What is the pathophysiology of HELLP (Hemolysis, Elevated Liver enzymes, and Low Platelet count) syndrome in a pregnant patient with preeclampsia?

Pathophysiology of HELLP Syndrome

HELLP syndrome results from severe endothelial dysfunction triggering a cascade of thrombotic microangiopathy, where platelet-fibrin thrombi form in microvessels causing platelet consumption, microangiopathic hemolysis, and hepatic ischemia with periportal necrosis. 1

Primary Pathophysiologic Mechanism

The fundamental defect begins with immunological maladaptation and endothelial injury that occurs early in the first trimester, affecting trophoblast invasion more extensively in HELLP than in isolated preeclampsia. 1 This initial insult sets off a progressive pathologic sequence:

Endothelial Activation and Anti-Angiogenic State

• Anti-angiogenic factors (sFlt1, endoglin, and Fas Ligand) are released into maternal circulation, with endoglin and Fas Ligand levels possibly higher in HELLP than preeclampsia alone. 1
• These factors trigger widespread vascular endothelial damage, resulting in an enhanced inflammatory response that is stronger in HELLP compared to preeclampsia without HELLP. 1
• The levels of fetal messenger RNAs in maternal blood at 15-20 weeks gestation are significantly more abnormal in HELLP, suggesting the placental insult is more extensive. 1

Thrombotic Microangiopathy Development

• Activated coagulation and complement systems, combined with high levels of activated leukocytes, inflammatory cytokines, TNF-α, and active von Willebrand factor, induce thrombotic microangiopathy. 1
• Platelet-fibrin thrombi form in microvessels throughout multiple organ systems, particularly affecting hepatic sinusoids and peripheral circulation. 1
• This microangiopathy results in consumption of circulating platelets, explaining the thrombocytopenia that defines the syndrome. 1

Hemolysis Mechanism

• Microangiopathic hemolytic anemia occurs when red blood cells are mechanically damaged passing through vessels containing platelet-fibrin thrombi. 2, 1
• This produces schistocytes and fragmented red blood cells visible on peripheral blood smear, which is a mandatory diagnostic finding. 2
• Hemolysis elevates indirect bilirubin and lactate dehydrogenase (LDH), with LDH >295 U/L reflecting both hemolysis extent and hepatic dysfunction. 2

Hepatic Injury Pathophysiology

The liver sustains damage through multiple mechanisms:

• Fibrin deposition within hepatic sinusoids causes sinusoidal obstruction and subsequent hepatic ischemia. 3
• This follows a predictable sequence: subcapsular hematomas → parenchymal hemorrhage → potential hepatic rupture. 3
• Reduced portal blood flow from microangiopathy compounds hepatic ischemia. 1
• Placental Fas Ligand directly damages hepatocytes, resulting in periportal necrosis and elevated transaminases (AST >200 U/L, ALT >159 U/L). 2, 1
• The degree of liver dysfunction correlates directly with thrombocytopenia severity and predicts adverse maternal outcomes. 3

Coagulation Cascade and DIC Risk

• In approximately 50% of women with HELLP, activation of coagulation factors and platelets precipitates disseminated intravascular coagulation (DIC). 1
• In a minority of cases, DIC becomes uncompensated and contributes to life-threatening multiorgan failure. 1
• Despite severe thrombocytopenia, prothrombin time, activated partial thromboplastin time, and fibrinogen concentration typically remain normal unless DIC develops. 2
• Elevated fibrin degradation products (>80 µg/L, normal <10 µg/L) indicate the ongoing microangiopathic process. 2

Genetic and Immunologic Factors

• No single worldwide genetic cause has been identified; rather, combinations of multiple gene variants with moderate risk, combined with maternal and environmental factors, represent probable etiological mechanisms. 1
• High levels of HLA-DR in maternal blood in women with HELLP may suggest similarity to transplant rejection reactions. 1
• The syndrome shows familial tendency, and previous HELLP pregnancy increases risk of recurrence and preeclampsia in subsequent pregnancies. 1

Critical Clinical Correlation

• 65% of symptomatic HELLP patients present with right upper quadrant or epigastric pain, which directly reflects hepatic capsular distension from subcapsular hematoma formation or periportal necrosis. 3, 2
• The pathophysiology explains why HELLP only resolves after delivery—removal of the placental source of anti-angiogenic factors and Fas Ligand is essential for disease resolution. 3
• 30% of cases occur or worsen postpartum because the inflammatory cascade and microangiopathy can continue for 48 hours after placental removal before resolution begins. 3, 4