Version July 2025
INTRODUCTION —
This monograph discusses the implications of genetic test results for the ADAMTS13 gene, the gene that is abnormal in hereditary thrombotic thrombocytopenic purpura (hTTP, also called congenital TTP [cTTP]). It does not discuss indications for ADAMTS13 testing.
Epidemiology of hereditary TTP, evaluation, differential diagnosis, management, and supporting evidence are discussed separately [1]. (See 'UpToDate topics' below.)
OVERVIEW
How to read the report and when to repeat testing — The checklist provides important caveats for genetic testing (table 1).
Variants are classified according to their pathogenicity, which is determined based on available research from clinical, genetic, and epidemiologic studies. Variants of uncertain significance (VUS) are those for which the role in causing disease is uncertain; these can be reclassified once more information becomes available. (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Penetrance and expressivity'.)
Any result obtained for research or by direct-to-consumer testing that has clinical implications for the tested individual or their relatives should be repeated in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory or other nationally certified laboratory with verified patient identification.
For a VUS, the testing laboratory of a clinical expert should be queried periodically (eg, annually) regarding whether the variant has been reclassified as pathogenic or benign.
Once a diagnosis of hereditary TTP has been made, there is no role for repeating ADAMTS13 genetic testing.
ADAMTS13 gene — ADAMTS13 encodes ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), an enzyme that cleaves ultra-large, string-like molecules of von Willebrand factor (VWF) synthesized by endothelial cells.
Upon exposure to shear stress, these VWF multimers undergo a conformational change that exposes the ADAMTS13 cleavage site. When ADAMTS13 activity is reduced due to a genetic variant or autoimmune destruction, these ultra-large VWF multimers accumulate and bind to platelets, causing microthromboses in small arterioles and capillaries.
Hereditary TTP results from biallelic pathogenic variants in ADAMTS13 (table 2). More than 200 pathogenic variants have been described, including insertions, deletions, missense and nonsense point mutations, and splice site mutations. Most are private, confined to a single kindred. They are listed in the hereditary TTP database. (See 'External resources' below.)
Genetic epidemiology studies suggest that the global prevalence of hereditary TTP may be as high as 23 per million, with the highest prevalence in individuals from East Asia (42 per million) [2].
Genotype-phenotype correlations are inconsistent, but genotypes associated with some residual ADAMTS13 activity, such as a common missense mutation in the United States and Europe, R1060W, may be associated with less severe disease and/or later age of presentation than genotypes associated with absent ADAMTS13 activity. Other factors that modify phenotype may include unidentified genetic variants and exposures such as infections.
Hereditary TTP — Hereditary TTP is autosomal recessive. Severe deficiency and clinical disease manifestation require biallelic pathogenic variants (one inherited from each parent), leading to severe ADAMTS13 deficiency (ADAMTS13 activity levels <10 percent). (See "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)", section on 'Deficient ADAMTS13 activity'.)
Most individuals with hereditary TTP come to medical attention after a relative is diagnosed with hereditary TTP or after they have an episode of TTP and laboratory testing reveals ADAMTS13 deficiency (activity <10 percent) without an autoantibody. Autoantibody-mediated ADAMTS13 deficiency is referred to as immune TTP.
Hereditary TTP is rare in adults (<5 percent of all TTP; approximately 23 to 42 per 1 million population) but is more common than immune TTP in infants and young children. (See "Hereditary thrombotic thrombocytopenic purpura (hTTP)", section on 'Epidemiology'.)
The times at greatest risk for an episode of TTP are birth and pregnancy, but disease can present at any age. (See "Hereditary thrombotic thrombocytopenic purpura (hTTP)", section on 'Times of greatest risk'.)
Heterozygous individuals — Heterozygosity for a pathogenic variant in ADAMTS13 is not sufficient to cause hereditary TTP. Parents of an individual with hereditary TTP are obligate heterozygous carriers but are not affected. (See 'Implications for first-degree relatives' below.)
However, heterozygous individuals may be at increased risk for certain vascular events, such as stroke or coronary artery disease. (See "Hereditary thrombotic thrombocytopenic purpura (hTTP)", section on 'Heterozygous individuals'.)
CLINICAL IMPLICATIONS
Treatment (symptomatic individuals) — Acute episodes of TTP can be life-threatening. Hereditary TTP is most likely to become symptomatic during the newborn period, pregnancy, or an acute illness.
