1. health and fitness
2. disease

Thrombotic Thrombocytopenic Purpura and
Hemolytic Uremic Syndrome in Children
and Adolescents
Eric J. Lowe, M.D.,1 and Eric J. Werner, M.D.1,2
ABSTRACT
Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome
(HUS) are both uncommon disorders that present with a microangiopathic hemolytic
anemia and thrombocytopenia. Although for TTP, neurologic manifestations predominate, and in HUS renal dysfunction is virtually always present, there is significant overlap
in their clinical presentation. In recent years, tremendous progress has been made in our
understanding of the pathogenesis of these disorders. It is now apparent that there are
subcategories of both TTP and HUS that can differ in their clinical manifestations,
etiology, and management. For instance, although most cases of HUS are due to infection
with organisms that produce Shiga-like toxin, other cases may be caused by defined genetic
abnormalities. Similarly, TTP is usually caused by genetic or acquired deficiency of the
ADAMTS13 enzyme; however, in other cases the relationship with this enzyme remains
to be established. Management includes supportive care, plasma transfusions for genetic
protein deficiencies, and plasma exchange transfusion for autoimmune TTP.
KEYWORDS: Thrombotic thrombocytopenic purpura (TTP), hemolytic uremic
syndrome (HUS), microangiopathy, children
Objectives: On completion of the article, the reader should be able to (1) list differences between childhood thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome, and (2) cite laboratory features of both and treatment options for both.
Accreditation: Tufts University School of Medicine (TUSM) is accredited by the Accreditation Council for Continuing Medical Education
to provide continuing medical education for physicians.
Credit: TUSM designates this educational activity for a maximum of 1 category 1 credit toward the AMA Physicians Recognition Award.
Each physician should claim only those credits that he/she actually spent in the activity.
T
hrombotic thrombocytopenic purpura (TTP)
and hemolytic uremic syndrome (HUS) are both causes
of microangiopathic hemolytic anemias in children and
adolescents. In the last few years, significant progress has
been made in the understanding of the pathogenesis of
these two disorders. This review discusses the pediatric
features of TTP and HUS. Given that much of the
information about recent advances in the understanding
of the pathophysiology of TTP and HUS is discussed
elsewhere in this issue, we limit our discussion of these
aspects to those that influence children and adolescent
illness.
Thrombotic Thrombocytopenic Purpura—2005; Editor in Chief, Eberhard F. Mammen, M.D.; Guest Editors, Hau C. Kwaan, M.D., Ph.D., and
Charles L. Bennett, M.D., Ph.D. Seminars in Thrombosis and Hemostasis, volume 31, number 6, 2005. Address for correspondence and reprint
requests: Eric J. Werner, M.D., Professor, Children’s Cancer and Blood Disorders Center, Children’s Hospital of the King’s Daughters, 601
Children’s Lane, Norfolk, VA 23507. E-mail: [email protected]. 1Division of Pediatric Hematology-Oncology, Eastern Virginia Medical
School, Children’s Hospital of the King’s Daughters, Norfolk, Virginia; 2Professor. Copyright # 2005 by Thieme Medical Publishers, Inc., 333
Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. 0094-6176,p;2005,31,06,717,730,ftx,en;sth01121x.
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SEMINARS IN THROMBOSIS AND HEMOSTASIS/VOLUME 31, NUMBER 6
TTP and HUS are discussed separately. In general, there are significant differences in their etiologies,
clinical features, epidemiology, treatment, and outcome.
In addition, it is now recognized that both congenital
and acquired forms of TTP and HUS exist. In the
following sections, we endeavor to describe the molecular etiology, the clinical manifestations, laboratory
diagnosis, and treatment approaches for each of these
disorders. The reader should keep in mind, however,
that there can be overlap between each aspect of these
two illnesses. At present, no one factor completely
separates the diagnosis of TTP from HUS.
