The n e w e ng l a n d j o u r na l of m e dic i n e

Review Article

Dan L. Longo, M.D., Editor

Hereditary Thrombotic Thrombocytopenic

Purpura
Johanna A. Kremer Hovinga, M.D., and James N. George, M.D.​​

H
ereditary thrombotic thrombocytopenic purpura (TTP), also From the Department of Hematology and
known as Upshaw–Schulman syndrome (Online Mendelian Inheritance in Central Hematology Laboratory, Inselspi-
tal, Bern University Hospital and the De-
Man number, 274150), is a rare autosomal recessive disorder caused by partment for Biomedical Research, Uni-
ADAMTS13 mutations that result in the absence or severe deficiency of the plasma versity of Bern, Bern, Switzerland (J.A.K.H.);
metalloprotease ADAMTS13. ADAMTS13 is required for cleavage of newly synthe- and the Department of Biostatistics and
Epidemiology, Hudson College of Public
sized von Willebrand factor multimers. Decreased ADAMTS13 activity is associated Health, Department of Medicine, College
with an increased size of von Willebrand factor multimers and an increased risk of of Medicine, University of Oklahoma
microvascular thrombosis. Patients with hereditary TTP may appear to be healthy, Health Sciences Center, Oklahoma City
(J.N.G.). Address reprint requests to Dr.
but their increased risk of critical thrombosis is always present. This review describes George at the Department of Biostatis-
the history, pathogenesis, prevalence, clinical features, and current management of tics and Epidemiology, Hudson College
hereditary TTP, as well as potential future treatments. of Public Health, University of Oklahoma
Health Sciences Center, 801 NE 13th St.,
Oklahoma City, OK 73104, or at j­ames
-george@​­ouhsc​.­edu.
His t or y of Her edi ta r y T TP
N Engl J Med 2019;381:1653-62.
TTP was described in 1924 as an acute, fatal disorder characterized by systemic DOI: 10.1056/NEJMra1813013
microvascular thrombosis.1 In 1947, systemic microvascular platelet thrombi were Copyright © 2019 Massachusetts Medical Society.

recognized as the cause of thrombocytopenia, and the name thrombotic thrombo-

cytopenic purpura was suggested to distinguish this disorder from immune
thrombocytopenic purpura (ITP).2 In 1966, the clinical features and outcomes of
all 271 reported patients with TTP were described; it was assumed that TTP was
an acquired disorder.3 The hereditary occurrence of TTP was clearly described in
1975 (Table S1 in the Supplementary Appendix, available with the full text of this
article at NEJM.org).4 The authors of that study recognized the pattern of autoso-
mal recessive inheritance and also that environmental factors such as infections
were often associated with acute episodes of thrombocytopenia and hemolysis.4
Subsequent studies involving patients with hereditary TTP provided the founda-
tion for understanding the pathogenesis of TTP. Reports of successful treatment
of acute episodes with plasma infusion revealed that some patients had frequent
recurrent episodes of a condition described as “chronic relapsing TTP”5-8; this
phrase was used to describe hereditary TTP before the pathogenesis was under-
stood. A seminal study in 1982 identified ultralarge von Willebrand factor multi­
mers9 in the plasma of four asymptomatic patients with chronic, relapsing (hereditary)
TTP.5-8 The dramatic difference in size between the von Willebrand factor multi­
mers in those patients and those present in healthy persons suggested the existence
of a process in normal plasma that prevents the circulation of ultralarge von
Willebrand factor multimers.9 In 1996, the von Willebrand factor–cleaving pro-
tease was identified,10-14 and in 2001, the protein15,16 and DNA sequence17,18 de-
fined the von Willebrand factor–cleaving protease as ADAMTS13.15-18 In acquired
TTP, severe ADAMTS13 deficiency is the result of circulating autoantibodies

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 The n e w e ng l a n d j o u r na l of m e dic i n e

inhibiting ADAMTS13 function or increasing lysis after administration of desmopressin, a drug

