What Causes HELLP Syndrome
HELLP syndrome is caused by inadequate placental perfusion and aberrant placental development, leading to endothelial dysfunction, intense systemic vasospasm, and subsequent multiorgan involvement through thrombotic microangiopathy.
Primary Pathophysiologic Mechanism
The fundamental cause begins with defective arterial placental perfusion and inadequate placental vessel development occurring early in the first trimester 1, 2. This placental ischemia triggers a cascade of pathologic events:
Placental ischemia releases circulating vasoconstrictors including thromboxane A2, angiotensin, prostaglandin F2, and endothelin-1, while simultaneously producing fewer vasodilators such as prostacyclin, prostaglandin E2, and nitric oxide 2.
The resulting imbalance in vasoactive substances causes intense systemic vasospasm and multiorgan endothelial damage 2.
Anti-angiogenic factors (particularly sFlt1, endoglin, and Fas Ligand) are released into maternal circulation, triggering enhanced inflammatory responses and vascular endothelial damage 3.
Thrombotic Microangiopathy and Organ Damage
Once endothelial damage occurs, the syndrome progresses through specific mechanisms:
Fibrin and platelets deposit on damaged endothelial surfaces, leading to thrombotic microangiopathy with platelet-fibrin thrombi forming in microvessels 2, 3.
This microangiopathy causes the classic triad: consumption of circulating platelets (low platelet count), hemolysis as red blood cells are damaged passing through affected microvessels (hemolysis), and reduced portal blood flow to the liver 2, 3.
Hepatic involvement results from fibrin deposition within hepatic sinusoids, causing sinusoidal obstruction and subsequent hepatic ischemia, which can progress to subcapsular hematomas, parenchymal hemorrhage, and potentially hepatic rupture 1.
Placental Fas Ligand directly damages hepatocytes, resulting in periportal necrosis and elevated liver enzymes 3.
Contributing Risk Factors and Genetic Predisposition
While the primary mechanism is placental, several factors increase susceptibility:
No single worldwide genetic cause has been identified; rather, combinations of multiple gene variants, each with moderate risk, combined with maternal and environmental factors, constitute the probable etiological mechanism 4, 3, 5.
A woman with previous HELLP pregnancy has high risk for recurrence in subsequent pregnancies, demonstrating familial tendency and genetic predisposition 4, 3.
Immunological maladaptation is the most probable trigger of the initial insult to invading trophoblast, occurring early in the first trimester 3.
The insult appears more extensive in HELLP than in preeclampsia alone, as evidenced by more abnormal levels of fetal messenger RNAs in maternal blood at 15-20 weeks gestation 3.
Relationship to Preeclampsia
HELLP occurs in 0.2-0.6% of all pregnancies, and in 70-80% of cases it coexists with preeclampsia 4, 3, 5. However, important distinctions exist:
HELLP can occur in patients with normal blood pressure (15% of cases have no hypertension), indicating it is not simply severe preeclampsia 1.
HELLP represents a more acute and predominant inflammatory process typically targeting the liver with greater activation of the coagulation system compared to preeclampsia alone 5.
The inflammatory response is stronger in HELLP, with higher levels of activated coagulation and complement, activated leukocytes, inflammatory cytokines, TNF-α, and active von Willebrand factor 3.
Critical Clinical Pitfall
In approximately 50% of women with HELLP, activation of coagulation factors and platelets precipitates disseminated intravascular coagulation (DIC), which in a minority becomes uncompensated and contributes to life-threatening multiorgan failure 3. This underscores why HELLP is considered a medical emergency requiring immediate delivery after maternal stabilization 1.