MICROANGIOPATHIC HEMOLYTIC
ANEMIA
Thrombotic microangiopathy is defined by endothelial
cell damage, resulting in platelet thrombosis, leading
to vessel obstruction. Histologically, this is manifested
by accumulation of platelet thrombi containing von
Willebrand factor (vWF) with very little fibrin in TTP1
or platelet-fibrin thrombi in HUS and disseminated
intravascular coagulation (DIC)2 in the vasculature
of specific organs, especially the brain in TTP and the
kidneys in HUS. Red cell destruction occurs in the vessels
narrowed by these thrombi, leading to schistocyte formation. Hence, the peripheral blood smear in these
disorders characteristically reveals schistocytes, helmet
cells, polychromasia, and thrombocytopenia. In addition
to TTP and HUS, other disorders that can present with a
microangiopathic anemia in this age group are shown in
Table 1. Unlike DIC, blood samples from patients
with HUS and TTP typically show normal values for
fibrinogen, prothrombin times (PTs), and activated
partial thromboplastin times (aPTTs). HUS is usually
considered to be a pediatric disease, although it may occur
in adults, whereas TTP is much more common in adults
and relatively rare in persons < 21 years of age.
Table 1 Causes of Microangiopathic Hemolytic
Anemias in Children and Adolescents
Hemolytic uremic syndrome
Thrombotic thrombocytopenic purpura
Disseminated intravascular coagulation
After bone marrow (or organ) transplantation TTP/HUS
Kasabach-Merritt syndrome
Radiation nephritis
Hemolysis with prosthetic cardiac devices (Waring blender
hemolysis)
Drug-induced microangiopathy
Antiphospholipid syndrome
Hemolysis, elevated liver enzymes, low platelets (HELLP
syndrome)
TTP, thrombotic thrombocytopenic purpura; HUS, hemolytic uremic
syndrome; HELLP, hemolysis, elevated liver enzymes, and low
platelet count.
2005
HEMOLYTIC-UREMIC SYNDROME
Etiology and Pathophysiology
The term HUS was first used in 1955 when Conrad von
Gasser et al3 reported a case series of five children with
thrombocytopenia, hemolytic anemia, and renal failure.3
Fifty years later, HUS is still defined by that clinical
triad. Fortunately, during the last 50 years, we have
seen significant progress toward elucidating the etiology
and pathophysiology of HUS. Although several
distinct etiologies of HUS exist, approximately 90% of
HUS in children is caused by Shiga toxin-producing
Escherichia coli.4,5
Shiga Toxin-Induced HUS (typical HUS)
Several strains of E. coli produce a toxin similar to Shigella
dysenteriae serotype 1. This toxin was found to be cytotoxic to Vero cells (African green monkey kidney cells),6
and E. coli that produce this toxin have been termed
subsequently verotoxin or Shiga-like toxin-producing E.
coli (STEC).7 Although many E. coli serotypes produce
Shiga-like toxin,8–15 the most common STEC is E. coli,
expressing the somatic (O) antigen 157 and the flagellar
(H) antigen 7. E. coli O157:H7 colonizes cattle, deer,
sheep, goats, and horses, and is transmitted through a
variety of food sources, water sources, and person-toperson contact. The bacterium is extremely hardy; it has
been identified in sawdust 42 weeks after an associated
outbreak.16 Following the ingestion of contaminated
food or water, the bacteria bind to the gastrointestinal
mucosa causing diarrhea. The E. coli then produce a toxin
that enters the circulation through the inflamed intestinal
epithelial cells. Because neither toxin nor bacteria is
identified in the circulation, it is speculated that the toxin
is transported to the site of injury bound to polymorphonuclear leukocytes.17 However, other cell types including
platelets18 and monocytes2 can bind Shiga toxin. The
toxin consists of pentamers of binding subunits (B) that
surround a single enzymatic subunit (A). At the site of
injury, the B subunits bind to the membrane receptor
globotriaosylceramide (Gb3) on the cell surface.19 The
toxin is then internalized, where it inhibits protein synthesis, leading to cell damage and death. Differences in
expression of Gb3 might explain the preferential damage
to the kidney because glomerular endothelial cells express
a very high level of Gb3.20,21
The hematologic consequences of infection with
STEC are a direct result of toxic injury to the endothelium. The vascular endothelium is a dynamic surface.
