HELLP syndrome is a serious pregnancy complication named for its three main features: Hemolysis (H), the breakdown of red blood cells; Elevated Liver enzymes (EL), indicating liver dysfunction; and a Low Platelet count (LP), a condition known as thrombocytopenia. It is considered a severe variant or complication of preeclampsia.
However, this relationship is debated, as 15% to 20% of individuals develop HELLP syndrome without prior signs of hypertension or protein in the urine. The syndrome manifests between the 28th and 36th week of gestation but can also occur earlier or in the postpartum period. Its sudden onset and variable presentation can lead to misdiagnosis.
Placental Maldevelopment as the Primary Trigger
The origin of HELLP syndrome is rooted in the abnormal development of the placenta during early pregnancy. The primary issue involves specialized placental cells called trophoblasts, which are responsible for anchoring the placenta and establishing a robust blood supply from the mother to the fetus.
In a normal pregnancy, these trophoblast cells invade the mother’s spiral arteries within the uterine lining. This invasion transforms them from narrow, muscular vessels into wide, low-resistance channels capable of delivering a high volume of blood to the placenta. This remodeling meets the increasing circulatory demands of the growing fetus.
In pregnancies that develop HELLP syndrome, this trophoblastic invasion is incomplete. The maternal spiral arteries fail to undergo these structural changes, remaining narrow and constricted. This results in high-resistance blood flow, leading to reduced blood supply (hypoperfusion) and insufficient oxygen (hypoxia) within the placental tissue.
Systemic Endothelial Dysfunction
The stressed and under-perfused placenta releases substances into the maternal bloodstream, including anti-angiogenic factors and pro-inflammatory molecules. These circulating factors travel throughout the mother’s body and trigger a systemic response by targeting the endothelium.
Endothelial cells form a thin, single-cell layer that lines the interior surface of all blood vessels. In a healthy state, the endothelium is a dynamic organ that regulates blood flow, controls the passage of fluids into tissues, and prevents blood clots. The placental factors cause these cells to become activated and damaged.
This widespread endothelial cell injury is a primary pathological event in HELLP syndrome. The damaged endothelium loses its ability to properly regulate vascular tone, leading to the vasospasm and hypertension seen in the syndrome. Furthermore, the junctions between endothelial cells become compromised, causing the blood vessels to become “leaky.” This allows plasma to seep into the surrounding tissues, and the damaged cell surfaces become prothrombotic, promoting the formation of blood clots.
The Cascade of Hemolysis and Thrombocytopenia
Widespread endothelial damage directly causes the hemolysis and low platelet count that characterize the syndrome. The hemolysis is a specific type known as microangiopathic hemolytic anemia (MAHA). This condition arises as red blood cells attempt to navigate small blood vessels that have been narrowed by endothelial swelling and the deposition of fibrin strands.
As red blood cells are forced through these constricted passages, they are subjected to mechanical shear stress that fragments the cells. The resulting cell fragments, known as schistocytes, are a key finding on a blood smear. This ongoing destruction of red blood cells leads to anemia.
Simultaneously, the body’s platelet levels fall. Platelets are small blood cells that play a primary role in initiating clotting. In response to the extensive endothelial damage, platelets are rapidly dispatched to these injury sites, adhering to the vessel walls and aggregating to form plugs, leading to their massive consumption and depletion from circulation.
Mechanism of Liver Injury
The systemic endothelial dysfunction and subsequent activation of the coagulation cascade also impact the liver. The liver’s vascular structure, which includes a dense network of small capillaries called sinusoids, makes it vulnerable to this type of injury. The widespread endothelial damage and prothrombotic state lead to the formation of tiny blood clots, or microthrombi, within these hepatic sinusoids.
These microthrombi, along with fibrin deposits, obstruct the flow of blood through the liver. This blockage creates patches of tissue that are starved of oxygen and nutrients, leading to cell death, a process known as periportal necrosis. This hepatocyte injury causes the liver cells to release their internal enzymes, such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT), into the bloodstream.
In severe cases, the obstruction and necrosis can lead to hemorrhage within the liver tissue, forming a subcapsular hematoma. The combination of tissue death and internal bleeding causes the liver to swell. This swelling stretches the membrane that encases the liver, known as Glisson’s capsule, which is rich in nerve endings. The stretching of this capsule produces the severe right-upper-quadrant abdominal pain associated with HELLP syndrome.