Pathogenesis of the syndrome of hemolysis, elevated liver enzymes, and low platelet count (HELLP): a review.

HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome is serious for the mother and the offspring. HELLP occurs in 0.2-0.8% of pregnancies and in 70-80% of cases it coexists with preeclampsia (PE). This review concerns the pathogenetic mechanisms of HELLP syndrome with an emphasis on differences between HELLP and early onset PE. The syndromes show a familial tendency. A previous HELLP pregnancy is associated with an increased risk of HELLP as well as PE in subsequent pregnancies, indicating related etiologies. No single world-wide genetic cause for excessive risk of HELLP or PE has been identified. Combinations of multiple gene variants, each with a moderate risk, with contributing effects of maternal and environmental factors, are probable etiological mechanisms. Immunological maladaptation is the most probable trigger of the insult to the invading trophoblast. This insult occurs early in the first trimester, as indicated by marker molecules in maternal blood. The levels of fetal messenger RNAs in maternal blood at gestational weeks 15-20 are significantly more abnormal in HELLP than in PE, suggesting that the insult is more extensive in HELLP. High levels of HLA-DR in maternal blood in women with HELLP may suggest a similarity to the rejection reaction. In third trimester placentas, gene derangement is more extensive in HELLP. Anti-angiogenic factors released into maternal blood induce the maternal syndromes. Maternal blood levels of anti-angiogenic sFlt1 are similar, but endoglin and Fas Ligand levels are possibly higher in HELLP than in PE. These factors trigger the vascular endothelium, resulting in an enhanced inflammatory response which is stronger in HELLP. Activated coagulation and complement, with high levels of activated leucocytes, inflammatory cytokines, TNF-α, and active von Willebrand factor, induce thrombotic microangiopathy with platelet-fibrin thrombi in microvessels. The angiopathy results in consumption of circulating platelets, causes hemolysis in affected microvessels and reduces portal blood flow in the liver. Placental Fas Ligand damages hepatocytes, resulting in periportal necrosis. In about one half of women with HELLP, activation of coagulation factors and platelets precipitates disseminated intravascular coagulation, which in a minority becomes uncompensated and contributes to life-threatening multiorgan failure.