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
inhibiting ADAMTS13 function or increasing
ADAMTS13 clearance.19-21 Congenital ADAMTS13
deficiency in hereditary TTP is caused by biallelic
ADAMTS13 mutations.17,18,20,21
Patho gene sis of A DA M T S1 3
a nd von W il l ebr a nd Fac t or
ADAMTS13, which is located on chromosome 9q34,
encodes a multidomain protein of 1427 amino
acids.17,18 Endothelial cells22 and hepatic stellate
cells23 are the principal sources of ADAMTS13.
ADAMTS13 is released as an active enzyme and
circulates in a closed conformation with its CUB
(complement C1r/C1s [complement component
1r/1s], sea urchin epidermal growth factor, and
bone morphogenetic protein) domains backfold-
ed and interacting with the spacer domain.24
The only known substrate of ADAMTS13 is
von Willebrand factor, which is exclusively synthe-
sized by endothelial cells and megakaryocytes.25
After synthesis, endothelial cells store von Wille-
brand factor as ultralarge multimers in Weibel–
Palade bodies. On stimulation of endothelial
cells by shear stress, catecholamines, cytokines,
or histamine, ultralarge von Willebrand factor
multimers are secreted and either remain at-
tached to the endothelial surface or are released
into the circulation. The shear conditions of flow-
ing blood unfold freshly released ultralarge von
Willebrand factor multimers,24 exposing the other-
wise cryptic platelet-binding sites in the von Wil-
lebrand factor A1 domains and the ADAMTS13
cleavage sites in the von Willebrand factor A2
domains. Binding of ADAMTS13 to von Wille-
brand factor leads to conformational activation
of ADAMTS13 and subsequently to proteolysis of
the ultralarge von Willebrand factor multimers
into smaller molecules with less capacity to bind
platelets.24,25 In the absence of ADAMTS13, the
ultralarge von Willebrand factor multimers persist,
leading to spontaneous platelet adherence and
aggregation (Fig. 1B).
The observation that patients with hereditary
TTP and undetectable ADAMTS13 activity can be
asymptomatic for many years, without overt symp-
toms of microvascular thrombosis, suggests that
increased concentrations of von Willebrand factor,
such as those that occur with infection, inflam-
mation, or pregnancy,27,28 are associated with overt
thrombotic episodes. The repeated occurrence of
acute episodes of thrombocytopenia and hemo-
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of m e dic i n e
lysis after administration of desmopressin, a drug
that is known to release von Willebrand factor,29
for management of nocturnal enuresis in a child
with hereditary TTP30 shows the risk associated
with increased plasma concentrations of von
Willebrand factor. In addition, clinically silent
is­chemic infarcts may occur without inflamma-
tion and without increased plasma levels of von
Willebrand factor.
A physiologic role of ADAMTS13 for protection
against thrombosis has been reported in older
adults with normal ADAMTS13 activity. In one
study, the frequency of stroke was significantly
higher among participants with lower ADAMTS13
activity (mean, 70% of normal activity) than
among participants with higher ADAMTS13 ac-
tivity (mean, 114%).31 This observation suggests
that the risk of thrombosis may also be increased
in the heterozygous parents and siblings of pa-
tients with hereditary TTP.
Pr e va l ence of Her edi ta r y T TP
Hereditary TTP is rare, and its prevalence is un-
certain (Table 1). Although most estimates sug-
gest a prevalence of 0.5 to 2 cases per million
population (Fujimura Y, Matsumoto M, and
Hrachovinova I: personal communication), a much
greater prevalence has been observed in the Cen-
tral Norway Health Region. Multiple intensive
case-finding strategies have been used to iden-
tify 11 surviving patients with hereditary TTP in
this region, where the estimated prevalence is 16.7
cases per million population.32 This high preva-
lence suggests that these strategies can be used
to identify more patients; the prevalence of heredi-
tary TTP will vary depending on the isolation of a
population and may be considerably higher than
1 case per million in large admixed populations.
