INTRODUCTION — Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy caused by severely reduced activity of the von Willebrand factor-cleaving protease ADAMTS13. It is characterized by arteriolar platelet-rich thrombi that cause organ ischemia and produce neurologic abnormalities, kidney dysfunction, thrombocytopenia, and microangiopathic hemolytic anemia (MAHA).
●Most cases of TTP are acquired, caused by autoantibody-mediated inhibition or clearance of ADAMTS13 activity.
●Hereditary TTP, caused by pathogenic variants in the ADAMTS13 gene, is much less common but no less life-threatening. Individuals with hereditary TTP require life-long care and special attention during certain life-stages, especially in the neonatal period and during pregnancy.
●Although acquired TTP accounts for more than 90 percent of cases of TTP in adults, the frequencies of acquired and hereditary TTP are similar in children <10 years old.
This topic discusses our approach to the diagnosis and management of hereditary TTP.
Separate topic reviews also present the diagnosis and management of other thrombotic microangiopathies (TMA) such as acquired TTP and hemolytic uremic syndrome (HUS):
●Overview of TMAs – (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)
●Acquired TTP diagnosis – (See "Diagnosis of immune TTP".)
●Acquired TTP management – (See "Immune TTP: Initial treatment" and "Immune TTP: Treatment of clinical relapse".)
●HUS – (See "Overview of hemolytic uremic syndrome in children" and "Complement-mediated hemolytic uremic syndrome in children" and "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS".)
TERMINOLOGY — We use the term hereditary TTP to refer to patients with severe deficiency of the ADAMTS13 protease (typically, undetectable activity) due to inherited, biallelic ADAMTS13 gene mutations. This condition is also called congenital TTP, inherited TTP, familial TTP, and Upshaw-Schulman syndrome [1].
ADAMTS13 is the protease that cleaves ultra-large von Willebrand factor multimers. (See "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)", section on 'Deficient ADAMTS13 activity'.)
Terminology for symptoms and illness in patients with hereditary TTP is related to their severity and to the recognition that ADAMTS13 activity in patients with hereditary TTP is always absent or severely deficient. Therefore:
●Symptoms – Minor or transient abnormalities, such as headaches, lethargy, abdominal discomfort, transient loss of attention, and/or brief syncope, are described as symptoms. Often they have no clearly defined times of onset or resolution. That they are caused by hereditary TTP is supported by their resolution in response to plasma therapy [2].
●Exacerbation – More severe illness, often presenting suddenly and often related to a precipitating event, such as pregnancy and the turbulent circulation in newborn infants, are described as exacerbations [3,4]. "Exacerbation" describes an acute increase in the severity of a chronic illness. Our use of exacerbation is distinct from the use of exacerbation in patients with acquired TTP, in which it describes the recurrence of severe thrombocytopenia following an initial response to plasma exchange and/or caplacizumab.
●Episode – The term "episode," as used for the descriptions of acquired TTP, is generally avoided for hereditary TTP because these patients have a lifetime illness, and the more severe symptoms may be incremental, without a defined onset or resolution.
Terminology for other primary thrombotic microangiopathies, including acquired autoimmune TTP and Shiga toxin-associated hemolytic uremic syndrome, is presented separately. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)", section on 'Overview of primary TMA syndromes'.)
GENETICS — Hereditary TTP (OMIM #274150) is an autosomal recessive condition.
●Disruption of both alleles of the ADAMTS13 gene is required to cause deficiency severe enough to lead to the clinical syndrome.
●Individuals who are heterozygous for an ADAMTS13 mutation (only one allele affected) do not appear to be at risk during pregnancy or other settings that can precipitate TTP episodes in patients with biallelic ADAMTS13 defects.
However, heterozygotes have lower baseline ADAMTS13 activity and may have increased risk for certain disorders. This has been illustrated in observations from the Rotterdam study, which evaluated cardiovascular outcomes in nearly 6000 healthy individuals 55 years of age or older. Those with ADAMTS13 activity in the lowest quartile of the normal range had a higher risk of stroke (7.3 percent, versus 3.8 percent in the highest quartile; adjusted hazard ratio, 1.65; 95% CI 1.16-2.32) and increased all-cause and cardiovascular mortality [5-7].
More than 200 pathogenic variants in ADAMTS13 have been described [1]. These include insertions, deletions, missense and nonsense point mutations, and splice site mutations [1,2,8,9]. These are cataloged by the Hereditary TTP Registry, which has enrolled over 140 patients and family members from 17 countries in America, Europe, Africa, the Middle East, and Asia [9,10]. Pathogenic mutations are spread throughout the ADAMTS13 gene [1,2,9]. Most mutations are private (confined to single families).
Siblings with the same mutations can have strikingly different clinical features. In one family enrolled in the Hereditary TTP Registry, a patient had recurrent strokes beginning at age 17 years while her younger brother, who was healthy, was only discovered to have absent ADAMTS13 activity and the same mutations at age 33 years.
Genotype-phenotype analyses have demonstrated inconsistent correlations between mutations and clinical features. However, genotypes associated with some residual ADAMTS13 activity, such as a common 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 [2,8,11].
Residual ADAMTS13 activity is only weakly correlated with age of diagnosis and severity of symptoms, indicating that other factors also modify disease phenotype [2,9]. Other modulators of clinical phenotype may include the physiologic stresses such as birth, pregnancy, or infections, as well as other unidentified genetic factors.
Additional discussion of ADAMTS13 function and its role in preventing microvascular thrombosis is presented separately. (See "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)", section on 'TTP pathogenesis'.)
EPIDEMIOLOGY — Hereditary TTP is rare. The prevalence is often described as one patient per one million population. In the Oklahoma TTP Registry, representing a population of 2.4 million people, we have identified only one family in 26 years. Three daughters in this family have hereditary TTP, a prevalence of 1.25 patients per one million people. During this same period, 92 patients with acquired TTP have been identified.
●In our overall experience, hereditary TTP represents <5 percent of all TTP cases.
●Among certain groups such as newborn infants and young children, hereditary TTP is more common than or has a similar prevalence to acquired TTP, which is uncommon in young children [12]. In the Oklahoma Registry, acquired TTP has only been identified in two patients less than 18 years old.
●In women presenting with TTP in their first pregnancy, up to one-fourth of the women may have hereditary TTP [13].
