom Time Ratio). THRM(+) included documented DVT, PE, stroke and TIA. We considered aPZ and aPS levels greater than 10 AU/ml as positive. Out data shows that in Group 1, statistically significant (SS) differences (p&lt;0.05) between pts vs. the control group (CTR) were noted as increased (inc) aPZ IgG & IgM, and aPS IgM (aPZ IgG 5.1+/−9.3 vs 1.3+/−2.9AU/ml, aPZ IgM 20.6+/−43.9 vs 3.9+/−6.0AU/ml, aPS IgM 4.0+/−4.0 vs 1.0+/−1.2AU/ml). When compared THRM(+) vs CTR showed SS inc aPZ IgG, aPS IgM (aPZ IgG 6.0+/−10.7AU/ml, aPS IgM 3.9+/−3.0AU/ml). The 15 APLA patients with inc aPZ and/or aPS antibodies are all associated with positive aB2GPI IgM. In Group 2, SS differences (p&lt;0.05) between pts vs. CTR were noted as inc aPS IgM (aPS IgM 3.2+/−4.0AU/ml). In Group 3, SS differences (p&lt;0.05) between pts vs. CTR were noted as inc aPZ IgM and aPS IgM (aPZ IgM 16.5+/−25.5AU/ml, aPS IgM 3.0+/−5.3AU/ml). When compared THRM(+) vs CTR showed SS increased aPZ (aPZ IgM 19.8+/−31.9AU/ml). When compared THRM(−) vs CTR showed SS increased aPZ IgG & IgM and aPS IgM. (aPZ IgG 3.0+/−1.2AU/ml and IgM 12.5+/−15.5AU/ml, aPS IgM 2.1+/−1.6AU/ml). The 15 pts with elevated aPZ and/or aPS are also all associated with positive aB2GPI. However, two pts were positive for IgG subgroup instead IgM subgroup. Elevated aPZ IgG was only found in THRM(+) pts (11%). This would indicate that the inc aPZ IgG is associated with THRM. The 8 pts who had both inc aPZ and aPS antibodies were positive for THRM. Our data would indicate that aPZ and aPS antibodies might play a role in the prothrombotic state associated with APLAS. Our positive APLA group has a high % of inc aB2GPI-IgM. Does this affect the results in the THRM(+) group? Is the presence of IgM APLA more likely to be associated with aPS or aPZ? Does the combination of aB2GPI and inc aPS/aPZ have greater prognostic implications for THRM? Are there functional coagulation assays that might be used to determine the prothrombotic effect of the inc levels of aPZ and aPS antibodies?