ADAMTS13 clearance.19-21 Congenital ADAMTS13 that is known to release von Willebrand factor,29
deficiency in hereditary TTP is caused by biallelic for management of nocturnal enuresis in a child
ADAMTS13 mutations.17,18,20,21 with hereditary TTP30 shows the risk associated
with increased plasma concentrations of von
Willebrand factor. In addition, clinically silent
Patho gene sis of A DA M T S1 3
a nd von W il l ebr a nd Fac t or is­chemic infarcts may occur without inflamma-
tion and without increased plasma levels of von
ADAMTS13, which is located on chromosome 9q34, Willebrand factor.
encodes a multidomain protein of 1427 amino A physiologic role of ADAMTS13 for protection
acids.17,18 Endothelial cells22 and hepatic stellate against thrombosis has been reported in older
cells23 are the principal sources of ADAMTS13. adults with normal ADAMTS13 activity. In one
ADAMTS13 is released as an active enzyme and study, the frequency of stroke was significantly
circulates in a closed conformation with its CUB higher among participants with lower ADAMTS13
(complement C1r/C1s [complement component activity (mean, 70% of normal activity) than
1r/1s], sea urchin epidermal growth factor, and among participants with higher ADAMTS13 ac-
bone morphogenetic protein) domains backfold- tivity (mean, 114%).31 This observation suggests
ed and interacting with the spacer domain.24 that the risk of thrombosis may also be increased
The only known substrate of ADAMTS13 is in the heterozygous parents and siblings of pa-
von Willebrand factor, which is exclusively synthe- tients with hereditary TTP.
sized by endothelial cells and megakaryocytes.25
After synthesis, endothelial cells store von Wille- Pr e va l ence of Her edi ta r y T TP
brand factor as ultralarge multimers in Weibel–
Palade bodies. On stimulation of endothelial Hereditary TTP is rare, and its prevalence is un-
cells by shear stress, catecholamines, cytokines, certain (Table 1). Although most estimates sug-
or histamine, ultralarge von Willebrand factor gest a prevalence of 0.5 to 2 cases per million
multimers are secreted and either remain at- population (Fujimura Y, Matsumoto M, and
tached to the endothelial surface or are released Hrachovinova I: personal communication), a much
into the circulation. The shear conditions of flow- greater prevalence has been observed in the Cen-
ing blood unfold freshly released ultralarge von tral Norway Health Region. Multiple intensive
Willebrand factor multimers,24 exposing the other- case-finding strategies have been used to iden-
wise cryptic platelet-binding sites in the von Wil- tify 11 surviving patients with hereditary TTP in
lebrand factor A1 domains and the ADAMTS13 this region, where the estimated prevalence is 16.7
cleavage sites in the von Willebrand factor A2 cases per million population.32 This high preva-
domains. Binding of ADAMTS13 to von Wille- lence suggests that these strategies can be used
brand factor leads to conformational activation to identify more patients; the prevalence of heredi-
of ADAMTS13 and subsequently to proteolysis of tary TTP will vary depending on the isolation of a
the ultralarge von Willebrand factor multimers population and may be considerably higher than
into smaller molecules with less capacity to bind 1 case per million in large admixed populations.
platelets.24,25 In the absence of ADAMTS13, the
ultralarge von Willebrand factor multimers persist, A DA MT S13 Mu tat ions
leading to spontaneous platelet adherence and in Her edi ta r y T TP
aggregation (Fig. 1B).
The observation that patients with hereditary More than 200 ADAMTS13 mutations, spread over
TTP and undetectable ADAMTS13 activity can be all ADAMTS13 protein domains, have been iden-
asymptomatic for many years, without overt symp- tified in patients with hereditary TTP.33-37 In addi-
toms of microvascular thrombosis, suggests that tion, there are at least 10 missense ADAMTS13
increased concentrations of von Willebrand factor, single-nucleotide polymorphisms, some of which
such as those that occur with infection, inflam- are in strong linkage disequilibrium with specific
mation, or pregnancy,27,28 are associated with overt ADAMTS13 mutations and influence their molecu-
thrombotic episodes. The repeated occurrence of lar effects.38-40
acute episodes of thrombocytopenia and hemo- Most ADAMTS13 mutations are private (i.e., con-

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 Hereditary Thrombotic Thrombocytopenic Purpur a

A Normal ADAMTS13 Activity

Von Willebrand factor ADAMTS13

Von Willebrand factor
V ESSEL
LUM EN

B L OOD F L OW

Platelet

Endothelial cell

SUB EN D O TH ELIU M

B ADAMTS13 Deficiency

B L OOD F L OW

Activated
platelet

Figure 1. Pathophysiology of Severe ADAMTS13 Deficiency.