A population-based cross-sectional study using medical records in one health district in Norway discovered a much higher prevalence, with 17 individuals affected per one million population [14]. The prevalence of the R1060W mutation in this Norway district was 0.3 to 1 percent, suggesting that the prevalence of hereditary TTP may be higher than estimated, at least in this region. A founder effect in this community may also explain the findings. The increased availability of ADAMTS13 activity measurement is likely to increase the frequency with which the diagnosis of hereditary TTP is made.
There do not appear to be any ethnic, racial, or geographic differences in the prevalence of hereditary TTP [9]. Since hereditary TTP is an autosomal recessive trait with a rare gene frequency, some affected families may have a history of consanguinity, and the incidence of hereditary TTP may be greater in populations in which consanguinity is common.
There is no sex disparity among patients diagnosed in infancy or childhood; however, among patients diagnosed as adults, young women are more frequently recognized than men because of the high risk of exacerbation during pregnancy [8]. (See 'Management of pregnancy' below.)
CLINICAL FEATURES
Typical presentation — The dramatic features of an acquired TTP episode are not typical of hereditary TTP. The episodes of acquired TTP typically have discreet onset and (with treatment) remission. Patients with hereditary TTP may often have seemingly mild and nonspecific symptoms such as lethargy, headache, loss of concentration, and abdominal discomfort [2]. We describe these as symptoms, rather than episodes, because the disorder, severe ADAMTS13 deficiency, is always present. (See 'Terminology' above.)
These symptoms may have no discrete onset or resolution, except for their response to plasma infusion. We use the word exacerbation for more severe illness, such as the occurrence of severe hemolysis in newborn infants and the occurrence of severe thrombocytopenia and neurologic symptoms during pregnancy. Neurologic symptoms can also occur without thrombocytopenia or anemia, or thrombocytopenia may occur without apparent hemolysis [1]. The times of greatest risk for severe symptomatic exacerbations are discussed below. (See 'Times of greatest risk' below.)
Although acute, severe exacerbations are uncommon in patients with hereditary TTP, they may be life-threatening without appropriate treatment. Case reports from before the era of plasma infusion have described healthy individuals with hereditary TTP who died from acute exacerbations. In the 1970s, we cared for two teenage sisters who presented with acute symptoms of TTP in the third trimester of their first pregnancies, two years apart; both died of TTP [15].
Remarkably, individuals with hereditary TTP and undetectable ADAMTS13 activity can be asymptomatic with apparently excellent health into adulthood. This variability in clinical presentation may be related to physiologic adaptation to continually absent ADAMTS13, such that some features of TTP occur in isolation. As noted above, siblings with the same genotype can have remarkably different clinical courses. (See 'Genetics' above.)
Uncharacteristic of acquired TTP, patients with hereditary TTP may present with severe kidney failure [8,9]. This may occur because the lifelong ADAMTS13 deficiency causes gradual accumulation of thromboses in the vasculature of the kidney. (See "The endothelium: A primer".)
Times of greatest risk — Two times of greatest risk are the neonatal period and pregnancy. However, individuals with hereditary TTP can present at any age including childhood and adulthood.
Triggering events also increase the risk of exacerbations. Common triggering events include infections and administration of DDAVP (desmopressin); eg, to treat enuresis in children [9,16]. DDAVP increases levels of circulating von Willebrand factor (VWF).
Neonatal period (first few days of life) — The first days of life are a critical period for hereditary TTP. Two case series have described severe hemolysis with neonatal hyperbilirubinemia requiring exchange blood transfusion in 42 and 45 percent of patients subsequently diagnosed with hereditary TTP [8,14]. None of these infants was recognized to have hereditary TTP at birth; they were subsequently diagnosed at ages 1 month up to 25 years.
Severe hyperbilirubinemia is rare in newborns, and neonatologists should be aware that hereditary TTP can cause severe hyperbilirubinemia. Severe neonatal hyperbilirubinemia accompanied by thrombocytopenia is an indication to suspect hereditary TTP and to measure ADAMTS13 activity. (See 'When to suspect the diagnosis' below.)
Following recovery, these infants may have recurrent episodes of thrombocytopenia or, occasionally, no symptoms of hereditary TTP until they are adults.
The reason neonates are at high risk of complications is the increased turbulence of blood caused by the reversal of flow in the patent ductus arteriosus and the abrupt changes in blood circulation. Also, the high neonatal hematocrit and increased concentration of VWF (especially the presence of ultra-large VWF multimers in neonatal blood), may contribute to the high risk [4,17-20].
If newborn infants with hereditary TTP are not treated with blood or plasma, they may die [21]. In the neonates described above, ADAMTS13 provided during exchange transfusion was life-saving [8,14]. (See 'Management' below.)
Pregnancy — Presentation in pregnancy is common. In some of the larger series, more than half of the affected females had their initial presentation or a severe exacerbation during pregnancy [2,8,9,15,22,23].
Pregnancy in a woman with undiagnosed hereditary TTP almost always causes severe complications. Analysis of 61 pregnancies in 35 women with previously undiagnosed hereditary TTP documented severe complications in 34 (97 percent) [3]. A history of a normal uncomplicated pregnancy is strong evidence against the diagnosis of hereditary TTP.
Presenting findings of hereditary TTP during pregnancy include the following findings:
●Signs of severe preeclampsia and/or hypertension before 20 weeks gestation [24,25]
●Severe thrombocytopenia (platelet count <50,000/microL) at any time during pregnancy
●Evidence of hemolysis with fragmented red blood cells on the blood smear (picture 1)
●Transient neurologic symptoms
●Signs of acute kidney injury
●Intrauterine fetal death [24,26]
In our experience, women who are not treated with plasma infusion during pregnancy have a high likelihood of spontaneous pregnancy loss or death. Women who have suggestive signs or symptoms, such as severe preeclampsia with atypical features before 20 weeks gestation, should be evaluated with measurement of ADAMTS13 activity. (See 'Laboratory testing' below.)
DIAGNOSTIC EVALUATION
When to suspect the diagnosis — The newborn period and pregnancy are common times for hereditary TTP to come to medical attention. Other common presentations are during early childhood or in young adults (eg, with unexplained neurologic symptoms or ischemic stroke).
Hereditary TTP should be considered in individuals with any of the following presentations:
●A newborn infant with severe hyperbilirubinemia (due to hemolysis) and thrombocytopenia [8,14,21]. Every newborn with severe hyperbilirubinemia should have ADAMTS13 activity measured to diagnose or exclude hereditary TTP. (See "Escalation of care for term and late preterm newborns with unconjugated hyperbilirubinemia".)
