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Abstract

  1. Top of page
  2. Abstract
  3. Disclosure of conflict of interests
  4. References

See also Drewlo S, Levytska K, Sobel M, Baczyk D, Lye SJ, Kingdom JCP. Heparin promotes soluble VEGF receptor expression in human placental villi to impair endothelial VEGF signalling. J Thromb Haemost 2011; 9: 2486–97.

We have read with very great interest the recent paper by Drewlo et al. [1]. It convincingly shows that a low molecular weight heparin (LMWH), dalteparin sodium, can induce in vitro the synthesis and release of the soluble vascular endothelial growth factor (VEGF) receptor-1 (sFLT1) by first-trimester placental villi, whereas no effect is observed on severe pre-eclampsia placental explants. The induced sFLT1 concentrations quantified in LMWH-conditioned media from first-trimester placental villi were similar to those detected in severe pre-eclampsia explants. The culture media were able to induce phosphorylation profiles of the endothelial cell receptors of VEGF and placental growth factor (PlGF), VEGFR1 and VEGFR2, tested with cultured human endothelial vein endothelial cells, ‘in a manner that is predicted to antagonize the actions of VEGF and PlGF at the level of the maternal vascular endothelium in vivo’. From this, it is concluded that ‘use of LMWH in severe pre-eclampsia should be done with caution based on these findings, since it could exacerbate sFLT1-mediated maternal hypertension’.

We warmly congratulate the authors of this nice in vitro cellular study, which conclusions are the direct consequences of the carefully chosen experimental conditions.

One point is, however, rather intriguing. At least five single-center controlled studies [2–6] are currently available showing that prophylactic LMWH dosages may have a preventive effect on the recurrence of the so-called ‘placental ischemic diseases’, with a net positive effect on pre-eclampsia recurrence rates. Even though these clinical results still have to be confirmed in a definitive multicenter randomized controlled trial focusing on severe pre-eclampsia recurrence, the global analysis of the pooled results shows no statistical heterogeneity between studies and is encouraging [7].

We may thus have a striking paradox: LMWH increasing normal placenta-derived sFLT1 production to the levels documented during pre-eclampsia but decreasing pre-eclampsia recurrence, and elevated sFLT1 plasma levels inducing the vascular and renal clinical manifestations of pre-eclampsia.

One may recall that LMWH is a systemic, not a placenta-restricted, therapeutic agent, and that peripheral, renal or vascular manifestations of pre-eclampsia may depend more on local sFLT1 bioavailability than on systemic sFLT1 concentrations. sFLT1 produced by vascular smooth muscle cells is stored in the arterial vessel wall, trapped in the heparan sulfate-rich basement membrane, protecting endothelial cells from excessive VEGFR engagement [8]. The main cause of pre-eclampsia-associated renal damage is thought to depend on the neutralization of VEGF function in the kidney glomerular basement membrane, podocyte-derived VEGF binding to locally accessible VEGFRs in close endothelial proximity [9]. The LMWH-mediated displacement of sFLT1 from vascular and glomerular heparin sulfate may thus facilitate the paracrine and sometimes autocrine VEGF endothelial receptor engagement, even in cases of high, placenta-derived sFLT1 concentrations.

We agree that experimental results can give indications calling for medical caution. However, global cellular experimental models, able to summarize a whole organism reaction, are rare. Apparent discrepancies from available clinical results must lead to criticism of the validity of generalizations from chosen experimental conditions, limited to a strict perimeter, to human systemic consequences. In the present case, it has been suggested, from experimental conditions inducing acute sFLT1 modifications, that peripheral cellular reactions may always only depend on placenta-derived sFLT1 concentrations. The strict dependance of peripheral reactions on systemic, circulating sFLT1 concentrations can be the rule during pre-eclampsia onset, when circulating sFLT1 molecules progressively saturate vascular and glomerular heparin sulfate molecules. The displacement of sFLT1 from heparin sulfate by long-lasting LMWH treatment throughout pregnancy may explain this LMWH-mediated, apparently paradoxical, prophylactic effect.

Disclosure of conflict of interests

  1. Top of page
  2. Abstract
  3. Disclosure of conflict of interests
  4. References

J. C. Gris and P. Marès have received speakers’ honoraria, council board honoraria and investigator-initiated grants-in-aid from various manufacturers of LMWH.

References

  1. Top of page
  2. Abstract
  3. Disclosure of conflict of interests
  4. References
  • 1
    Drewlo S, Levytska K, Sobel M, Baczyk D, Lye SJ, Kingdom JCP. Heparin promotes soluble VEGF receptor expression in human placental villi to impair endothelial VEGF signalling. J Thromb Haemost 2011; 9: 248697.
  • 2
    Mello G, Parretti E, Fatini C, Riviello C, Gensini F, Marchionni M, Scarselli GF, Gensini GF, Abbate R. Low-molecular-weight heparin lowers the recurrence rate of preeclampsia and restores the physiological vascular changes in angiotensin-converting enzyme DD women. Hypertension 2005; 45: 8691.
  • 3
    Rey E, Garneau P, David M, Gauthier R, Leduc L, Michon N, Morin F, Demers C, Kahn SR, Magee LA, Rodger M. Dalteparin for the prevention of recurrence of placental-mediated complications of pregnancy in women without thrombophilia: a pilot randomized controlled trial. J Thromb Haemost 2009; 7: 5864.
  • 4
    Gris JC, Chauleur C, Faillie JL, Baer G, Marès P, Fabbro-Peray P, Quéré I, Lefrant JY, Haddad B, Dauzat M. Enoxaparin for the secondary prevention of placental vascular complications in women with abruptio placentae. The pilot randomised controlled NOH-AP trial. Thromb Haemost 2010; 104: 7719.
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    Gris JC, Chauleur C, Molinari N, Marès P, Fabbro-Peray P, Quere I, Lefrant JY, Haddad B, Dauzat M. Addition of enoxaparin to aspirin for the secondary prevention of placental vascular complications in women with severe pre-eclampsia. The pilot randomised controlled NOH-PE trial. Thromb Haemost 2011; 106: 105361.
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    Kupferminc M, Rimon E, Many A, Maslovit S, Lessibng JB, Gamzu R. Low molecular weight heparin versus no treatment in women with previous severe pregnancy complications and placenta findings without thrombophilia. Blood Coagul Fibrinolysis 2011; 22: 1236.
  • 7
    Rodger M, Gris JC, Rey E, Carrier M, Le Gal G. Low molecular weight heparin for the secondary prevention of placental-mediated pregnancy complications: a systematic review and meta analysis. XXIII Congress of the International Society on Thrombosis and Haemostasis, Kyoto, Japan, 23–28 July 2011, O-TH-091.
  • 8
    Sela S, Natanson-Yaron S, Zcharia E, Vlodavsky I, Yagel S, Keshet E. Local retention versus systemic release of soluble VEGF receptor-1 are mediated by heparin-binding and regulated by heparanase. Circ Res 2011; 108: 106370.
  • 9
    Eremina V, Sood M, Haigh J, Nagy A, Lajoie G, Ferrara N, Gerber HP, Kikkawa Y, Miner JH, Quaggin SE. Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest 2003; 111: 70716.