Normally, the endothelial surface inhibits platelet
adherence and thrombin generation. However, when
damaged, these properties change and the endothelial
surface can promote thrombin generation, resulting
in fibrin deposition and formation of platelet-fibrin
thrombi. In addition, fibrinolysis is inhibited by increased
TTP AND HUS IN CHILDREN AND ADOLESCENTS/LOWE, WERNER
activity of plasminogen activator inhibitor 1, further
increasing the prothrombotic milieu.22,23 In addition,
separation of endothelial cells from their attachment to
the basement membrane exposes the blood to the adhesive and prothrombotic elements of the basement membrane including collagen and vWF.24 The result of this
endothelial injury is platelet activation, thrombosis, and
thrombotic injury; it is this thrombotic injury of the
microvasculature of the kidney that causes the clinical
triad of HUS (microangiopathic hemolytic anemia,
thrombocytopenia, and renal dysfunction).25 In addition
to causing endothelial cell damage, the Shiga toxin
possesses other traits that contribute to the development
of HUS. The toxin has been shown to induce expression
of tumor necrosis factor (TNF)-a, which upregulates the
Gb3 receptor, causing more toxin to be delivered to the
cell.26 Shiga toxin, when associated with TNF-a, causes
an increased expression of tissue factor,27 which then
activates factor VII, ultimately leading to thrombin formation, subsequent platelet activation, and fibrin generation. Shiga toxin can also directly injure monocytes,28
which are another source of tissue factor and inflammatory cytokines. Lastly, several types of renal cells have
receptors for Shiga toxin,20,29 suggesting that renal injury
might be a combination of thrombotic injury and direct
injury by the toxin to the parenchymal cells.
Atypical HUS
Although STEC induced HUS is a relatively homogeneous disease, atypical HUS is very heterogeneous.
Atypical HUS arises from numerous causes, including
cancer,30 drugs,31 bone marrow transplantation,5 autoimmune disorders, and disorders of intracellular cobalamin metabolism.32 The two most common etiologies of
atypical HUS are Streptococcus pneumoniae infection and
abnormalities of complement regulation.
HUS is a complication of S. pneumoniae infection
in an estimated 0.6% of invasive S. pneumoniae cases.33
S. pneumoniae possess a neuroaminidase, which cleaves
the N-acetyl neuraminic acid, resulting in the exposure
of a cryptic T antigen present on erythrocytes and
endothelial cells.34 Naturally occurring anti-T immunoglobulin (IgM) then reacts with this antigen, injuring
red blood cells and endothelial cells to cause HUS.
Interestingly, HUS secondary to S. pneumoniae is almost
exclusively associated with invasive disease,35,36 lending
credit to the theory that a large bacterial load and/or
severe inflammation are required as cofactors for the
development of HUS.
Disorders of complement regulation have also
been described as a cause of atypical HUS.2,37 Complement is an important part of a person’s innate immunity.
Fully activated complement is capable of killing cells and
organisms. The activation products are closely regulated
by proteins such as factor H, factor I, and membrane
cofactor protein (MCP). Factor H binds to C3b, and as a
cofactor for factor I, accelerates the decay of the alternate
complement pathway convertase, destroying C3 convertase activity. Complement factor I cleaves the a chains of
C3b and C4b, inactivating these enzymes, thus preventing the formation of C3/C5 convertases. MCP is a
cofactor for factor I in the cleavage of C3b and C4b.
Disorders of complement regulation result in uninhibited
activated complement, with subsequent endothelial damage and thrombotic microangiopathy. Mutations in factor
H,38–42 factor I,43 and MCP44,45 have been reported to
cause HUS. Most defects are congenital but an acquired
factor H deficiency secondary to autoantibodies has been
reported.46 Because most of the abnormalities in complement regulation are recent discoveries, it is likely that
additional disorders of the complement system will be
implicated as causes of HUS.
The role of ADAMTS13 (named for the combination of a disintegrin-like and metalloprotease with
thrombospondin type 1 motifs) in HUS is much less
clear. Most studies have shown that the ADAMTS13
levels are normal or nearly normal in patients with
HUS.47,48 However, some cases of atypical HUS secondary to the classic defect in TTP (ADAMTS13
deficiency) have been reported.49,50 This overlap in
pathogenesis is of utmost importance when considering
the work-up for a patient with microangiopathic anemia
and thrombocytopenia.
Clinical Manifestations of HUS
HUS is the most common cause of acute renal failure in
children.51 The syndrome is defined by the triad of
microangiopathic hemolytic anemia, thrombocytopenia,
and renal impairment. However, the pathogenesis leading to HUS can alter the clinical manifestations vastly.
Table 2 lists a comparison of TTP, STEC-related HUS,
and atypical HUS.
Typical childhood HUS is a complication of a
STEC infection (most commonly E. coli O157:H7).
Approximately 3 days (range, 1 to 12 days) following
ingestion of the bacteria, nonbloody diarrhea occurs.