●Recurrent thrombocytopenia in a child or young adult, especially if there is also anemia with evidence for microangiopathic hemolysis. Thrombocytopenia may spontaneously resolve, similar to childhood immune thrombocytopenia (ITP) [1]. In a series of 43 patients, seven (16 percent) were diagnosed as children (ages 1 month to 14 years) [8]. Some had recurrent episodes of thrombocytopenia and were mistakenly thought to have ITP. Other series have reported similar findings, with a median age of 3 years (range, 0 to 12 years) for childhood presentations [2]. Acute symptomatic exacerbations are commonly precipitated by infections [2].
●Transient neurologic symptoms or stroke in a child or young adult. The occurrence of stroke in patients with hereditary TTP is 25 to 31 percent [2,9,27]. The median age for stroke is 19 years [27].
●Embolic stroke of undetermined source in a patient of any age [28]. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)".)
●All siblings of an affected individual, regardless of whether symptoms have occurred. This is especially important for sisters of a patient with hereditary TTP, to know if plasma prophylaxis will be required during pregnancy. (See 'Genetic counseling and testing of siblings' below.)
●Any adult with new onset TTP without an inhibitor. Lack of a detectable inhibitor does not exclude the diagnosis of acquired TTP. Among Oklahoma Registry participants with acquired TTP, a functional ADAMTS13 inhibitor was not initially identified in 15 of 86 individuals (17 percent) [29].
Laboratory testing — Laboratory testing includes:
●CBC – Complete blood count (CBC) with platelet count. Each individual has a normal range for their own platelet count [30]. Thus, for an individual with a normal platelet count in the higher range, it is possible to have a significant decrease while still falling into the normal range (>150,000/microL). In hereditary TTP, a platelet count lower than normal for that individual suggests increased platelet consumption in microthrombi and should be an indication for plasma infusion. (See 'Plasma infusion' below.)
●Hemolysis labs – Laboratory studies to confirm nonimmune hemolysis. Evidence of hemolysis includes increased indirect bilirubin, increased lactate dehydrogenase, and a negative direct antiglobulin (Coombs) test (table 1). The laboratory criteria of the PLASMIC algorithm, developed from patients with acquired TTP, may not be appropriate for the diagnosis of hereditary TTP [31].
●Creatinine – A metabolic panel that includes serum creatinine. In hereditary TTP, the creatinine may be normal or mildly increased, similar to acquired TTP. However, some patients with hereditary TTP may present with acute kidney injury, mimicking Shiga toxin-induced hemolytic uremic syndrome [2,9]. Acute kidney injury may progress to end-stage kidney disease, requiring dialysis or kidney transplantation [32].
●Blood smear – Evaluation of the peripheral blood smear for schistocytes (picture 1) is critical. Thrombocytopenia and microangiopathic hemolytic anemia (MAHA), characterized by schistocytes, are characteristically present. Rarely, some patients may have thrombocytopenia (mild or severe) without evidence for hemolysis and without increased schistocytes on the blood smear. Abnormal red blood cell (RBC) morphology may be more common in neonates without TTP due to physiologic hyposplenism.
●ADAMTS13 – ADAMTS13 activity should be measured; if there is severe deficiency (activity <10 percent), inhibitor testing should be performed; often, a laboratory will perform reflex testing for an inhibitor if activity is severely deficient. Hereditary TTP is characterized by severe ADAMTS13 deficiency without an inhibitor; however, this finding is not specific for hereditary TTP because some individuals with acquired TTP do not have a detectable inhibitor for a variety of reasons. (See "Diagnosis of immune TTP", section on 'ADAMTS13 testing'.)
In some cases, severe ADAMTS13 deficiency may be obscured by transfusion of any plasma-containing product (plasma, RBCs, or platelets) or by plasma exchange. It is appropriate to retest ADAMTS13 activity following recovery for individuals suspected of having hereditary TTP. In hereditary TTP, ADAMTS13 activity remains low due to the genetic defect. In acquired TTP, ADAMTS13 activity may normalize or remain low.
If an individual has had an acute episode of MAHA and thrombocytopenia associated with severe ADAMTS13 deficiency without an inhibitor that responds promptly to plasma infusion, we repeat the ADAMTS13 activity measurement following recovery, as the likelihood of hereditary TTP is high and the persistence of severe ADAMTS13 deficiency without an inhibitor is supportive. The likelihood of hereditary TTP is further increased in patients with severe ADAMTS13 deficiency (activity <10 percent) without a demonstrable inhibitor during remission on at least two occasions four weeks apart. However, persistent severe ADAMTS13 deficiency in remission is not diagnostic of hereditary TTP, because some patients with acquired TTP may have persistent severe ADAMTS13 deficiency in clinical remission and a false-negative inhibitor assay. (See "Diagnosis of immune TTP", section on 'ADAMTS13 testing'.)
●PT/aPTT – Coagulation testing is typically indicated in individuals with unexplained anemia and/or thrombocytopenia. In hereditary TTP (and other primary thrombotic microangiopathies [TMAs]), baseline coagulation studies typically are normal, including the prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, and D-dimer, although D-dimer might be increased during acute presentations. An exception may be a patient who develops disseminated intravascular coagulation (DIC) as a result of severe organ ischemia associated with TTP. In acute DIC, the PT and aPTT are typically prolonged and the fibrinogen is typically low.
●Genetic testing – Genetic testing is necessary to confirm the diagnosis in all individuals with a presumptive diagnosis of hereditary TTP due to persistent ADAMTS13 deficiency without an inhibitor. (See 'Diagnosis' below and 'Genetic testing' below.)
Diagnosis — A presumptive diagnosis of hereditary TTP is made in an individual who has severe ADAMTS13 deficiency without an inhibitor in the appropriate clinical setting. Genetic testing is confirmatory. Identification of biallelic pathogenic variants in ADAMTS13 documents the diagnosis of hereditary TTP.
In a family member of a patient with hereditary TTP, diagnosis is made based on severely deficient ADAMTS13 activity and biallelic ADAMTS13 mutations.
An asymptomatic family member with a heterozygous ADAMTS13 mutation may have an increased risk for stroke or cardiovascular disease but is not considered to have hereditary TTP. (See 'Genetic counseling and testing of siblings' below.)
Genetic testing — Genetic testing of the ADAMTS13 gene is the definitive means of documenting the diagnosis of hereditary TTP. Genetic testing is appropriate in any individual with suspected hereditary TTP and undetectable or severe deficiency of ADAMTS13 activity without an inhibitor.
