Profile of serum pregnancy-associated plasma protein A after sustained subcutaneous low molecular weight heparin administration in patients with cerebrovascular diseases.

Pregnancy-associated plasma protein A (PAPP-A), considered a surrogate marker of increased risk of unstable atherosclerosis and its complications (1, 2 ), is reversibly bound to the surfaces of several cell types because of heparin’s effective competition for surface binding (3 ). Heparins, however, especially low molecular weight heparins (LMWH), are routinely used for the treatment and prevention of thromboembolism. Because of the observation that intravenous administration of LMWH and heparin elicits a rapid increase in serum PAPP-A (4 ), we investigated the time profile of the effect of subcutaneous LMWH administration on PAPP-A concentration in a cerebrovascular disorder population. Blood samples were collected from 10 patients with ischemic stroke receiving 5000 U of subcutaneous LMWH twice daily (group A) and 10 patients with percutaneous carotid intervention receiving 4375 U heparin intravenously just before stenting (group B). For each patient in group A, the first venous blood sample was drawn after admission. We also collected samples at 3 h after LMWH administration on days 2, 3, and 7, and at 36 h after the last LMWH administration. For group B patients, samples were collected from the arterial sheath just before heparin administration and at 3, 5, 15, 40, 60, and 100 min after administration. The exact time of blood collection was recorded. Serum samples were separated by centrifugation at 1760g at 4 °C for 10 min and stored at 80 °C until analysis. The study protocol was approved by the Medical Ethics Committee of Qilu Hospital, and written informed consent was obtained from each patient. Serum total PAPP-A concentrations were measured with an ultrasensitive ELISA kit with polyclonal anti–PAPP-A antibody (DRG International). The intraassay CVs were 6.9% and 4.3% at 2.7 mU/L and 38.5 mU/L, respectively; interassay CVs were 9.4% and 5.9% at 2.2 mU/L and 36.5 mU/L, respectively. Both LMWH and heparin administration increased serum PAPP-A concentrations (median, 1.8-fold in group A; median, 4.1fold in group B). In group A, PAPP-A concentrations increased continuously during the period of LMWH administration (median change, from 12.03 mU/L to 21.80 mU/L; P 0.002). This increase was followed by a normalization of the concentration after the drug was discontinued (Fig. 1). In group B, the PAPP-A concentration peaked within 5 min (median, 51.56 mU/L), remained increased for 15 min (median, 43.75 mU/L), and then decreased to 16.4 mU/L at 100 min. The response in group A was lower (peak median concentration, 21.80 mU/L vs 51.56 mU/L; P 0.0001) but more sustained than in group B, possibly because of the differences of medication, dose, and administration patterns. To document the relationship between sustained subcutaneous LMWH administration and serum PAPP-A concentration more clearly, we also measured the serum LMWH concentration by highperformance capillary electrophoresis. After subcutaneous injection twice daily for about 1 week, the LMWH concentration gradually increased (median, from 370 U/L on day 2 to 650 U/L on day 7; Fig. 1), which may have contributed to the gradually increasing PAPP-A concentration. Because the LMWH concentration showed patient-to-patient variation (Fig. 1), we could not investigate whether the extent of heparin-induced PAPP-A release correlated with the atherosclerotic lesions of the vasculature. Further1 Nonstandard abbreviations: PAPP-A, pregnancyassociated plasma protein A; LMWH, low molecular weight heparin. Fig. 1. PAPP-A concentration and LMWH concentration at baseline, day 1, day 2, and day 7. PAPP-A and LMWH concentrations are presented as the median and 25th and 75th percentiles. Letters to the Editor