A DA MT S13 Mu tat ions
in Her edi ta r y T TP
More than 200 ADAMTS13 mutations, spread over
all ADAMTS13 protein domains, have been iden-
tified in patients with hereditary TTP.33-37 In addi-
tion, there are at least 10 missense ADAMTS13
single-nucleotide polymorphisms, some of which
are in strong linkage disequilibrium with specific
ADAMTS13 mutations and influence their molecu-
lar effects.38-40
Most ADAMTS13 mutations are private (i.e., con-
 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
Prevalence of hereditary TTP
Neonatal hyperbilirubinemia
Pregnancy complications
Stroke
Cognitive function, depression
Antithrombotic prophylaxis
Kidney function
ADAMTS13 prophylaxis
ADAMTS13 alloantibody formation
Family health
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.
Perform additional studies with active case-finding strategies32 to determine
whether the prevalence is actually greater than 1 case per million.
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.
Evaluate women with very-early-onset preeclampsia (<25 wk) systematically and
measure ADAMTS13 activity to increase recognition of hereditary TTP and
increase survival.
Perform MRI at a patient’s initial evaluation and during follow-up to detect silent
brain infarction.
Use serial measurements to document the occurrence and frequency of these
conditions. Silent brain infarction may be the cause of these disorders.
Evaluate the efficacy and safety of antithrombotic agents, as used for other
causes of stroke.
Document early evidence of kidney injury and make efforts to prevent chronic
kidney disease.
Determine the appropriate indication for prophylaxis, which may be appropriate
at the time of diagnosis.
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).
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
1.0% of the population and the insertion c.4143_
4144dupA in 0.04 to 0.3%. The prevalence of
ADAMTS13 mutations identified in population
studies supports our impression that the preva-
lence of hereditary TTP may be considerably higher
than the commonly cited prevalence of 1 case
per million population. Whereas c.4143_4144dupA
clusters around the Baltic Sea, in central Europe,
and in Scandinavia,21,32,36 the geographic distri-
bution of p.R1060W is much broader. The muta-
tion p.R1060W has been shown to be associated
with residual ADAMTS13 activity; in homozygotes,
ADAMTS13 activity is usually 5 to 10% of that in
normal plasma. This mutation is present in many
patients with adult-onset hereditary TTP, particu-
larly in women in whom the disease is identified
during their first pregnancy and who may have
severe preeclampsia early in the second trimes-
ter (Fig. 2).32,41,42 However, in the largest reported
cohort, residual ADAMTS13 activity correlated only
weakly with the age at diagnosis and the severity
of hereditary TTP.36
Cl inic a l Fe at ur e s
Some patients with hereditary TTP may have
symptoms that manifest at birth, whereas others
remain asymptomatic for decades. When symp-
toms occur, the clinical features may be indis-
tinguishable from an acute episode of acquired
TTP or they may differ substantially (Fig. 2).
Times of Risk
Although patients with hereditary TTP are at in-
creased risk for manifestations of microvascular
thrombosis throughout their lives, two periods
appear to be associated with extreme risk. These
periods are the first days of life and pregnancy.
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
study in Japan34; 18 infants (42%) underwent
exchange transfusion of whole blood. Among
20 neonatal patients in Norway, 9 (45%) under-
went whole-blood exchange transfusion.32 None
of the 27 infants from Japan and Norway re-
ceived a diagnosis of hereditary TTP at the time
of the initial exchange transfusion. The diagno-
sis was delayed until a median age of 4 years
(range, 1 month to 25 years) in Japan34 and 24
years (range, 2 to 49) in Norway.32
These acute neonatal episodes can be fatal. A
recent article described a newborn who had pre-
sented with hyperbilirubinemia, anemia, and se-
vere thrombocytopenia and died 34 hours after
birth. He did not receive plasma or an exchange
transfusion. The diagnosis of hereditary TTP was
established post mortem.46 This case, together
with the decrease in the occurrence of alloim-
mune hemolysis since the introduction of prophy-
laxis against rhesus disease, suggests that the
diagnosis of hereditary TTP should be considered
in all neonates who have severe hyperbilirubine-
mia, especially when thrombocytopenia is pres-
ent. Plasma infusion is simple and lifesaving.