Sisters of patients with documented hereditary TTP should have measurements of ADAMTS13 activity. If it is severely deficient, hereditary TTP should be confirmed by genetic testing. (See 'Genetic counseling and testing of siblings' below.)
Identification of biallelic pathogenic variants in ADAMTS13 confirms the diagnosis of hereditary TTP. Heterozygotes for a pathogenic variant in ADAMTS13 are considered unaffected, but they may have an increased risk of stroke or cardiovascular disease. (See 'Genetics' above.)
Genetic analysis is available for patients in whom hereditary TTP is strongly suspected by these criteria at no cost through the Hereditary TTP (Upshaw-Schulman syndrome) Registry (www.ttpregistry.net). In appropriately selected patients, the likelihood of identifying biallelic pathogenic variants in ADAMTS13 is very high.
Differential diagnosis — Of conditions in the differential diagnosis, only acquired TTP is associated with severe ADAMTS13 deficiency (activity <10 percent). The remainder have normal or mildly decreased activity, as can be seen with any acute illness. (See "Diagnosis of immune TTP", section on 'ADAMTS13 activity'.)
●Acquired TTP – Like hereditary TTP, acquired TTP is characterized by severe ADAMTS13 deficiency (activity <10 percent). Unlike hereditary TTP, acquired TTP is caused by an autoantibody that inhibits ADAMTS13 activity or increases clearance, and this is usually (but not always) detected at the time of ADAMTS13 measurement. (See "Diagnosis of immune TTP".)
●Other primary TMAs – Like hereditary TTP, other primary thrombotic microangiopathies (TMAs) can present with thrombocytopenia and MAHA and may include neurologic symptoms and/or various degrees of kidney dysfunction. Unlike hereditary and acquired TTP, other TMA syndromes do not have severe ADAMTS13 deficiency. Although severe acute kidney injury is evidence against the diagnosis of acquired TTP, it can occur in patients with hereditary TTP. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)
●DIC – Disseminated intravascular coagulation (DIC) typically occurs in critically ill patients with an apparent cause, such as sepsis or malignancy, and DIC can cause severe anemia with fragmented red cells and thrombocytopenia. Unlike TTP, in DIC, coagulation parameters (PT, aPTT, fibrinogen, D-dimer) are abnormal. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults".)
●Pregnancy-associated syndromes – Preeclampsia with severe features and HELLP syndrome (hemolysis, elevated liver function tests, low platelets) may mimic all of the features of TTP. Like hereditary TTP, preeclampsia and HELLP are associated with thrombocytopenia and MAHA. Unlike hereditary TTP, patients with these syndromes do not have severe ADAMTS13 deficiency, and they require treatment of the underlying syndrome (which may include delivery) rather than plasma infusion. Unlike preeclampsia and HELLP, delivery of the infant does not affect the clinical course of hereditary TTP. (See "Thrombocytopenia in pregnancy" and "Preeclampsia: Antepartum management and timing of delivery".)
●Hemolytic disease of the fetus and newborn (HDFN) – HDFN results from maternal alloantibodies to fetal RBC antigens, leading to fetal/neonatal hemolytic anemia. HDFN due to RhD incompatibility is very rare in developed countries due to near-universal use of anti-D immune globulin when indicated, but HDFN can also be caused by maternal alloantibodies against other RBC antigens. Like hereditary TTP in the newborn, HDFN causes hemolytic anemia and hyperbilirubinemia, and there may be a history of hemolysis in a sibling. Unlike hereditary TTP, in HDFN the hemolysis is immune mediated and there is no thrombocytopenia. (See "Alloimmune hemolytic disease of the newborn: Postnatal diagnosis and management".)
●Immune thrombocytopenia (ITP) – Hereditary TTP is often misdiagnosed as ITP in children. Like hereditary TTP, ITP can manifest as severe thrombocytopenia and/or recurrent episodes of spontaneously resolving thrombocytopenia, especially in children. Unlike hereditary TTP, ITP is not typically associated with hemolytic anemia (unless part of Evans syndrome), and ITP does not cause kidney disease or neurologic abnormalities (unless caused by bleeding, which is rare). Unlike hereditary TTP, ITP is not associated with MAHA or severe ADAMTS13 deficiency. (See "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis".)
●Evans syndrome – Evans syndrome involves two autoimmune cytopenias. Like hereditary TTP, patients with Evans syndrome often present in childhood with hemolytic anemia and thrombocytopenia. Unlike hereditary TTP, Evans syndrome is not associated with microangiopathic changes on the peripheral blood smear, and the anemia in Evans syndrome is immune mediated (Coombs positive). (See "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Evans syndrome'.)
●Inherited thrombocytopenia – Like hereditary TTP, an individual with an inherited platelet disorder will have thrombocytopenia, and siblings may be affected. Unlike TTP, patients with inherited thrombocytopenia do not have hemolytic anemia or ADAMTS13 deficiency. (See "Neonatal thrombocytopenia: Etiology", section on 'Genetic disorders' and "Causes of thrombocytopenia in children", section on 'Inherited platelet disorders' and "Congenital and acquired disorders of platelet function".)
MANAGEMENT
Overview of approach — The major components of management are summarized in the algorithm (algorithm 1). Key points include the following:
●Rapid treatment of symptoms and exacerbations using plasma infusion (see 'Newborns and symptomatic individuals' below)
●Decision-making regarding regular (prophylactic) plasma infusion (see 'Prophylaxis/prevention of future exacerbations' below)
●Planning for pregnancy, with prophylactic plasma infusion for all pregnant women (see 'Management of pregnancy' below)
●Counseling and testing of siblings to identify other affected family members (see 'Genetic counseling and testing of siblings' below)
We also reinforce general guidelines regarding appropriate immunizations, healthy diet, exercise, and avoidance of nicotine to reduce the risk of infectious and cardiovascular illnesses that could contribute to an exacerbation. (See "Standard immunizations for nonpregnant adults" and "Healthy diet in adults" and "Prevention of smoking and vaping initiation in children and adolescents" and "Overview of smoking cessation management in adults" and "Standard immunizations for children and adolescents: Overview", section on 'Routine schedule'.)
For those with severely impaired kidney function, kidney transplantation has been used successfully [32]. (See "Kidney transplantation in adults: Evaluation of the potential kidney transplant recipient".)