After 2 days of nonbloody diarrhea and vomiting, the
diarrhea becomes painful and bloody. Although most
children infected with STEC develop bloody diarrhea,11,52 a large subset only develop nonbloody diarrhea.
In fact, some patients have no gastrointestinal symptoms
but do have evidence of STEC infection.11,53 In addition, HUS following a urinary tract infection with
STEC has been reported.54 Therefore, diarrhea should
not be used to differentiate typical versus atypical HUS.
The incidence of HUS varies in different parts of
the world, with estimates between 0.3 and 3.3 cases per
100,000 children.11–14 In a review of either insurance files
(United States) or computerized medical records (United
Kingdom and Saskatchewan, Canada) from the years
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Table 2
2005
Comparison of Chronic Relapsing TTP, Acquired TTP, Classic HUS, and Atypical HUS
Characteristic
Chronic Relapsing TTP
Acquired TTP
STEC HUS
Atypical HUS
Schistocytic hemolytic anemia
Yes
Yes
Yes
Yes
Thrombocytopenia
Yes
Yes
Yes
Yes
Hypofibrinogenemia
No
No
No
No
Neurologic manifestations
Renal manifestations
Very common
Some
Very common
Some
Common
Yes
Common
Yes
Absent ADAMTS13
Yes
Yes
Rare
Occasional
Inhibitor to ADAMTS13
No
Most
No
Occasional
TTP, thrombotic thrombocytopenic purpura; HUS, hemolytic uremic syndrome; STEC, Shiga-like toxin-producing Escherichia coli.
1990 to 2000, Miller et al55 calculated the incidence rates
for HUS to be 2.7 per million patient-years in the United
States and 2.1 per million patient-years in the United
Kingdom and Saskatchewan. Of note, the incidence rates
were higher from 1995 to 2000 than in the preceding 5
years. STEC-associated HUS usually occurs in young
children, with 75% of cases occurring before age 5.11
HUS occurs 7 to 14 days after initial symptoms in
approximately 5 to 15% of children who present with
STEC infection.22,56–58 Many children with STEC infection develop the hematological abnormalities of HUS
but have normal renal function (incomplete HUS).59 An
explanation of incomplete HUS is revealed in the seminal
article, which demonstrated that thrombotic changes can
be found during the acute diarrheal phase of many
patients who do not proceed onto HUS.22 It is unclear
why some children with STEC infections develop HUS
and others do not; it may be a net effect of E. coli
virulence, toxin load, and host factors.
HUS has significant associated morbidity and
mortality. Anemia and thrombocytopenia occur in all
patients, with red blood cell transfusion support required
in many cases. Renal complications are common, with
dialysis required in 50 to 60% of children.11,52 Dialysis is
usually temporary, lasting 5 to 7 days when required.5
Acute and chronic hypertension are also complications of
impaired renal function. Renal injury progressing to endstage renal failure and kidney transplantation is rare in
STEC-associated HUS. Gastrointestinal complications
including cholelithiasis and pancreatitis are also common.60–62 Although neurological complications (seizures,
altered mental status, etc.) are thought of as complications of TTP, they occur in approximately 25% of
children with HUS .11,62,63 Death occurs in approximately 2 to 4% of HUS cases.4,8,11,13,64 Although
detailed studies are scarce, there appears to be no clinical
difference in outcome between HUS secondary to E. coli
O157 and non-O157 STEC cases.52
Atypical HUS accounts for approximately 10% of
HUS cases in children. Although definitive incidence
data are lacking, abnormalities of complement regulatory
proteins can present in the newborn period, whereas
HUS secondary to S. Pneumoniae infection can present
at all ages. S. pneumoniae is the most common etiology
of atypical HUS, accounting for 38% of cases in one
series.62 The hematological, neurological, renal, and gastrointestinal manifestations of atypical HUS are similar in
nature to those of typical HUS. These complications have
been thought to be more frequent and severe in atypical
HUS.62 Brandt et al60 reviewed 58 cases of HUS secondary to S. pneumoniae and found a mortality rate of 24%.