In an arteriole of a healthy person (Panel A), von Willebrand factor is synthesized by endothelial cells and stored in
Weibel–Palade bodies as long strings of repeating subunits. After stimulation of endothelial cells, these ultralarge
von Willebrand factor multimers are secreted and some of these molecules remain anchored to the endothelial-cell
surface; others are released into the circulation. Flowing blood unfolds ultralarge von Willebrand factor multimers,
exposing the platelet binding and the ADAMTS13 cleavage sites. After ADAMTS13 cleavage, von Willebrand factor
molecules again adopt a coiled, condensed shape without exposed platelet binding or ADAMTS13 cleavage sites.
In the absence of ADAMTS13 (Panel B), many platelets attach to the exposed platelet-binding sites on the ultra-
large von Willebrand factor multimer strings. Some of these multimers remain attached to the endothelial surface,
coating the vessel wall. Other ultralarge von Willebrand factor strings detach from the endothelial-cell surface and
enter the circulation, where they become coated with adherent platelets. As these platelet-loaded ultralarge von
Willebrand factor multimers approach small vessels and bifurcations with sharp turns, blood flow accelerates, in-
creasing shear stress. Increased shear stress causes further unfolding of the ultralarge von Willebrand factor mole-
cules, exposing more platelet-binding sites. In conditions involving increased von Willebrand factor synthesis and
release into plasma (e.g., during infection, inflammation, and pregnancy), the circulating ultralarge von Willebrand
factor molecules with their many attached platelets form webs at the sites of increased shear stress, obstructing
blood flow and causing thrombosis.26

fined to single families).34,36 Some mutations tions are prominent in patients with hereditary
stand out because of their increased frequency TTP and are common in large population
in different geographic regions (Table S2). In screenings: p.R1060W32,35-37,41-44 and the inser-
populations of European ancestry, two muta- tion c.4143_4144dupA.32,35,36,45 Studies in Norway32

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 1. Unresolved Clinical Issues and Future Clinical Investigation of Hereditary TTP.*

Clinical Issue Future Clinical Investigation

Natural history of hereditary TTP Since the long-term outcomes of patients with hereditary TTP are not known,
assess lifetime follow-up of patients in order to understand the risk of organ
injury and the duration of survival.
Prevalence of hereditary TTP Perform additional studies with active case-finding strategies32 to determine
whether the prevalence is actually greater than 1 case per million.
Neonatal hyperbilirubinemia Establish a prospective registry of newborn infants with severe hyperbilirubine-
mia, hemolysis, and thrombocytopenia, along with measurements of
ADAMTS13 activity, to increase recognition of hereditary TTP and increase
survival.
Pregnancy complications Evaluate women with very-early-onset preeclampsia (<25 wk) systematically and
measure ADAMTS13 activity to increase recognition of hereditary TTP and
increase survival.
Stroke Perform MRI at a patient’s initial evaluation and during follow-up to detect silent
brain infarction.
Cognitive function, depression Use serial measurements to document the occurrence and frequency of these
conditions. Silent brain infarction may be the cause of these disorders.
Antithrombotic prophylaxis Evaluate the efficacy and safety of antithrombotic agents, as used for other
causes of stroke.
Kidney function Document early evidence of kidney injury and make efforts to prevent chronic
kidney disease.
ADAMTS13 prophylaxis Determine the appropriate indication for prophylaxis, which may be appropriate
at the time of diagnosis.
ADAMTS13 alloantibody formation Assess data from patient cohorts with long-term follow-up to determine the fre-
quency of alloantibody formation in patients with hereditary TTP who are ex-
posed to plasma (exogenous ADAMTS13).
Family health Provide follow-up care for the parents and heterozygous siblings of patients with
hereditary TTP to determine whether they have an increased risk of pregnancy
complications, premature occurrence of stroke, and cardiovascular disease.31

* MRI denotes magnetic resonance imaging, and TTP thrombotic thrombocytopenic purpura.