Newborns and symptomatic individuals — As described above, disease activity may be manifested by hyperbilirubinemia in newborns and by thrombocytopenia; microangiopathic hemolytic anemia (MAHA); or subtle neurologic symptoms, abdominal pain, lethargy, or headaches in children and adults. (See 'Typical presentation' above.)
The platelet count reflects disease activity in hereditary TTP. If the platelet count is <150,000/microL or lower than the patient's unique normal platelet count, which may be much higher than 150,000/microL [30], it must be assumed that microvascular thrombosis is occurring and treatment is required. (See 'Laboratory testing' above.)
●Individuals with one or more of these signs of active disease should be treated with plasma infusion. (See 'Plasma infusion' below.)
●Rapid resolution of symptoms provides further confirmation of the diagnosis [2]. (See 'Expected recovery' below.)
Plasma infusion — Plasma infusion is used to provide a source of ADAMTS13 for individuals with hereditary TTP, either to treat persistent symptoms or an exacerbation (treatment) or to prevent future exacerbations (prophylaxis). Its efficacy is highly predictable, as evidenced by our own observations and other published reports such as those described below. Any plasma product (Fresh Frozen Plasma, solvent/detergent plasma, thawed plasma, Plasma Frozen Within 24 Hours of Collection) can be used. (See "Clinical use of plasma components", section on 'Plasma products'.)
The main difference between treatment and prophylactic dosing is the frequency (typically, daily for treatment versus every two weeks for prophylaxis) [33].
●Treatment (signs and symptoms of disease):
•Dose – A typical initial plasma dose is 10 to 15 mL/kg.
•Frequency – Plasma infusion is given once daily for treatment.
•Duration – We treat patients until the platelet count recovers to normal, which may require only one to three days of plasma infusion.
●Prophylaxis (when clinically well, to prevent recurrent symptoms or an exacerbation):
•Dose – A typical initial plasma dose is 10 to 15 mL/kg.
•Frequency – Plasma infusion is given once every two weeks for prophylaxis.
•Duration – Indefinite.
In an average-sized adult, 10 to 15 mL/kg is equivalent to two to three units of plasma (approximately 500 to 750 mL). The dose for adults may be rounded to the nearest unit of plasma (ie, we do not discard unused plasma in order to administer an exact dose). The dosing frequencies are based on a half-life of ADAMTS13 in the circulation of 2.5 to 5.4 days [1]. The target ADAMTS13 activity is higher for treating an exacerbation than for prophylaxis. However, specific targets have not been defined, and we do not measure ADAMTS13 activity to guide therapy. (See 'Routine monitoring' below.)
For patients with high confidence for the diagnosis of hereditary rather than acquired TTP, we recommend plasma transfusion rather than plasma exchange (PEX). PEX is not required to treat hereditary TTP because patients do not have an ADAMTS13 inhibitor that needs to be removed. Moreover, the PEX process carries additional risk for adverse effects, especially those related to the use of a central venous catheter, which is often (but not always) required [29]. The ability to use plasma infusion rather than PEX eliminates the need to mobilize the apheresis staff and/or transfer the patient to a facility capable of performing PEX.
However, if there is a suspicion for acquired, autoimmune TTP, PEX rather than plasma infusion should be used. PEX will effectively treat both acquired and hereditary TTP.
Often (especially with the initial presentation), the diagnosis of hereditary TTP is uncertain, due to the delay in ADAMTS13 activity results, lack of precision in inhibitor testing, and more extensive delay in genetic testing. Features that increase the confidence that treatment with plasma transfusion for hereditary TTP is sufficient and PEX for acquired TTP is not required include the following:
•Newborn infant with severe hemolytic anemia and thrombocytopenia
•Child <10 years old with repeated episodes of thrombocytopenia, sometimes associated with MAHA
•Family member of a patient with hereditary TTP
•Previous episode of TTP that responded rapidly (within one to two days) and completely to plasma infusion
For all other individuals with a clinical presentation consistent with TTP and for whom an alternative diagnosis has not been made, we presume the diagnosis is acquired autoimmune TTP and treat accordingly with urgent PEX and other therapies. This includes the majority of adults and pregnant women. The rationale is that hereditary TTP is rare in adults (less than 5 percent of all TTP cases), plasma infusion is not sufficient therapy for acquired TTP, and delays in instituting PEX for an acute episode of acquired TTP may be life-threatening. Details of management are presented separately. (See "Immune TTP: Initial treatment".)
As noted below and in a separate topic review, individuals who cannot accept plasma (eg, Jehovah's Witnesses) or do not tolerate plasma due to side effects may be treated with caplacizumab or a plasma-derived factor VIII concentrate (Koate DVI) that contains ADAMTS13. Supporting evidence is presented separately. (See "Immune TTP: Initial treatment", section on 'Patient who cannot accept plasma/Jehovah's Witness'.)
Expected recovery — In contrast to acquired TTP, individuals with hereditary TTP experience prompt, complete recovery following plasma infusion. Typically, the platelet count increases within one to two days.
●For individuals whose disease responds completely and rapidly to plasma infusion, we continue to monitor the platelet count and pursue further testing (eg, genetic testing) to confirm the diagnosis. (See 'Genetic testing' above.)
●For individuals with a presentation consistent with TTP whose disease does not respond rapidly to plasma infusion, confidence that hereditary TTP is causing the findings decreases, and we treat presumptively for acquired TTP while continuing to evaluate for other possible diagnoses. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)
As noted above, some individuals with hereditary TTP may have only subtle symptoms suggesting that their disease continues to be active (see 'Typical presentation' above). These individuals may benefit from prophylactic plasma infusion, although the decision to use regular prophylactic plasma infusions requires considerable thought and discussion with the patient [2]. (See 'Prophylaxis/prevention of future exacerbations' below.)
Prophylaxis/prevention of future exacerbations — The decision to initiate routine prophylactic therapy is complex and requires thorough discussions with the individual (and/or family members) to ensure that risks and benefits as well as patient values and preferences have been adequately weighed [34]. Larger case series have reported the use of routine prophylaxis in approximately 70 percent of affected individuals, the majority for recurrent symptoms or thrombocytopenia [2,9].
It is likely that all patients would benefit from lifelong prophylactic treatment. However, there are no randomized trials comparing routine prophylactic plasma with on-demand administration at the time of an exacerbation. In addition, the primary means of prophylaxis is plasma administration, and this carries numerous burdens and risks.
