What are the causes of Thrombotic Thrombocytopenic Purpura (TTP) in the first trimester of pregnancy?

Causes of TTP in First Trimester Pregnancy

TTP in the first trimester is caused by severe ADAMTS13 deficiency, which can be either acquired (immune-mediated with autoantibodies) or congenital (Upshaw-Schulman Syndrome from ADAMTS13 gene mutations), with pregnancy serving as a precipitating trigger rather than a direct cause. 1, 2

Pathophysiologic Mechanisms

The underlying etiology involves two distinct mechanisms:

Acquired (Immune) TTP

• Anti-ADAMTS13 autoantibodies develop and inhibit the metalloprotease responsible for cleaving ultra-large von Willebrand factor (ULvWF) multimers, leading to systemic platelet aggregation and microvascular thrombosis 1, 3
• This represents the majority of pregnancy-associated TTP cases 1
• Pregnancy acts as an immunologic trigger that precipitates acute episodes in susceptible women 1, 4

Congenital TTP (Upshaw-Schulman Syndrome)

• Homozygous or compound heterozygous mutations in the ADAMTS13 gene cause constitutive severe deficiency of the enzyme 2, 3
• This accounts for only 2-4% of all TTP cases but is particularly relevant in pregnancy 2
• Autosomal recessive inheritance pattern means many women remain undiagnosed until pregnancy unmasks the condition 2
• The physiologic stress of pregnancy triggers acute manifestations in previously compensated patients 2, 5

Why Pregnancy Precipitates TTP

Pregnancy creates a prothrombotic milieu through several mechanisms that unmask or exacerbate underlying ADAMTS13 deficiency:

• Increased levels of fibrinogen, factor VIII, and von Willebrand factor create additional substrate for thrombosis 6
• Suppressed fibrinolysis and reduced protein S activity further shift the hemostatic balance 6
• Hemodilution and increased platelet activation/clearance stress the ADAMTS13 system 6
• These changes are most pronounced in the third trimester but begin in the first trimester 6, 5

Critical Diagnostic Distinction

The first trimester presentation is particularly challenging because pregnancy-specific causes of thrombocytopenia do not typically occur this early:

• Gestational thrombocytopenia, preeclampsia, HELLP syndrome, and acute fatty liver are predominantly third-trimester complications 6, 7
• A high index of suspicion for TTP is essential when thrombocytopenia with microangiopathic hemolytic anemia presents in the first trimester 1, 5
• ADAMTS13 activity testing should be obtained immediately, as levels <10% confirm the diagnosis 1, 5, 3

Clinical Implications

First trimester TTP carries particularly poor prognosis with high fetal mortality if not promptly recognized and treated 5:

• Neurologic and renal manifestations may precede laboratory abnormalities 5
• Immediate plasma exchange (30 mL/kg/day) combined with fresh-frozen plasma infusion (10 mL/kg/day) is life-saving 5, 3
• Distinguishing congenital from acquired TTP is mandatory for counseling about future pregnancies 1, 4