Pathogenesis of HELLP Syndrome
HELLP syndrome is initiated by inadequate placental vessel development leading to placental ischemia, which triggers a cascade of systemic vasospasm, endothelial damage, and subsequent microangiopathic hemolysis, hepatocellular injury, and platelet consumption. 1
Primary Pathophysiologic Mechanism
The fundamental defect begins with incomplete trophoblast invasion of spiral arteries, resulting in placental ischemia that serves as the central trigger for the entire syndrome. 2 This ischemic placenta then releases circulating vasoconstrictors while simultaneously producing fewer vasodilators, creating a critical imbalance. 1
Vasoactive Substance Imbalance
The ischemic placenta releases powerful vasoconstrictors including:
Simultaneously, production of vasodilators is reduced:
This imbalance causes intense systemic vasospasm and multiorgan endothelial damage, which is the critical pathophysiologic step linking placental dysfunction to the clinical manifestations. 1
Secondary Mechanisms and Contributing Factors
Endothelial Activation and Damage
Beyond the vasoactive imbalance, systemic endothelial activation and damage occur, particularly in severe pre-eclampsia and HELLP syndrome. 2 Multiple factors contribute to this endothelial injury:
- Genetic disorders that predispose to endothelial dysfunction 1
- Coagulation abnormalities including increased vascular thrombosis and activation of the coagulation system 1, 3
- Immunologic disorders contributing to endothelial damage 1
- Inflammatory cytokines derived from the placenta play a central role in endothelial activation 2
Autoimmune Component
Most obstetricians presume that HELLP derives from an autoimmune reaction leading to a materno-fetal imbalance, with accompanying platelet aggregation and endothelial malfunction. 4 This represents a change in the immune feto-maternal balance that contributes to the syndrome's development. 5
Metabolic Factors
Inborn errors of fatty acid oxidative metabolism have been implicated as contributing factors to the pathogenesis. 4, 5
Final Common Pathway: The HELLP Triad
Once endothelial damage occurs, fibrin and platelets are deposited on endothelial surfaces, directly producing the three defining features:
Hemolysis (H)
Microangiopathic hemolytic anemia results from red blood cell fragmentation as they pass through damaged endothelium with fibrin deposition. 1 This is evidenced by peripheral blood smear showing schistocytes and elevated LDH. 6
Elevated Liver Enzymes (EL)
Hepatic involvement occurs through intravascular fibrin deposition and hypovolemia, leading to hepatocellular injury and elevated transaminases. 5 The liver damage reflects both direct endothelial injury in hepatic sinusoids and ischemic injury from vasospasm. 1
Low Platelets (LP)
Platelet consumption occurs as platelets aggregate and deposit on damaged endothelial surfaces throughout the microvasculature. 4, 5 The degree of thrombocytopenia correlates directly with the severity of liver dysfunction and predicts adverse maternal outcomes. 7
Clinical Implications of Pathogenesis
LDH and platelet count are the two most important clinical tools for disease assessment because LDH reflects both the extent of hemolysis and hepatic dysfunction, making it a dual marker of the pathophysiologic process. 5
The pathogenesis explains why the intensity of HELLP syndrome peaks 24 hours after delivery 1, as the inflammatory cascade and endothelial damage continue despite removal of the ischemic placenta, and why laboratory abnormalities take up to 10 days to fully resolve. 8
Critical Pitfall
Understanding that HELLP is fundamentally an endothelial disease explains why delivery is the only definitive treatment 3, 4—removing the ischemic placenta stops the source of vasoactive substances and inflammatory mediators, though the downstream effects persist for days postpartum.