Plasma infusion carries risks of transfusion reactions (eg, transfusion-related acute lung injury, allergic reactions) and risks of transfusion-transmitted infection, which is extremely unlikely in the developed world but theoretically possible. Prophylactic plasma infusion also requires intravenous access and travel to a facility every other week, which may present a significant burden and/or cost for some patients. These risks may be acceptable for patients with recurrent thrombocytopenia or persistent symptoms, even minor nonspecific symptoms [2]. (See "Clinical use of plasma components", section on 'Risks'.)
Most individuals who receive regular plasma prophylaxis will eventually require a central venous catheter, such as an implanted port for plasma administration. In our experience, it is better to consider this soon after plasma prophylaxis has begun to avoid the issues of difficult venipunctures for infusion. Additionally, once the decision to use prophylaxis has been made, it is assumed that this therapy will continue for life. (See "Central venous access: Device and site selection in adults", section on 'Long-term'.)
Once prophylactic plasma infusion has begun, the patient may notice changes that validate the decision. Energy and attentiveness may improve, or headaches may become less frequent or disappear. In one series, 88 percent of individuals with headaches, lethargy, and/or abdominal pain had symptom resolution once they started prophylactic plasma infusions [2]. The resulting improvement in quality of life provides the incentive to continue regular plasma infusions.
Our approach is summarized in the algorithm (algorithm 1); key points include the following:
●For patients with recurrent exacerbations, especially with neurologic symptoms, or those who have significant morbidity from ongoing TTP activity (eg, headaches, lethargy, or other symptoms), we suggest prophylactic plasma infusion. Initial dosing is 10 to 15 mL/kg once every two weeks [33]. (See 'Plasma infusion' above.)
Symptoms and platelet count are the most reliable and direct measure of disease activity. If symptoms or platelet counts resolve with this therapy, this provides additional evidence that the therapy is appropriate. If symptoms and/or the platelet count do not improve, potential reasons should be evaluated, including an alternative or additional diagnosis or insufficient plasma dose.
For those who do not completely recover, the dose may be increased or the interval may be shortened. The decision of which to change is individualized based on the clinical picture and burdens of additional infusions; reducing the interval is most common. In one series, administration of plasma every three weeks was insufficient in the majority of individuals; every two weeks was the most common frequency, and shorter intervals were required in a subset [2]. Children were more likely to increase the frequency of plasma infusion due to thrombocytopenia; adults due to persistent lethargy or neurologic symptoms [2].
●For women who become pregnant, we give prophylactic plasma infusions throughout the pregnancy, beginning as soon as the pregnancy is documented, and for six weeks postpartum, without waiting for an acute episode to develop. (See 'Management of pregnancy' below.)
●A single prophylactic dose of plasma may also be appropriate for individuals with the following:
•Undergoing surgical procedures
•Trauma
•Acute illness, especially if requiring hospitalization or treatment
●A reasonable alternative for selected individuals is close observation with a plan for plasma infusion at the first signs or symptoms attributable to TTP. These decisions are individualized based on the patient's history, degree of physiologic stress, prior episodes, values, and preferences. Those who use routine prophylactic infusions may elect to discontinue them if the frequency of triggering events diminishes.
●For individuals who have never had symptoms of TTP (eg, individuals diagnosed by genetic testing of a family member), we suggest not using prophylactic plasma infusion. Prophylactic plasma infusion may be reasonably omitted for those who have only brief or minor symptoms, those who had only one acute TTP exacerbation with a clear and obvious trigger (eg, pregnancy), and those who prefer to avoid the harms and burdens associated with plasma infusion (see 'Complications of plasma infusion' below). Close monitoring for symptoms of disease activity continues to be important for these individuals.
There are no randomized trials comparing routine prophylaxis versus expectant management. Although it is assumed that prophylactic plasma will protect the patient from complications of hereditary TTP, the International Hereditary TTP Registry found that the frequency of episodes was no different between patients managed with plasma prophylaxis and patients managed without prophylaxis [35]. Possible explanations for this unexpected observation are that the recommended plasma dose of 10 to 15 mL/kg every two weeks is insufficient, or that adherence to this regimen is inconsistent. We believe both explanations are valid. Receiving plasma infusions every two weeks is a great inconvenience and a burden for patients with active lives.
Our experience and published reports demonstrate that individuals with frequent or persistent symptoms or recurrent exacerbations who do not receive regular prophylaxis are at risk of permanent morbidities (eg, stroke, kidney failure) [14]. Use of plasma for prophylaxis creates substantial logistical burdens as well as risk for allergic reactions to plasma components. Simpler prophylaxis is expected to become available with recombinant ADAMTS13 [36]; when this happens, prophylaxis in asymptomatic patients for prevention of morbidities may be considered. (See 'Therapies under development' below.)
Complications of plasma infusion — The main complications of plasma infusion are allergic reactions. These may be treated or prevented (if they occur repeatedly) using antihistamines. (See "Immunologic transfusion reactions".)
Other transfusion reactions are also possible, although less likely. (See "Approach to the patient with a suspected acute transfusion reaction", section on 'Types of acute transfusion reactions'.)
If allergic reactions become severe or the patient cannot use plasma for another reason, an alternative product may be required. A plasma-derived factor VIII concentrate containing high concentrations of ADAMTS13 (Koate-DVI) has been used for this purpose in patients with acquired TTP who cannot receive (or refuse) plasma [37]. One of our patients who used plasma prophylaxis every two weeks for six years has switched to Koate because of severe allergic reactions to plasma. She receives 1500 units of factor VIII (30 units of factor VIII/kg, estimated 3 units/kg of ADAMTS13) once per week, which she can self-administer. This has resulted in fewer TTP symptoms, fewer adverse effects, and much greater convenience. (See "Immune TTP: Initial treatment", section on 'Patient who cannot accept plasma/Jehovah's Witness'.)
An apparently rare complication of plasma infusion is the development of an alloantibody (inhibitor) to ADAMTS13. In principle, this may occur in an individual with no endogenous ADAMTS13 expression, for whom ADAMTS13 in donor plasma is recognized as a foreign protein. Only two cases have been reported in patients with hereditary TTP [8,38]. Appropriate management of an inhibitor is unknown and would be managed on a case-by-case basis.
Routine monitoring — If our patients have no symptoms and are not receiving prophylactic plasma infusions, we see them at four- to six-month intervals. These evaluations are to confirm the absence of minor symptoms and to confirm that the platelet count remains within the patient's normal range. The main component of monitoring is attention to clinical symptoms.