have identified the mutation p.R1060W in 0.3 to cohort, residual ADAMTS13 activity correlated only
1.0% of the population and the insertion c.4143_ weakly with the age at diagnosis and the severity
4144dupA in 0.04 to 0.3%. The prevalence of of hereditary TTP.36
ADAMTS13 mutations identified in population
studies supports our impression that the preva- Cl inic a l Fe at ur e s
lence of hereditary TTP may be considerably higher
than the commonly cited prevalence of 1 case Some patients with hereditary TTP may have
per million population. Whereas c.4143_4144dupA symptoms that manifest at birth, whereas others
clusters around the Baltic Sea, in central Europe, remain asymptomatic for decades. When symp-
and in Scandinavia,21,32,36 the geographic distri- toms occur, the clinical features may be indis-
bution of p.R1060W is much broader. The muta- tinguishable from an acute episode of acquired
tion p.R1060W has been shown to be associated TTP or they may differ substantially (Fig. 2).
with residual ADAMTS13 activity; in homozygotes,
ADAMTS13 activity is usually 5 to 10% of that in Times of Risk
normal plasma. This mutation is present in many Although patients with hereditary TTP are at in-
patients with adult-onset hereditary TTP, particu- creased risk for manifestations of microvascular
larly in women in whom the disease is identified thrombosis throughout their lives, two periods
during their first pregnancy and who may have appear to be associated with extreme risk. These
severe preeclampsia early in the second trimes- periods are the first days of life and pregnancy.
ter (Fig. 2).32,41,42 However, in the largest reported Neonatal jaundice, which is attributed to he-

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 Hereditary Thrombotic Thrombocytopenic Purpur a

molysis, was documented in all 43 patients in a tions.52 In a Norwegian study involving 15 preg-
study in Japan34; 18 infants (42%) underwent nancies in 8 women, all the pregnancies were
exchange transfusion of whole blood. Among associated with severe complications.53 Frequent
20 neonatal patients in Norway, 9 (45%) under- initial recognition of hereditary TTP during a
went whole-blood exchange transfusion.32 None woman’s first pregnancy and the subsequent out-
of the 27 infants from Japan and Norway re- comes of hereditary TTP have been reported in
ceived a diagnosis of hereditary TTP at the time cohorts in France42 and the United Kingdom41; in
of the initial exchange transfusion. The diagno- both cohorts, three quarters of the women were
sis was delayed until a median age of 4 years reported to carry at least one p.R1060W allele.
(range, 1 month to 25 years) in Japan34 and 24 In women presenting with very-early-onset pre-
years (range, 2 to 49) in Norway.32 eclampsia (e.g., at <25 weeks of gestation), heredi-
These acute neonatal episodes can be fatal. A tary TTP should be considered. Prophylactic treat-
recent article described a newborn who had pre- ment with plasma, initiated as soon as pregnancy
sented with hyperbilirubinemia, anemia, and se- is confirmed in women with hereditary TTP, can
vere thrombocytopenia and died 34 hours after prevent complications and provide support for
birth. He did not receive plasma or an exchange term deliveries of healthy infants.41,42
transfusion. The diagnosis of hereditary TTP was Inflammatory conditions such as infection and
established post mortem.46 This case, together trauma and the use of drugs30 or excessive alcohol
with the decrease in the occurrence of alloim- intake36 can increase the risk of thrombosis by
mune hemolysis since the introduction of prophy- causing increased endothelial secretion of von
laxis against rhesus disease, suggests that the Willebrand factor.27 However, acute episodes may
diagnosis of hereditary TTP should be considered have no apparent triggering factor, and microvas-
in all neonates who have severe hyperbilirubine- cular thrombosis may be silent.
mia, especially when thrombocytopenia is pres-
ent. Plasma infusion is simple and lifesaving. Clinical Manifestations
Among infants who survive, there may be no sub- Patients with hereditary TTP have a high risk of
sequent symptoms for many years34; thus, the first transient ischemic attack (TIA) and stroke, be-
hours of life are a critical time of risk. ginning at a young age. Among 120 enrolled pa-
Multiple unique features may contribute to tients in the International Hereditary Thrombotic
the manifestations of hereditary TTP in the neo- Thrombocytopenic Purpura Registry, 25 (21%)
natal period. First, pulmonary vascular resistance reported having had stroke and an additional
abruptly decreases as lung function begins, while 5 patients (4%) reported having had a TIA. Most
systemic vascular resistance abruptly increases of these events occurred in children and young
as circulation to the placenta stops. These fac- adults.36 In a study involving 73 patients from the
tors cause the ductus arteriosus to have bidirec- United Kingdom, stroke occurred in 14 patients
tional turbulent flow, which could contribute to (19%) and TIA occurred in 6 (8%); the age of the
hemolysis.47 Second, the hematocrit is high at patients when the stroke occurred was not re-
birth (approximately 61%) and continues to rise ported.37 Clinicians caring for patients who have
during the first hours after birth; this increases a TIA or stroke at a young age, particularly when
blood viscosity48 and the risk of thrombosis. there is concurrent thrombocytopenia, should
Third, in healthy neonates, ultralarge von Will- consider the diagnosis of TTP.
ebrand factor multimers are present in concen- A total of 5 of the 120 patients (4%) in the In-
trations similar to those seen in patients with ternational Hereditary Thrombotic Thrombocyto-
hereditary TTP,49 and the total plasma concen- penic Purpura Registry36 and none of the 73 pa-
tration of von Willebrand factor is increased.50 tients in the cohort from the United Kingdom37
An association between hereditary TTP and were reported to have myocardial infarction. Many
pregnancy was reported in 1976.51 Among the 43 patients with acquired TTP have an increased se-
patients in the Japanese cohort, 9 of 24 women rum troponin I level, indicating cardiac ischemia
(38%) received an initial diagnosis of TTP during and a critical disease course.54 Data on cardiac
pregnancy.34 In these 9 women, 14 pregnancies troponin levels in patients with hereditary TTP
preceded the diagnosis of TTP, and all the preg- are lacking.34,36,37 The apparently uncommon oc-
nancies were associated with severe complica- currence of myocardial infarction and the more

