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Subject 101: The complex pathophysiology of the HELLP-syndrome

The complex pathophysiology of the HELLP-syndrome

Introduction

The HELLP-syndrome is a complex and life-threatening pregnancy complication that occurs in 0,5-0,9% of all pregnancies.1, 2 The three defining characteristics are Hemolysis, Elevated Liver enzymes and a Low Platelet count. Two other trademarks are proteinuria and hypertension. The HELLP syndrome can occur self-contained during pregnancy or often in combination with preeclampsia. Although HELLP is a relatively rare complication of pregnancy, it is a major cause of maternal morbidity and mortality.3 In spite of the potential severe complications; there is no other known treatment for the syndrome other than inducing labour. Unfortunately, the exact cause and pathophysiology have yet to be understood.

Symptoms, complications and risk factors

Symptoms occur primarily during the second or third trimester and include oedema of face, eyes and feet, headaches, changes in vision, sudden nausea/vomiting, shortness of breath and upper abdominal pain. These symptoms are a result of the activation of the coagulation cascade, reduced portal blood flow to the liver and the release of anti-angiogenic factors into the maternal blood.4
These factors can lead to severe complications, including preterm labour, eclampsia, placental abruption, organ failure (particularly liver and kidney failure) and blood-clotting disorders.5 The perinatal outcome for the foetus are dependent on the gestational age and the severity of the maternal disease. Potential complications are malnutrition due to the utero-placental vascular insufficiency, growth retardation, disrupted haematopoiesis and a pro-inflammatory immune state.6 This includes neonatal thrombocytopenia, neutropenia, a reduction in T-regulatory cells and an increased cytotoxic natural killer cell profile.6 There is also an increased risk of developing hypertension, coronary artery disease and (non-insulin-dependent) diabetes as an adult.7
Risk factors for developing the HELLP-syndrome are diabetes, heart and vascular disease, impaired kidney function, multiparity, obesity, hypertension prior to the pregnancy, autoimmune illnesses and a maternal age above thirty-four. Female children are five times more likely to develop preeclampsia or HELLP during a pregnancy.8

Pathophysiology theories

As mentioned earlier, the exact cause of the HELLP-syndrome has yet to be discovered. Research has identified factors involved in the development of the HELLP-syndrome: a genetic predisposition, maternal immunological response resulting in the activation of the coagulation cascade and placental insufficiency. These three factors form the foundation of the various theories behind the pathophysiology of the HELLP-syndrome.4

A potential genetic cause was researched in multiple countries, including Iceland, Australia and the Netherlands. At least 178 genes and genetic abnormalities have been linked to preeclampsia or the HELLP syndrome, including a foetal homozygous LCHAD deficiency.9 The results of one Dutch study focuses on a long intergenic noncoding RNA (lincRNA) transcript on chromosome 12q23.2.10 This lincRNA is expressed in trophoblasts and influences a large set of genes in the cell cycle, particularly by activating the G2/M phase of the cycle while deactivating the G1/S phase. Its presence in trophoblasts could explain the placental origin of the HELLP-syndrome, in which there is a reduced invasion of extravillous trophoblasts into the maternal decidua. The placental dysfunction results in compensatory pathways in an attempt to increase the perfusion and transfer or nutrients, oxygen and waste products between mother and foetus.

When trophoblasts cannot invade the maternal decidua, placental dysfunction occurs in the first semester which results in the release of anti-angiogenic factors into the maternal blood, including sFlt1. This is the foundation of another pathophysiological theory: an inflammatory response as the cause of the HELLP-syndrome. Anti-angiogenic factors fight against the formation of new blood vessels and trigger an inflammatory response in the vascular endothelium. This leads to elevated levels of activated leukocytes, inflammatory cytokines, TNF-α and active von Willebrand factor. The result is thrombosis in capillaries and arterioles, known as thrombotic microangiopathy. Hemolysis and reduced portal blood flow in the liver are a result of thrombotic microangiopathy. Fas ligand (FasL) is a member of the TNF protein family involved in the regulation of cell death.11 Its increased levels in the placenta damage hepatocytes and lead to periportal necrosis.4 Another immunological hypothesis states that the HELLP-syndrome could be a maternal immune rejection of foetal cells.8 This response could occur as a result of maternal immune cells coming into contact with foetal cells, leading to platelet activation and aggregation as well as arterial hypertension.

Finally, there is a theory that the pathophysiology of the HELLP-syndrome is closely related to that of preeclampsia. Preeclampsia is another complication of pregnancy that results in maternal hypertension, proteinuria and oedema. Although the specific cause is unknown, it is associated with defective placental vascular remodelling during the 16th and 22nd week of pregnancy, which leads to inadequate placental perfusion and the release of soluble vascular endothelial growth factor-1 (sVEGFR-1/sFlt1), which then results in endothelial and placental dysfunction.8

Each of these theories contribute to the pathophysiology of the HELLP-syndrome. The most likely conclusion is HELLP-syndrome is caused by a combination of genetic, immunological and maternal factors. Ideally, exploring the etiology could provide new insights for the treatment and prevention.

M.S. Haverkort & K.G.J.A. Voogdt

References

  1. Khan H, Meirowitz NB, Pritzker JG. HELLP Syndrome [Internet]. HELLP Syndrome: Practice Essentials, Pathophysiology, Etiology. Medscape; 2018. Available here
  2. Mol, B., Shuerman, F., van Lingen, R., van Kaam, A., Dijk, P., Kortbeek, L., van den Born, B., Mantel, G., Erwich, J. and Wolf, H. (2012). Richtlijn Hypertensieve
    aandoeningen in de zwangerschap. [online] Nederlandse Vereniging voor Obstetrie en Gynaecologie (NVOG). Available here
  3. Haram, K., Svendsen, E. and Abildgaard, U. (2009). The HELLP syndrome: Clinical issues and management. A Review. BMC Pregnancy and Childbirth, 9(1).
  4. Ulrich A, Heimdal K. Pathogenesis of the syndrome of hemolysis, elevated liver enzymes, and low platelet count (HELLP): a review. European Journal of Obstetrics & Gynaecology and Reproductive Biology [Internet]. 2013;166:117–23. Available here
  5. www.medistart.nl, M. (2018). HELLP-syndroom – Gynaecologie.nl. [online] Available here
  6. Marins LR, Anizelli LB, Romanowski MD, Sarquis AL. How does preeclampsia affect neonates? Highlights in the disease’s immunity. The Journal of Maternal-Fetal & Neonatal Medicine. November 2017:1-8. doi:10.1080/14767058.2017.1401996.
  7. Lapidus A.M. Effects of preeclampsia on the mother, fetus and child. OBGYN.net. Published October 10, 2010. Available here
  8. Khan, H. and Meirowitz, N. (2018). HELLP Syndrome: Practice Essentials, Pathophysiology, Etiology. [online] Emedicine.medscape.com. Available here
  9. Jebbink, J., Wolters, A., Fernando, F., Afink, G., Post, J. and Ris-Stalpers, C. (2012). Molecular genetics of preeclampsia and HELLP syndrome — A review. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease, 1822(12), pp.1960-1969.
  10. Dijk MV, Thulluru HK, Mulders J, Michel OJ, Poutsma A, Windhorst S, et al. HELLP babies link a novel lincRNA to the trophoblast cell cycle. Journal of Clinical
    Investigation [Internet]. 2012;122:4003–11. Available here
  11. Volpe E, Sambucci M, Battistini L, Borsellino G. Fas–Fas Ligand: Checkpoint of T Cell Functions in Multiple Sclerosis. Frontiers in Immunology [Internet]. 2016;7. Available here

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