Why is D‑dimer elevated in HELLP syndrome but typically normal in thrombotic thrombocytopenic purpura in a pregnant woman presenting with thrombocytopenia, hemolysis, elevated liver enzymes, and hypertension?

Why D-dimer is Elevated in HELLP Syndrome but Not in TTP

D-dimer is elevated in HELLP syndrome because it involves disseminated intravascular coagulation (DIC) with widespread fibrin formation and degradation in hepatic sinusoids, whereas TTP is characterized by platelet-rich microthrombi without significant fibrin deposition or activation of the coagulation cascade.

Pathophysiologic Mechanisms

HELLP Syndrome and Coagulation Activation

• HELLP syndrome triggers DIC through hepatic sinusoidal endothelial damage, leading to fibrin deposition within hepatic sinusoids, activation of the coagulation cascade, and subsequent fibrinolysis that generates D-dimer 1.

• The pathophysiology involves inadequate placental perfusion progressing to endothelial dysfunction, with the placenta releasing factors that induce platelet aggregation and endothelial damage, causing fibrin release and cross-linked network formation in small blood vessels 1.

• Hepatic involvement results from fibrin deposition within hepatic sinusoids causing sinusoidal obstruction and hepatic ischemia, which activates both coagulation and fibrinolytic pathways 1.

• Patients with HELLP syndrome demonstrate mean D-dimer values of 3848±2551 ng/mL compared to 1578±1077 ng/mL in preeclampsia alone (P<0.001), reflecting the consumptive coagulopathy 2.

• The D-dimer elevation in HELLP reflects systemic coagulation activation with DIC present in severe cases, distinguishing it from isolated microangiopathic processes 1, 3.

TTP and Absence of Coagulation Activation

• TTP results from severe ADAMTS13 deficiency (<5% activity) causing accumulation of ultra-large von Willebrand factor multimers that trigger platelet aggregation without activating the coagulation cascade 4, 5.

• The microthrombi in TTP are platelet-rich and fibrin-poor, meaning there is minimal fibrin formation and therefore minimal fibrin degradation to generate D-dimer 4, 5.

• Coagulation parameters (PT, aPTT, fibrinogen) typically remain normal in TTP because the primary pathology is platelet aggregation rather than thrombin generation 4, 5.

Clinical Implications for Differential Diagnosis

Laboratory Patterns

• In HELLP syndrome, expect elevated D-dimer (often >2000 ng/mL), prolonged PT/aPTT, and decreased fibrinogen reflecting consumptive coagulopathy 1, 2, 3.

• In TTP, D-dimer is typically normal or only mildly elevated, with normal PT/aPTT and normal fibrinogen despite severe thrombocytopenia and hemolysis 4, 5.

• A D-dimer >2170 ng/mL has 91% sensitivity for HELLP syndrome in preeclamptic patients, though specificity is only 40% 2.

• Negative D-dimer testing has a negative predictive value of 0.89 for excluding HELLP syndrome in preeclamptic women 3.

Diagnostic Algorithm

• When evaluating a pregnant woman with thrombocytopenia and hemolysis:

  • Check D-dimer, PT/aPTT, fibrinogen, and peripheral smear 1, 6
  • Elevated D-dimer + coagulopathy + elevated liver enzymes + hypertension → HELLP syndrome 1, 2
  • Normal D-dimer + normal coagulation studies + neurologic symptoms → consider TTP 4, 5
  • Order ADAMTS13 activity if TTP suspected (though results take days) 4, 5

• Critical pitfall: HELLP-induced acute liver failure can secondarily cause ADAMTS13 deficiency and TTP-like presentation, as the liver produces ADAMTS13 4.

• If laboratory parameters fail to normalize after delivery in presumed HELLP syndrome, consider secondary TTP and initiate plasma exchange 4, 5.

Pregnancy-Specific Considerations

• Normal pregnancy elevates D-dimer progressively, with third-trimester values of 0.16-1.3 μg/mL (up to 2.0 μg/mL may be normal) 7, 8.

• D-dimer values >2000 ng/mL in a pregnant woman with hypertension and thrombocytopenia are pathologic and suggest HELLP syndrome rather than physiologic pregnancy changes 7, 2.

• The hypercoagulable state of pregnancy predisposes to DIC when HELLP syndrome develops, amplifying D-dimer elevation beyond pregnancy baseline 8, 3.

Management Implications

• HELLP syndrome requires urgent delivery after maternal stabilization, as the coagulopathy only resolves postpartum 1, 6.

• TTP requires plasma exchange as first-line therapy, not delivery, since it is not pregnancy-specific and persists postpartum without treatment 4, 5.

• Do not delay delivery in HELLP syndrome to pursue ADAMTS13 testing, as prompt delivery is life-saving regardless of ADAMTS13 levels 1, 6.

• If coagulopathy persists postpartum despite delivery, measure ADAMTS13 activity and consider plasma exchange for possible secondary TTP 4, 5.