Accurate Prediction of Total PlGF (Placental Growth Factor) From Free PlGF and sFlt-1 (Soluble Fms-Like Tyrosine Kinase-1): Evidence for Markedly Elevated PlGF Levels in Women With Acute Fatty Liver of Pregnancy

Abstract

Acute fatty liver of pregnancy (AFLP) is characterized by elevated circulating sFlt-1 (soluble Fms-like tyrosine kinase-1), although the free circulating levels of its ligand, PlGF (placental growth factor) are not decreased. Here, we hypothesized that women with AFLP exhibit elevated PlGF production in comparison to women with preeclampsia or hemolysis elevated liver enzymes and low platelet count syndrome. Making use of the well-known mathematical formulas describing drug-receptor interactions, we established that serum total PlGF could be accurately predicted from sFlt-1 and free PlGF levels (n=42; mean calculated K D of 50 pmol/L), yielding similar values as the previously published method of thermal dissociation of the sFlt-1-PlGF complexes ( r =0.94, P <0.0001). We found that median levels of free PlGF were significantly lower in women with preeclampsia (n=13; 117pg/mL) or hemolysis elevated liver enzymes and low platelet count syndrome (n=12; 59 pg/mL) compared with women without preeclampsia (n=11; 349pg/mL, P <0.0001). In contrast, median total PlGF did not differ between women with no preeclampsia, preeclampsia, and hemolysis elevated liver enzymes and low platelet count syndrome (354 versus 435 versus 344pg/mL), whereas it was markedly elevated in AFLP compared with all groups (2054 pg/mL, P <0.0001). Furthermore, in AFLP, both sFlt-1 and total PlGF declined rapidly postdelivery, with significantly higher predelivery total PlGF (n=12; median, 2054 pg/mL) than postpartum levels (n=14; median, 163pg/mL, P <0.0001), suggesting that in AFLP, PlGF is largely placenta-derived. Collectively, our findings indicate that like sFlt-1, PlGF production is significantly upregulated in AFLP, mainly originating from the placenta. Importantly, total PlGF can now be easily calculated from already available free PlGF and sFlt-1 levels, allowing subsequent evaluation of other groups in whom PlGF is altered.