Among infants who survive, there may be no sub-
sequent symptoms for many years34; thus, the first
hours of life are a critical time of risk.
Multiple unique features may contribute to
the manifestations of hereditary TTP in the neo-
natal period. First, pulmonary vascular resistance
abruptly decreases as lung function begins, while
systemic vascular resistance abruptly increases
as circulation to the placenta stops. These fac-
tors cause the ductus arteriosus to have bidirec-
tional turbulent flow, which could contribute to
hemolysis.47 Second, the hematocrit is high at
birth (approximately 61%) and continues to rise
during the first hours after birth; this increases
blood viscosity48 and the risk of thrombosis.
Third, in healthy neonates, ultralarge von Will-
ebrand factor multimers are present in concen-
trations similar to those seen in patients with
hereditary TTP,49 and the total plasma concen-
tration of von Willebrand factor is increased.50
An association between hereditary TTP and
pregnancy was reported in 1976.51 Among the 43
patients in the Japanese cohort, 9 of 24 women
(38%) received an initial diagnosis of TTP during
pregnancy.34 In these 9 women, 14 pregnancies
preceded the diagnosis of TTP, and all the preg-
nancies were associated with severe complica-
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tions.52 In a Norwegian study involving 15 preg-
nancies in 8 women, all the pregnancies were
associated with severe complications.53 Frequent
initial recognition of hereditary TTP during a
woman’s first pregnancy and the subsequent out-
comes of hereditary TTP have been reported in
cohorts in France42 and the United Kingdom41; in
both cohorts, three quarters of the women were
reported to carry at least one p.R1060W allele.
In women presenting with very-early-onset pre-
eclampsia (e.g., at <25 weeks of gestation), heredi-
tary TTP should be considered. Prophylactic treat-
ment with plasma, initiated as soon as pregnancy
is confirmed in women with hereditary TTP, can
prevent complications and provide support for
term deliveries of healthy infants.41,42
Inflammatory conditions such as infection and
trauma and the use of drugs30 or excessive alcohol
intake36 can increase the risk of thrombosis by
causing increased endothelial secretion of von
Willebrand factor.27 However, acute episodes may
have no apparent triggering factor, and microvas-
cular thrombosis may be silent.
Clinical Manifestations
Patients with hereditary TTP have a high risk of
transient ischemic attack (TIA) and stroke, be-
ginning at a young age. Among 120 enrolled pa-
tients in the International Hereditary Thrombotic
Thrombocytopenic Purpura Registry, 25 (21%)
reported having had stroke and an additional
5 patients (4%) reported having had a TIA. Most
of these events occurred in children and young
adults.36 In a study involving 73 patients from the
United Kingdom, stroke occurred in 14 patients
(19%) and TIA occurred in 6 (8%); the age of the
patients when the stroke occurred was not re-
ported.37 Clinicians caring for patients who have
a TIA or stroke at a young age, particularly when
there is concurrent thrombocytopenia, should
consider the diagnosis of TTP.
A total of 5 of the 120 patients (4%) in the In-
ternational Hereditary Thrombotic Thrombocyto-
penic Purpura Registry36 and none of the 73 pa-
tients in the cohort from the United Kingdom37
were reported to have myocardial infarction. Many
patients with acquired TTP have an increased se-
rum troponin I level, indicating cardiac ischemia
and a critical disease course.54 Data on cardiac
troponin levels in patients with hereditary TTP
are lacking.34,36,37 The apparently uncommon oc-
currence of myocardial infarction and the more
1657
 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

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

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

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