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Patient 1: Neonatal jaundice Patient 2: Purpura

Healthy, full-term infant, 20 hr old, with a twitching 12-year-old girl with purpura on
left hand. Brain CT shows right cortical infarct. her arms and legs. Hemoglobin
Extreme jaundice (bilirubin level, >30 mg/dl; level, 10.5 g/dl; platelet count,
hemoglobin level, 16 g/dl decreasing to 9 g/dl; 13,000/mm3. Diagnosis, ITP. No
platelet count, 146,000/mm3 decreasing to treatment. Platelet count,
23,000/mm3). Exchange transfusion, complete 149,000/mm3 at 4 wk. Hereditary
recovery, good health until 18 yr of age when TTP diagnosed the following year
hereditary TTP diagnosed. when her sister (Patient 1)
received diagnosis.

Neurologic abnormalities 3 yr
later: sudden blurred vision,
slurred speech. Left pupil dilated,
right leg and right arm weakness,
numbness on right side of face.
Hemoglobin level, 13.0 g/dl, and
platelet count, 173,000/mm3.

Patient 4: Pregnancy
34-year-old woman, previously
healthy, 13 wk gestation, first
pregnancy: sudden vision loss
(serous retinal detachments).
Blood pressure, 180/125 mm Hg.
Hemoglobin level, 13.2 g/dl;
platelet count, 55,000/mm3. MRI
of brain: right parietal infarct.
Hereditary TTP diagnosed.

Patient 3: Alcohol excess

18-year-old man. After drinking an excessive
amount of wine, abdominal pain, vomiting
for several days, no neurologic abnormalities.
Hemoglobin level, 13.3 g/dl, and platelet count,
9000/mm3. Hereditary TTP diagnosed. Four subsequent
acute episodes after ingestion of wine or whisky.