●Symptoms that may suggest ongoing microvascular thrombosis include headache, especially if preceded by migraine aura; transient moments of loss of attention; or syncopal episodes.
●Even nonspecific symptoms such as fatigue or abdominal discomfort may respond to plasma infusion, indicating their association with hereditary TTP [2].
Measurement of the platelet count in a patient who experiences these symptoms may be helpful, especially if it is low. However, even if the platelet count remains greater than 150,000/microL, symptoms attributable to TTP may occur and may resolve with plasma infusions; the platelet count will also increase to the patient's unique level [2].
Documentation of an individual's platelet count when well is critical for determining whether a decrease in platelet count has occurred. There is no role for additional testing of ADAMTS13 activity.
Management of pregnancy — Pregnancy should not be discouraged in women with hereditary TTP, but it should be treated as extremely high risk (see 'Times of greatest risk' above). Management requires close collaboration between the hematologist and obstetrician specializing in maternal-fetal medicine.
Complications with pregnancy may be inevitable in women with hereditary TTP, as discussed above. (See 'Pregnancy' above.)
We recommend plasma infusion, to be started as soon as the pregnancy is established, as a means of preventing potentially life-threatening complications (algorithm 1). This is consistent with 2020 Guidelines from the International Society on Thrombosis and Haemostasis, which makes a strong recommendation for prophylactic treatment in women with hereditary TTP who become pregnant [39].
●Dose – Regular prophylactic plasma infusions are started as soon as pregnancy is known. The initial dose is 10 to 15 mL/kg.
●Frequency/monitoring/dose adjustments – The initial frequency is once every two weeks. We monitor the patient clinically with a focus on TTP-related symptoms and blood pressure, and we measure the platelet count at every prenatal visit. If symptoms related to TTP develop or if the platelet count decreases to less than 150,000/microL or to less than the patient's normal value, as it typically does in the second or third trimester, then the dose of plasma is increased to 15 mL/kg; the frequency often needs to be increased to once weekly during the third trimester.
●Duration – We continue prophylactic plasma infusion after delivery, at a dose of 10 mL/kg every two weeks, for a total of six weeks postpartum. At six weeks postpartum, we are more confident that the risk of an exacerbation has returned to baseline. Plasma infusions are not a contraindication to breastfeeding during this period.
Severe complications of pregnancy may be inevitable in women with hereditary TTP and can cause fetal and/or maternal death if prompt recognition and treatment are not instituted [3]. In the era before hereditary TTP was recognized and plasma treatment was known to be effective, women died with pregnancy [15]. However, in our experience and the experience of others, many women have had successful pregnancies when treated as soon as possible with regular plasma infusions [40,41].
Although data are lacking for hereditary TTP, we presume women with hereditary TTP are at increased risk of preeclampsia, similar to women with acquired TTP [42].
There is no role for premature delivery outside of standard indications, because prophylactic plasma infusions can prevent symptoms related to TTP. If prophylactic plasma infusion does not result in normalization of the platelet count within one to two days, there is likely to be another reason for the patient's thrombocytopenia (or symptoms). Possible alternative or additional diagnoses are discussed separately. (See "Thrombocytopenia in pregnancy".)
Therapies under development — Recombinant ADAMTS13 (rADAMTS13; SHP655) is not clinically available. This is a promising approach for individuals with hereditary TTP because it provides the deficient enzyme without exposing the patient to donor plasma [34]. Studies of its efficacy and safety are ongoing.
●In preclinical studies (mouse model, patient plasma), rADAMTS13 was able to cleave von Willebrand factor (VWF) and reduce ultra-large VWF multimers; it also abrogated symptoms in the mouse model [43,44].
●In a prospective study in 15 individuals with hereditary TTP, rADAMTS13 was well tolerated and did not cause serious adverse events or development of anti-ADAMTS13 antibodies [36].
●A randomized trial comparing prophylaxis versus on-demand therapy with rADAMTS13 is underway [45]. This trial will evaluate markers of subtle neurologic findings using brain magnetic resonance imaging (MRI) [34].
If/when this product becomes the standard of care for patients with hereditary TTP, treatment of persistent symptoms or an acute exacerbation, as well as prophylaxis, may become more straightforward, and the percentage of individuals who use prophylactic therapy to prevent stroke and other serious thrombotic events may increase, though cost may be prohibitive for certain individuals. (See 'Prophylaxis/prevention of future exacerbations' above.)
Genetic counseling and testing of siblings — Some asymptomatic patients are only identified when genetic testing is performed after diagnosis is made in a family member (typically a sibling).
Hereditary TTP is an autosomal recessive condition. Thus, siblings of an individual with hereditary TTP have a 25 percent chance of being affected, a 50 percent chance of being heterozygotes, and a 25 percent chance of carrying no pathogenic variants in the ADAMTS13 gene. (See 'Heterozygotes for ADAMTS13 variants' below.)
We measure ADAMTS13 activity in all siblings as soon as the index case is identified. If ADAMTS13 activity is severely deficient, we confirm the diagnosis of hereditary TTP with genetic testing. This is critical because symptoms (including life-threatening thrombocytopenia or neurologic abnormalities) commonly occur in childhood. This is especially important for sisters, to prevent severe pregnancy-related complications. (See 'Times of greatest risk' above.)
Individuals with hereditary TTP are counseled that the likelihood of their own children being affected with hereditary TTP is exceedingly low, due to the extreme rarity of ADAMTS13 mutations in the general population. In contrast to some of the more common autosomal recessive disorders, we do not test the partner for an ADAMTS13 gene mutation.
We also do not test parents or children of an individual with hereditary TTP for heterozygosity for an ADAMTS13 mutation outside of a research study. An exception may be a setting in which the likelihood of consanguinity (and hence the possibility of having an affected child) is greater. (See 'Epidemiology' above.)
Prognosis — Prior to the era of plasma infusion, hereditary TTP was a fatal disorder [15]. The long-term prognosis for patients with hereditary TTP in the era of plasma infusion is uncertain, although prophylactic plasma infusion is potentially life-saving in pregnancy, preventing the almost inevitable severe complications [3]. Thus, we expect that regular prophylaxis should prevent serious thrombotic events such as stroke, as well as more indolent morbidities, including diminished kidney function.
Very long-term follow-up of patients with hereditary TTP has not been published, in part because the etiology and genetic documentation of hereditary TTP has only been available since 2001 [46]. Some individuals in the pre-plasma era had major morbidities, especially stroke and complications of end-stage kidney disease (ESKD) [2,9].
