Protein Z Variants Associated With Protein Z Plasma Levels and With Risk of Idiopathic Recurrent Miscarriage

AlShaikh, F.S.; Sater, Mai S.; Finan, Ramzi R.; Racoubian, Eddie; Abu-Hijleh, Tala M.; Mustafa, Fekria E.; Almawi, Wassim Y.

doi:10.1177/1933719112473659

Cited by 9 publications

(15 citation statements)

References 40 publications

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“…The study of Grandone et al (2004) has also reported that PZ deficiency is not linked with unexplained fetal loss, which is due to the small sample size, low plasma PZ cut-off values (1.43G0.76 mg/ml in healthy controls), and exclusion of women with known inherited (FV Leiden or FII G20210A mutations and protein C, protein S, or antithrombin deficiency) or acquired (antiphospholipid antibodies) thrombophilia. The above-mentioned studies involved lower numbers of subjects compared with the studies of Gris et al (2002Gris et al ( , 2003 and Sofi et al (2010), and our study (Sater et al 2011, AlShaikh et al 2013), indicating study under-power. Interestingly, both the Bretelle et al …”

Section: Pz In Pregnancy Complicationsmentioning

confidence: 84%

“…More recent studies, including a meta-analysis (Sofi et al 2010) and our case-control Bahraini study (AlShaikh et al 2013), have confirmed the strong relationship between low PZ levels and adverse pregnancy complications. The meta-analysis of Sofi et al (2010) involving 714 patients and 515 controls has demonstrated a strong association of PZ deficiency with pregnancy complications (OR (95% CI)Z3.42 (2.51-4.66)).…”

Section: Pz In Pregnancy Complicationsmentioning

confidence: 89%

“…The mechanism by which PZ deficiency leads to poor pregnancy outcomes is not clear and may be attributed to anti-PZ IgG and IgM autoantibodies (Gris et al 2003, Sater et al 2011) and the presence of functional mutations in the PROZ gene, in particular, in the G79A variant (Dossenbach-Glaninger et al 2008, El-Hamid & El-Khayat 2011, AlShaikh et al 2013). An earlier report by Gris involving 171 women with pathological pregnancies and 191 multiparous control women has demonstrated high levels of anti-PZ IgG and IgM antibodies, which are distinct from classical antiphospholipid/anticofactor antibodies, and a dose-effect relationship between anti-PZ antibody levels and poor pregnancy outcomes has been documented (Grandone et al 2004).…”

Section: Pz Autoantibodies and Adverse Pregnancy Outcomesmentioning

confidence: 99%

“…Reduced PZ levels (!1 mg/ml) have been linked with several pregnancy complications including fetal demise (Erez et al 2009), intrauterine growth restriction (Bretelle et al 2005), PE (Erez et al 2009), small for gestational age (SGA) (Erez et al 2009), HELLP syndrome (H, hemolysis; EL, elevated liver enzymes; LP, low platelet counts), which represents a severe form of PE and can be observed with or without preceding PE (Kaygusuz et al 2011), and idiopathic recurrent miscarriage (Gris et al 2002, AlShaikh et al 2013). …”

Section: Pz In Pregnancy Complicationsmentioning

confidence: 99%

“…A recent meta-analysis has demonstrated that reduced PZ levels are linked with an increased risk of thrombotic events, such as arterial vascular and venous thromboembolic diseases (Sofi et al 2010), and pregnancy complications. The latter include preeclampsia (PE; Erez et al 2007Erez et al , 2009, early fetal death (Vasse 2011), intrauterine growth restriction (Bretelle et al 2005), and recurrent spontaneous miscarriage (Topalidou et al 2009, AlShaikh et al 2013.…”

Section: Pz Deficiencymentioning

confidence: 99%

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Protein Z, an anticoagulant protein with expanding role in reproductive biology

Almawi¹,

AlShaikh²,

Melemedjian³

et al. 2013

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Protein Z (PZ) is a vitamin K-dependent factor characterized by its homology to other vitamin K-dependent factors (factors VII, IX, and X, protein C and protein S), but lacks any enzymatic activity. Instead, PZ acts as a cofactor for the inhibition of factor Xa through the serpin PZ-dependent protease inhibitor (ZPI). PZ deficiency is associated with a procoagulant state, highlighted by excessive FXa secretion and thrombin production, and is linked with several thrombotic disorders, including arterial vascular and venous thromboembolic diseases. A role for the PZ-ZPI complex in the regulation of physiological pregnancy has been demonstrated, highlighted by the progressive elevation in PZ levels in the first trimester of gestation, which then steadily decline toward delivery. An association between altered plasma PZ concentrations and adverse pregnancy outcomes (recurrent miscarriage, stillbirth, preeclampsia, intrauterine growth restriction, and placental abruption) has been reported. The mechanism by which PZ deficiency leads to adverse pregnancy outcomes is not clear, but it is multifactorial. It may be attributed to the anti-PZ IgG and IgM autoantibodies, which apparently act independently of classical antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, and anti-b2-glycoprotein I antibodies). PZ deficiency has also been reported to be constitutional, and a number of variants in the PROZ (PZ) gene and SERPINA10 (ZPI) gene are linked with specific adverse pregnancy complications. This review summarizes the relationship between adverse pregnancy outcomes and acquired and constitutional PZ-ZPI deficiency, in order to understand whether or not PZ deficiency could be considered as a risk factor for poor pregnancy outcomes.

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