Acute activation of the endothelium results in increased levels of active von Willebrand factor in hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome

Abstract

To cite this article: Hulstein JJJ, van Runnard Heimel PJ, Franx A, Lenting PJ, Bruinse HW, Silence K, de Groot PhG, Fijnheer R. Acute activation of the endothelium results in increased levels of active von Willebrand factor in hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome. 2006; 4: 2569-75. Summary. Background: HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome is a severe complication of pre-eclampsia in pregnancy, characterized by microvascular platelet thrombi. Activation of the endothelium is thought to play a key role in pre-eclampsia and HELLP syndrome. Activation of endothelial cells may lead to release of von Willebrand factor (VWF) multimers, which are highly reactive with platelets. Normally, newly released multimers are cleaved by ADAMTS13, resulting in less reactive derivatives. Objective: We hypothesized that HELLP syndrome is characterized by increased amounts of active VWF compared with healthy pregnancy and pre-eclampsia, due to acute activation of endothelial cells. This might contribute to thrombocytopenia and thrombotic microangiopathy. Methods: Active VWF and ADAMTS13 activity were measured in healthy pregnant volunteers (n ¼ 9), patients with pre-eclampsia (n ¼ 6) and patients with HELLP syndrome (n ¼ 14) at similar gestational ages. To study the role of endothelial cell activation, the propeptide/mature VWF ratio was determined, and VWF released by cultured endothelial cells was analyzed. Results: Active VWF levels were increased 2.1-fold in HELLP syndrome compared with healthy pregnant volunteers (P < 0.001) and 1.6-fold compared with patients with pre-eclampsia (P ¼ 0.001). ADAMTS13 activity was moderately decreased in patients with HELLP syndrome compared with healthy pregnant volunteers (P < 0.004), but not compared with patients with pre-eclampsia. The propeptide/mature VWF ratio was increased 1.7-fold compared with healthy pregnant volunteers (P < 0.001) and 1.5-fold compared with patients with pre-eclampsia (P < 0.05). A significant correlation was found between this ratio and the activation factor of VWF (r ¼ 0.68, P < 0.001). The amount of active VWF was increased 1.4-fold in medium of stimulated endothelial cells when compared with non-stimulated cells (P < 0.05). Conclusion: Acute endothelial cell activation in HELLP syndrome and decreased ADAMTS13 activity result in increased amounts of active VWF. This might explain the consumptive thrombocytopenia and thrombotic microangiopathy associated with HELLP syndrome. Inhibition of circulating active VWF could be a potential new approach in the treatment of patients with HELLP syndrome. J Thromb Haemost

ADAMTS13 gene variants and function in women with preeclampsia: A population- based nested case- control study from the HUNT Study

“…Lower levels are found in new-borns and in older people, and in the second and third trimester of normal pregnancies [36,37]. Alpoim and colleagues found decreased ADAMTS13 levels in preeclamptic women compared to normotensive pregnant women [38], while in other studies a significant ADAMTS13 reduction was limited to the rarer pregnancy complication HELLP syndrome (Haemolysis Elevated Liver enzymes, Low Platelets) [39]. Others again have found normal ADAMTS13 levels but increased VWF in preeclampsia [40].…”

ADAMTS, Thrombotic Thrombocytopenic Purpura and Pregnancy

“…First, it may be a consequence of the feminine predominance of TTP (being itself at least partially linked to the feminine predominance classically observed in any disease with an autoimmune background); furthermore, most women with TTP (between 60 and 70%) are child-bearing age women [1,2]. Second, pregnancy is associated with physiological coagulation changes predisposing to hypercoagulability and particularly to a dysbalance of the VWF/ADAMTS13 system: indeed, during the course of pregnancy, VWF levels in plasma increase progressively to reach levels 2.5-3 fold higher levels at term (with peak values occurring immediately following delivery) while ADAMTS13 decreases progressively (ADAMTS13 activity decreases of about 30% at term when compared to baseline levels before pregnancy) (Supplementary Table 1) [16][17][18][19][20][21][22][23]. The physiological decrease of ADAMTS13 during pregnancy may be due either to a consumption mechanism by its VWF substrate [16], or to a direct effect of hormonal substances on ADAMTS13 metabolism [24].…”

“…Indeed, puerperium and post-partum TTP are more rare than ante-partum TTP and they usually occur following a late 3 rd trimester delivery (about 38 WG) and a median 4 th day postpartum (range 0-42 days) [9]. Third, several studies led in women with pregnancy-associated TMA showed that a severe ADAMTS13 deficiency (activity <10%) was specific for TTP: indeed, only normal or partially deficient ADAMTS13 levels (usually >20%) have been described in either PE, HELLP syndrome or HUS (Supplementary Table 4) [17,19,[21][22][23]. ADAMTS13 activity measurement remains however unavailable in emergency as a routine assay and it may not be useful to argue for a TTP diagnosis at presentation in emergency.…”

Current insights into thrombotic microangiopathies: Thrombotic thrombocytopenic purpura and pregnancy

“…Preeclampsia and HELLP are much more common than acute TTP. Patients with HELLP syndrome have normal or moderately decreased ADAMTS13 activity but show increased VWF levels, a high VWF propeptide/VWF antigen ratio (suggestive of endothelial stimulation/damage) and an increased binding affinity of the VWF A1 domain to platelet glycoprotein Ib resembling the situation with the unusually large VWF multimers in severely ADAMTS13 deficient TTP (20). In (severe) preeclampsia the antiangiogenic factors, fms-like tyrosine kinase 1 (sFlt-1), an antagonist of vascular endothelial growth factor (VEGF) and endoglin, an inhibitor of transforming growth factor β (TGF-β) are released from the hypoperfused, hypoxic placenta and elevated in plasma (4).…”