Symptomatic individuals who are at risk of hereditary TTP, such as siblings of an individual known to have biallelic ADATMS13 pathogenic variants, who have not yet been diagnosed should be tested for ADAMTS13 activity and treated as rapidly as possible (presumptive treatment pending results of ADAMTS13 activity if suspicion for TTP is high). (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)", section on 'Presumptive diagnosis of TTP: Start therapeutic plasma exchange (TPE) and possibly caplacizumab'.)
Treatment of hereditary TTP involves supplying a source of ADAMTS13, from either a recombinant ADAMTS13 product or plasma infusion (algorithm 1).
Once the diagnosis of immune TTP has been excluded and hereditary TTP confirmed, there is no role for plasma exchange or immunosuppressive agents. (See "Hereditary thrombotic thrombocytopenic purpura (hTTP)", section on 'Treatment of an acute episode (newborns and symptomatic individuals)'.)
Prophylaxis (asymptomatic individuals) — Individuals who are found to have biallelic pathogenic variants in ADAMTS13 should be evaluated by a TTP expert, regardless of whether they have had an acute TTP event.
This applies to individuals who are tested for any reason including:
●An affected relative. (See 'Implications for first-degree relatives' below.)
●Secondary finding after having genetic testing for another reason. (See "Secondary findings from genetic testing".)
●Evaluation for a previous event that might have been due to hereditary TTP, such as neonatal hemolytic anemia or unexplained stroke in a young individual. (See "Unconjugated hyperbilirubinemia in neonates: Etiology and pathogenesis".)
Some experts provide prophylactic ADAMTS13 around times of increased stress, especially pregnancy or acute infections. (See "Hereditary thrombotic thrombocytopenic purpura (hTTP)", section on 'Management of pregnancy'.)
Some experts provide chronic prophylactic ADAMTS13, especially if the individual has a history of frequent symptoms or exacerbations. (See "Hereditary thrombotic thrombocytopenic purpura (hTTP)", section on 'Prophylaxis/prevention of future exacerbations'.)
IMPLICATIONS FOR FIRST-DEGREE RELATIVES —
First-degree relatives should have the opportunity to speak with a genetics professional or TTP expert to understand potential implications. Testing is most important in siblings of an affected individual who are at risk of also being affected. Other relatives may have heterozygous ADAMTS13 pathogenic variants but are unlikely to be affected unless there is consanguinity.
Hereditary TTP is autosomal recessive. Biallelic pathogenic variants in ADAMTS13 are required for the disease to manifest (table 2). (See 'ADAMTS13 gene' above.)
●Siblings – Siblings of an individual with hereditary TTP should be offered testing. They have the following risks:
•25 percent chance of being affected
•50 percent chance of being an unaffected carrier
•25 percent chance of not inheriting any pathogenic variants
The optimal age for testing and appropriate testing strategy (ADAMTS13 activity, genetic testing, or both) depend on whether they are symptomatic or asymptomatic. (See 'Clinical implications' above.)
●Parents and children – Parents and children of an individual with hereditary TTP are obligate carriers (heterozygous for a pathogenic variant) and are not expected to be affected. (See 'Heterozygous individuals' above.)
Testing may not be indicated due to the low prevalence of ADAMTS13 variants in the general population; however, if there is a higher likelihood of inheriting biallelic pathogenic variants in ADAMTS13 (eg, due to consanguinity) then testing may be appropriate.
Laws to prevent genetic discrimination vary by jurisdiction. (See "Genetic testing", section on 'Genetic discrimination'.)
RESOURCES
UpToDate topics
●Hereditary TTP – (See "Hereditary thrombotic thrombocytopenic purpura (hTTP)".)
●Immune TTP diagnosis – (See "Diagnosis of immune TTP".)
●Immune TTP management – (See "Immune TTP: Initial treatment".)
●Differential diagnosis – (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)
External resources
●Hereditary TTP registry – TTPregistry.net
●United States Thrombotic Microangiopathy Alliance (USTMA)
●TTP Network – ttpnetwork
Genetics professionals
●Clinical geneticists – American College of Medical Genetics and Genomics (ACMG)
●Genetic counselors – National Society of Genetic Counselors (NSGC)