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 Hereditary Thrombotic Thrombocytopenic Purpur a

Figure 2 (facing page). Typical Triggers of Disease

plasma hemoglobin concentration (≥2 g per decili-
Manifestations and Heterogeneous Clinical ter), which can cause false positive results in func-
Presentations in Hereditary TTP. tional ADAMTS13 inhibitor assays.58 Although the
Shown are four patients with hereditary TTP who pres- absence of a functional ADAMTS13 inhibitor is
ent at times of risk (i.e., the neonatal period, after heavy characteristic of hereditary TTP, it does not rule
alcohol intake, and during pregnancy) or with mani- out the diagnosis of acquired TTP. Among patients
festations that occur spontaneously. All the patients
have common clinical features that are distinct from
with acquired TTP in the Oklahoma Thrombotic
those that are characteristic of patients with acquired Thrombocytopenic Purpura–Hemolytic Uremic
TTP. Some patient data are courtesy of Eric Avery, Syndrome Registry, a functional ADAMTS13 in-
M.D., Lincoln, Nebraska. CT denotes computed to- hibitor was not initially identified in 15 of 86
mography, and MRI magnetic resonance imaging. patients (17%).59 An important clue to the diag-
nosis of hereditary TTP is the persistence of se-
vere ADAMTS13 deficiency in remission. Although
common occurrence of stroke in patients with this can occur in patients with acquired TTP, it
hereditary TTP are similar to the occurrences in is rare in the absence of a functional inhibitor or
patients with sickle cell disease, in whom myo- anti–ADAMTS13 antibodies.
cardial infarction rarely occurs in spite of the The clinical features of hereditary TTP may
high risk of stroke and silent brain infarction at be different from the typical clinical features of
a young age.55 acquired TTP. For instance, in patients with he-
Acute kidney injury and chronic kidney dis- reditary TTP, a TIA may occur without thrombo-
ease were reported in a patient who was subse- cytopenia or evidence of hemolysis. Thrombo-
quently identified as having hereditary TTP.5 At cytopenia may not be severe, and patients may
13 years of age, severe acute kidney injury devel- present with acute kidney injury.34 Finally, patients
oped.56 At approximately 50 years of age, she had with hereditary TTP recover rapidly after one or
end-stage renal disease (Moake JL: personal com- a few plasma exchanges.
munication). In the Japanese cohort, 3 of the 43
patients (7%) initially presented with acute kid- L ong -Ter m Ou t c ome s
ney injury, and chronic kidney disease developed
in 4 patients (9%), including a patient who had Data on long-term outcomes in patients with
an acute kidney injury at 2 years of age.34 Among hereditary TTP are lacking (Table 1). In the Japa-
the 120 patients in the International Hereditary nese cohort of 43 patients,34 only 13 patients
Thrombotic Thrombocytopenic Purpura Registry, (30%) were followed after 35 years of age, and
12 (10%) received dialysis and 3 (2%) underwent only 6 (14%) were followed after 45 years of age.
kidney transplantation.36 Among the 73 patients Three of the 43 patients (7%) died at the ages of
from the United Kingdom, end-stage renal dis- 38 to 79 years — 2 from chronic kidney disease
ease developed in 3 (4%), and 1 underwent kid- and 1 from stroke. In the Norwegian cohort of
ney transplantation.37 21 patients (including 3 siblings who were prob-
ably affected), 5 (24%) died. Two of these patients
died before 1 year of age, and the other 3 died at
Dis t inguishing Her edi ta r y
T TP from Ac quir ed T TP 40 to 60 years of age. The causes of death were
not reported.32 In the cohort in the United King-
The patient’s age may help to distinguish between dom, 4 of the 73 patients (5%) died from stroke;
hereditary TTP and acquired TTP. Acquired TTP the patients’ ages were not reported.37 Five of the
is much less common in young children than in 120 patients (4%) in the International Hereditary
adults,20,57 whereas hereditary TTP is commonly Thrombotic Thrombocytopenic Purpura Registry
diagnosed in children. In the Japanese cohort, the died; their ages and causes of death were not re-
disease first manifested in 33 of the 43 patients ported.36
(77%) before 10 years of age.34 The presence of a
functional ADAMTS13 inhibitor or an increased Cur r en t M a nagemen t
anti–ADAMTS13 IgG antibody titer argues against
the diagnosis of hereditary TTP. An exception is Plasma infusion is usually sufficient to treat acute
the occurrence of severe hemolysis with a high episodes in patients with hereditary TTP, although

