Congenital
Thrombotic Thrombocytopenic Purpura

Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare and life-threatening thrombotic microangiopathy (TMA) characterized by thrombocytopenia, microangiopathic hemolytic anemia (MAHA), and microvascular thrombosis leading to end-organ damage.1-3

cTTP results from genetic mutations of the ADAMTS13 enzyme responsible for regulating the activity of von Willebrand factor (VWF) by cleaving large and ultra-large VWF multimers into smaller subunits.1 Patients with cTTP have a severe deficiency in the ADAMTS13 enzyme which leads to increased large and ultra-large VWF multimers in the circulation causing platelet accumulation and microthrombi formation which occlude small blood vessels.1,3

Congenital thrombotic thrombocytopenic purpura illustration

Epidemiology

Incidence/prevalence: Approximately 0.5 to 2 cases per million people.1

Population and distribution: cTTP affects men and women equally, with half of patients presenting with first episode by 2-5 years of age, and half presenting in early adulthood (often during pregnancy).4

Pathophysiology

Thrombotic thrombocytopenic purpura (TTP) can be congenital (cTTP, also referred to as hereditary TTP) or immune-mediated (iTTP, also referred to as acquired TTP).4

cTTP comprises <5% of all TTP cases, while iTTP accounts for the remaining ~95% of all TTP cases.4,5

cTTP is caused by mutations in ADAMTS13 gene, resulting in a severe ADAMTS13 deficiency (activity <10% of normal).4,6 There are more than 200 genetic mutations that have been linked to cTTP.3 Most of these mutations are compound heterozygous, and only 15 homozygous mutations have been described.7 Mutations either reduce secretion of ADAMTS13 or impair its catalytic activity resulting in a deficiency of ADAMTS13. This causes ultra large VWF multimers to remain uncleaved in the bloodstream which adhere to platelets and aggregate in the microcirculation, forming platelet-rich microthrombi.8 This can lead to acute TTP events that cause consumptive thrombocytopenia, fragmentation of circulating erythrocytes or MAHA, and eventually irreversible organ damage due to local ischemia (especially in the brain, heart, and kidneys).1,4

iTTP is an autoimmune disorder caused by auto-antibodies against endogenous ADAMTS13.4

Diagnosis

When a TMA is suspected, platelet count, creatinine levels, and peripheral blood smear should be assessed.4 If platelet count is <30 × 109 cells/L, creatinine level <2.25 mg/dL, and schistocytes are present in peripheral blood smear, then TTP is suspected. ADAMTS13 activity assay can confirm TTP if it indicates <10% of normal ADAMTS13 activity. To differentiate between iTTP and cTTP, an anti-ADAMTS13 IgG assay is carried out, and if negative, then cTTP is suspected. cTTP can be confirmed by genetic sequence analysis.

Navigating cTTP

Long-term morbidity:
cTTP can affect many organs and systems, and can cause neurologic symptoms (like confusion, headache, focal neurological deficits, paresis, speech impairment, visual changes, encephalopathy, coma, and depression), cardiovascular symptoms (like chest pain, heart failure, hypotension, and stroke/transient ischemic attack), gastrointestinal symptoms (like abdominal pain), and/or renal symptoms (like proteinuria and microhematuria), in addition to fever and purpura, which appears as purplish bruises or pinpoint-sized dots on skin or mucous membranes.4,9

TTP manifests as acute events with short- and long-term outcomes and is associated with a significant disease burden.4,5 Quality of life and lifespan are significantly reduced compared to the general population due to serious, ongoing widespread organ damage and other comorbidities resulting from an ADAMTS13-deficient state.

Patients’ quality of life also suffers due to the treatment burden and complications.10

Mortality:
cTTP is associated with a 90% mortality rate if left untreated and even with treatment, the mortality rate remains high (5-16%) especially during acute episodes.9,11