Women with the Prothrombophilic HPA-1b Genotype of Platelet Integrin αIIbβ3 Are at Increased Risk of Intrauterine Growth Restriction.

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Background: Disturbances in the placental vascular development with endothelial inflammation and thrombotic occlusion of the placental vasculature are associated with fetal intrauterine growth restriction (IGR). As shown in previous studies, the HPA-1b allele of the b subunit of the essential platelet integrin αIIbβ3, also known as glycoprotein IIb–IIIa, can be associated with increased platelet thrombogenicity, leading to arterial vascular occlusion also triggered by inflammatory endothelial alterations. We performed a case-control study to assess HPA-1b as risk determinant for fetal IGR.Materials and Methods: Fifty two women with fetal IGR (defined by birth weight below the 5th- and 10th percentile for gestational age and sex) were evaluated. Women with other reasons of IGR (history of venous thrombosis, fetal loss, and preeclampsia) were excluded. The fetuses were born alive after the 24th week of gestation. As control subjects, 307 normal women with at least one previous pregnancy and no previous pregnancy complication were included.Results: There was a significant risk association of the HPA-1b/1b genotype (birth weight below 5% percentile: odds ratio (OR) 6.3 (95% confidence interval (CI) 1.4–21); birth weight below 10% percentile: OR 4.6 (95% CI 1.4–15). OR for the HPA-1b/1b genotype (birth weight below 5% percentile) in subgroups with increased levels of fibrinogen (above median > 284mg/dl) were 17.7 (95% CI 2.9–106) and increased levels of FVIII:C (above median > 147%) were 22.1 (95% CI 3.8–127). No significant difference between the genotype distribution was found in patients with low levels of fibrinogen and/or FVIII:C. Similar results were found for women with IGR with a birth weight below the 10% percentile. There was no significant risk association for factor V Leiden G1691A, prothrombin G20210A mutation, and MTHFR 677TT.Conclusions: The platelet receptor genotype HPA-1b/1b is significantly associated with IGR. As possible pathological mechanism, an increased HPA-1b-associated thrombogenicity of platelets leading to IGR via interaction with an inflammatory vascular process and/or via increased levels of FVIII:C or plasma fibrinogen have to be considered. Pharmacological control of the observed platelet thrombogenicity in patients at risk may be of clinical relevance. In consequence, it will be of importance to examine whether this critical subgroup of patients can benefit from prevention with specific antiplatelet agents.