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 The n e w e ng l a n d j o u r na l of m e dic i n e

for severe manifestations (e.g., in pregnancy) F u t ur e M a nagemen t

therapeutic plasma exchange may be appropriate. of Her edi ta r y T TP
For patients who have recurrent symptoms, regu-
lar lifetime prophylactic plasma infusions are The availability of rhADAMTS1363 may revolution-
appropriate, although the decision to begin pro- ize the management of hereditary TTP. The sim-
phylaxis is difficult, especially in a child. The plicity of this treatment, which consists of the
half-life of ADAMTS13 activity in patients re- injection of approximately 5 ml of rhADAMTS13
ceiving regular prophylactic plasma infusions every 2 to 3 weeks at home, may allow patients
is 2.5 to 3.5 days.60-62 This duration is similar to to begin lifetime treatment when the diagnosis of
the terminal half-life of recombinant human hereditary TTP is established. Gene therapy has
ADAMTS13 (rhADAMTS13) of 2.5 days.63 In one been reported to be successful in ADAMTS13
study involving six patients receiving regular knockout mice,68,69 although whether it will have
prophylactic plasma infusions, a higher median a role in the future management of hereditary TTP
plasma half-life of 5.4 days (range, 3.4 to 7.9) is currently unknown.
was reported.62 Therefore, after an infusion of 10
to 15 ml of plasma per kilogram of body weight, C onclusions
ADAMTS13 will return to its baseline activity in
5 to 10 days. On the basis of the clinical symp- Much has been learned during the past 20 years
toms and the goal to maintain each patient’s about the cause of hereditary TTP. However, lit-
normal platelet count, treatment intervals between tle is still known about the clinical features and
plasma infusions of 14 to 21 days are possi- long-term outcomes in these patients, who should
ble,36,61,62 but the best ADAMTS13 threshold to be regularly followed and assessed for the devel-
prevent long-term end-organ damage is unknown opment of organ damage. Table 1 lists unresolved
(Table 1). clinical issues with suggestions for future inves-
Two plasma-derived concentrates containing tigation. With the availability of simpler, life-
factor VIII and von Willebrand factor have been long, effective treatment, we think that during
used for the treatment and prophylaxis of heredi- the next 20 years, hereditary TTP will be recog-
tary TTP: antihemophilic factor (Koate-DVI)64 and nized more frequently and managed more ef-
intermediate purity factor VIII (BPL 8Y).65 Al- fectively.
though the volume required is less than the Dr. Kremer Hovinga reports receiving grant support, consult-
volume of plasma infusions and plasma allergic ing fees, and advisory board fees paid to Inselspital, Bern Uni-
reactions are avoided, these concentrates may versity Hospital, from Shire, consulting fees and fees for serving
on a speakers’ bureau, paid to Inselspital, Bern University Hos-
need to be given more frequently than plasma pital, from Ablynx, fees for serving on a speakers’ bureau and
infusions.64 advisory board and advisory fees, paid to Inselspital, Bern Uni-
The development of inhibitory ADAMTS13 versity Hospital, and travel support from CSL Behring, travel
support and advisory board and advisory fees paid to Inselspital,
alloantibodies in patients receiving plasma ther- Bern University Hospital, from Bayer, fees for serving on a
apy has been reported twice.34,66 This outcome is speakers’ bureau, and advisory board and advisory fees paid to
different from the outcome with factor VIII re- Inselspital, Bern University Hospital, from Roche, and advisory
board and advisory fees paid to Inselspital, Bern University Hos-
placement in patients with hemophilia A, in pital, from Novo Nordisk and Sobi. No other potential conflict
whom anti–factor VIII alloantibodies have devel- of interest relevant to this article was reported.
oped in one third.67 Fluctuating titers of nonin- Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
hibitory anti-ADAMTS13 antibodies in other pa- We thank Joel L. Moake, Rice University, Houston; Yoshihiro
tients have been reported. However, in the few Fujimura and Masanori Matsumoto, Department of Blood
trials of plasma infusion involving these pa- Transfusion Medicine, Nara Medical University, Kashihara, Ja-
pan; and Ingrid Hrachovinova, Institute of Hematology and
tients, these antibodies did not appear to affect Blood Transfusion, Prague, Czech Republic, for their personal
ADAMTS13 recovery or plasma half-life.21 communications.

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