●The original patient described by Schulman in 1960 was diagnosed at the age of eight years and developed ESKD requiring dialysis 45 years later [47,48]. Another case report described a patient who developed ESKD at age 22 and had been on dialysis for 19 years [49]. In a 2019 series involving individuals with hereditary TTP, one-fourth of those diagnosed in adulthood had a stroke or transient ischemic attack prior to diagnosis [2]. In a 2019 series from the Hereditary TTP Registry, one-fourth had chronic kidney disease, including 10 percent requiring dialysis and 2.5 percent undergoing kidney transplantation [9].
●Another report described the clinical course of a family with two affected brothers followed for 44 years [50]. One brother had a splenectomy for thrombocytopenia before hereditary TTP was diagnosed, followed by recurrent pulmonary emboli requiring lifelong anticoagulation. The other brother had chronic renal failure, atrial fibrillation, and stroke. Splenectomy is not a component of management of hereditary TTP and may have exacerbated thrombotic risk. (See "Elective (diagnostic or therapeutic) splenectomy", section on 'Postoperative risks'.)
●Experimental studies have suggested that the absence of ADAMTS13 can contribute to cardiovascular complications [51,52]. These observations suggest the possibility of major risk for cardiac morbidity with advancing age.
HETEROZYGOTES FOR ADAMTS13 VARIANTS — An individual may become aware that they are heterozygous for a pathogenic variant in ADAMTS13 during a family evaluation.
Heterozygotes may have excellent health. However, as noted above, their risk for stroke or cardiovascular disease may be greater than in people without a heterozygous ADAMTS13 mutation [5-7]. (See 'Genetics' above.)
Aside from general health maintenance (eg, smoking cessation, management of lipids), we do not alter their medical care based on heterozygosity for an ADAMTS13 variant.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Thrombotic microangiopathies (TTP, HUS, and related disorders)".)
SUMMARY AND RECOMMENDATIONS
●Disease definition – Hereditary thrombotic thrombocytopenic purpura (Upshaw-Schulman syndrome) is an autosomal recessive thrombotic microangiopathy caused by biallelic mutations in the ADAMTS13 gene. Affected individuals have severe ADAMTS13 deficiency (typically, undetectable) without an inhibitor. (See 'Terminology' above and 'Genetics' above.)
●Prevalence – Hereditary TTP is very rare, representing <5 percent of TTP in adults, but it is more common than acquired autoimmune TTP in infants and children. (See 'Epidemiology' above.)
●Presentation – Severe hemolysis at birth related to the turbulent circulation changes is the most common presentation. Subsequently, patients may be asymptomatic for years. Presenting findings include acute illness with thrombocytopenia and microangiopathic hemolytic anemia (MAHA) with schistocytes (picture 1) and hemolysis, especially during pregnancy. Minor nonspecific findings such as neurologic symptoms, lethargy, headache, loss of concentration, and abdominal discomfort are also common presentations. (See 'Clinical features' above.)
●When to consider the diagnosis – Hereditary TTP should be suspected in any individual with unexplained thrombocytopenia and/or MAHA, especially in a newborn infant with severe hyperbilirubinemia; unexplained ischemic stroke, neurologic findings, or intermittent thrombocytopenia; or during pregnancy, with apparent preeclampsia before 20 weeks. (See 'When to suspect the diagnosis' above.)
●Evaluation – A complete blood count with platelet count, hemolysis testing (table 1), creatinine, and blood smear should be reviewed. Severe ADAMTS13 deficiency (activity <10 percent) without an inhibitor that persists during remission is consistent with the diagnosis; genetic testing is confirmatory and can be obtained without cost for patients enrolled in the Hereditary TTP Registry (www.ttpregistry.net). Hereditary TTP is characterized by severe ADAMTS13 deficiency without an inhibitor and biallelic pathogenic variants in ADAMTS13. (See 'Diagnostic evaluation' above.)
●Exacerbations – Persistent headache, lethargy, abdominal discomfort, acute neurologic findings, and/or a decrease in platelet count below baseline, should be treated with plasma infusion (typical dose, 10 to 15 mL/kg daily until resolution) (algorithm 1). (See 'Newborns and symptomatic individuals' above.)
●Prophylaxis – The decision to initiate routine prophylactic therapy is complex and requires thorough discussions with the individual (and/or family members). The benefit of routine prophylaxis compared with on-demand therapy is uncertain, and regular plasma infusions carry risks and burdens (transfusion reactions, risks associated with a central venous catheter, frequent travel to a facility that can administer the plasma). In many cases, benefits outweigh these risks, especially in pregnancy, where nearly all patients develop complications if not treated with plasma. Some nonpregnant individuals may reasonably prefer on-demand therapy. (See 'Prophylaxis/prevention of future exacerbations' above.)
Our approach is illustrated in the algorithm (algorithm 1) and includes the following:
•Episodic symptoms – For recurrent exacerbations, especially with neurologic symptoms, or significant morbidity from ongoing TTP symptoms (eg, headaches, lethargy, or other symptoms) or occasional thrombocytopenia, we suggest regular prophylactic plasma infusion (Grade 2C). The dose is 10 to 15 mL/kg every two weeks, adjusted according to symptoms and platelet count rather than ADAMTS13 activity.
An alternative is to receive prophylactic plasma infusion at times of physiologic stress (surgery, trauma, hospitalization).
•Pregnancy – Pregnancy should be treated as extremely high risk, with collaboration between the hematologist and maternal-fetal medicine specialist. Prophylactic plasma is essential to prevent life-threatening complications. For these individuals, we recommend plasma infusion as soon as the pregnancy is documented (Grade 1B). The initial dose is 10 to 15 mL/kg of plasma every two weeks, throughout the pregnancy and six weeks postpartum, adjusted for symptoms and platelet count. There is no role for premature delivery outside of standard indications. (See 'Management of pregnancy' above.)
●Siblings – Siblings of an individual with hereditary TTP have a 25 percent chance of being affected; we test their ADAMTS13 activity as soon as possible. If ADAMTS13 activity is severely deficient, we confirm the diagnosis with genetic testing. This is urgent, because major morbidities can occur in early childhood. We do not test parents, children, or partners of an individual with hereditary TTP outside of a clinical trial, as the prevalence is very low; consanguinity is an exception. Heterozygotes do not have hereditary TTP but may have an increased risk of cardiovascular disease. (See 'Genetic counseling and testing of siblings' above and 'Heterozygotes for ADAMTS13 variants' above.)
