Relationship between human development and disappearance of unusually large von Willebrand factor multimers from plasma

Abstract

von Willebrand factor (vWF) multimers were examined in fetal, umbilical cord, and neonatal platelet-poor plasma (PPP) specimens. Sixty-five of 65 (100%) fetal PPP samples aged less than 35 weeks and seven of ten (70%) fetal samples aged greater than 35 weeks had unusually large vWF (ULvWF) multimers. Thirty of 46 (65%) cord PPP samples from neonates ranging in gestational age from 34 to 41 weeks had ULvWF. There was no significant relationship between either gestational age at time of delivery or birth weight and likelihood of finding ULvWF multimers in cord PPP samples. No maternal PPP sample contained ULvWF multimers. Serial heelstick samples from 16 preterm and term neonates were analyzed for 8 weeks. ULvWF multimers disappeared from the PPP of ten of the neonates during this time. The PPP of four neonates had vWF patterns similar to those in normal adult PPP throughout the sampling period. The ULvWF multimeric forms of fetal and neonatal PPP samples were similar to those constitutively released from endothelial cells. They were not as slowly migrating in a very porous 0.5% agarose gel system as the ULvWF multimers released from Weibel-Palade bodies in response to the calcium ionophore A23187. A vWF protomer was present in 97% of fetal samples, 83% of cord blood specimens, and 11% of neonatal heelstick samples, but was not found in any maternal sample. These results indicate that control mechanisms operative in older children and adults to prevent circulation of ULvWF multimers and vWF protomeric forms are normally acquired late in uterine life or during the neonatal period. ULvWF multimers, which are normal components of fetal, most cord, and some neonatal plasma samples, may contribute to in utero and postnatal hemostasis.

The Proportions of Low- and Intermediate-Molecular-Weight von Willebrand Factor Multimers Are Different in Neonates and Infants Compared to Adults

“…11,12 Previous studies investigating vWF multimers have shown that neonates have increased amounts of HMWM. 13,14 Conversely, we demonstrated that in healthy neonates and children, proportions of LMWM are increased and proportions of IMWM are decreased in neonates and young children compared with adults. However, proportions of HMWM were relatively the same across the age spectrum.…”

“…Differences between our findings and previous studies could be explained by: (1) differences in the age (e.g., neonates born <36 weeks' gestation) and health status (e.g., thrombotic thrombocytopenic purpura, necrotizing enterocolitis) of the participants used across studies, and (2) different methodological techniques used to investigate vWF multimers. Specifically, the vWF multimer analysis techniques utilized in the studies conducted by Katz et al 13 and Weinstein et al 14 are in-house, labor-intensive, manual laboratory tests that are operator-dependent. On the other hand, the semi-automated method produced by Sebia reduces operator dependence and has been shown to be reliable and successful in correctly visualizing and interpreting vWF multimers.…”

Platelets in the neonate: Not just a small adult

“…Taken together, these studies demonstrated that full‐term neonates have more robust primary hemostasis than healthy adults, despite the pronounced hyporeactivity of neonatal platelets. The explanation for this finding is that the platelet hyporeactivity is counterbalanced by several factors in neonatal blood that stimulate clotting, including a high hematocrit, high mean corpuscular volume, high levels of von Willebrand factor (VWF), and the predominance of ultra‐large VWF multimers 39–42 . The slightly shorter bleeding and closure times seen in neonates are the net result of this balance.…”

“…The explanation for this finding is that the platelet hyporeactivity is counterbalanced by several factors in neonatal blood that stimulate clotting, including a high hematocrit, high mean corpuscular volume, high levels of von Willebrand factor (VWF), and the predominance of ultra-large VWF multimers. [39][40][41][42] The slightly shorter bleeding and closure times seen in neonates are the net result of this balance. Given these data, it is clear that the hyporeactivity of neonatal platelets is not a developmental deficiency, but rather an integral part of a different but well-balanced neonatal primary hemostatic system (Table 1).…”

Hemostasis in neonatal ECMO

“…Term newborns have CT shorter than preterm ones accordingly to the hyporeactivity of the preterm platelets (29). Primary hemostasis is maintained through higher hematocrit levels, mean corpuscular volume (MCV) of neonatal erythrocytes, vWf, and a large amount of high molecular weight multimers of vWf, which counterbalance platelets hyporeactivity (26,27,30).…”