However, at least one group has reported fewer acute
renal complications and no increase in mortality.65 Undisputed, however, is the fact that relapse rates for
patients with abnormalities of complement regulatory
proteins are much higher than for other causes of
HUS.42 Noris et al66 found that 62% of patients with
familial HUS died and that there was a high frequency of
renal failure in the survivors. Of those undergoing renal
transplantation, 16% will lose their graft in the first
month.2
Diagnostic Studies
The clinical scenario and laboratory values alone are
often sufficient to suggest strongly the diagnosis of
HUS. Confronted with a child who has microangiopathic hemolytic anemia and thrombocytopenia, one
should begin to examine possible etiologies listed in
Table 1. In patients with diarrhea, one should instigate
an investigation for a Shiga toxin-producing organism or
the toxin itself. Stool culture on sorbitol-MacConkey
agar will detect most E. coli O157 infections but will
miss non-O157 STEC because they usually ferment
sorbitol.67 Therefore, direct detection of the Shiga toxin
in the stool is required to identify all serotypes of STEC.
In patients without diarrhea, the investigation needs to
be broader. First, the clinician needs to evaluate other
etiologies such as drugs, DIC, TTP, and other illnesses
that may mimic the disease (Table 1). Second, given
that many cases of nondiarrheal HUS were proven to be
caused by STEC, a search for STEC is warranted
through examination of stool and urine.25 C3 levels
should be sent to screen for possible complement factor
deficiencies. Factors H, I, and MCP should also be
measured. It should be noted that in some cases of factor
TTP AND HUS IN CHILDREN AND ADOLESCENTS/LOWE, WERNER
H deficiency, the defect is qualitative, not quantitative,
leading to a misleading result of normal factor H
levels.38,68 Lastly, urinary methylmalonic acid levels
can be obtained to evaluate for the rare disorder of
intracellular cobalamin metabolism, especially in children with clinical features such as developmental delay
and macrocytic anemia.69
Treatment of HUS
The mainstay of treatment for HUS is supportive care.
Early recognition and early intravenous volume expansion have been shown to provide renal protection.70 The
challenge is to provide sufficient intravenous fluids to
maintain renal perfusion while avoiding fluid overload.
As such, we recommend the hospitalization of children
with HUS to provide continuous monitoring and correction of volume depletion or overload.
Children with HUS can become severely anemic.
Packed red cell transfusions should be used if clinically
indicated. Conversely, despite thrombocytopenia, platelets should be given only when absolutely necessary, such
as for life-threatening hemorrhage, because they could
potentially exacerbate the platelet-fibrin thrombosis.
of the HUS, one can avoid administering additional
anti-T immunoglobulins by washing red blood cells or
platelets prior to any transfusion (although this has not
been shown to be effective). Early appropriate antibiotic
therapy should be initiated if invasive S. pneumoniae
infection is considered likely. If patients do develop
end-stage renal disease, renal transplantation should be
considered because HUS is unlikely to recur as long as
there is no inherited complement deficiency.
Treatment for defects within the complement
regulatory system varies. Treatment with plasma infusions has resulted in recovery of kidney function by
stopping the complement activation.74,75 Theoretically,
chronic plasma replacement should be an effective treatment for these disorders. Unfortunately, many patients
progress to end-stage renal disease. Treatment then
has been kidney transplantation. A large majority of
patients have experienced relapse following transplantation9,43,76–78 because the inherited defect has not been
repaired. As such, there has been at least one attempt to
treat factor H deficiency with a liver transplantation.79
Lastly, although renal transplantation may not correct
factor H deficiency, because MCP is a transmembrane
protein, a kidney transplantation should rectify the
problem.45
TYPICAL HUS
Antibiotics should not be administered routinely to
children with STEC, given that most studies have shown
no benefit57 or higher rates of HUS.58 However, if there
is consideration of S. pneumoniae-induced HUS, early
antibiotic therapy to cover that organism is indicated, as
discussed in the section ‘‘Atypical HUS’’. Many other
treatments including corticosteroids, plasmapheresis, and
heparin have been used without any clear benefit.25 Our
better understanding of STEC-associated HUS has resulted in new treatment proposals to try either monoclonal antibodies against Shiga toxin71 or Shiga toxin
receptor analogs72 to prevent the disease. However, the
utility of these treatments has yet to be proven.
Prevention might be the most important treatment available for HUS. Awareness of the disease
increased significantly with the described outbreak in
the 1990s.73 This increased public awareness provided a
platform for improved standards for meat processing,
food handling, and food preparation. Although many of
the initial outbreaks described were associated with fastfood hamburger meat, there have been no reported
similar outbreaks since 1995, indicating that the increased awareness and preventive measures may have
helped.56 Hand washing should be performed to prevent
person-to-person contamination.
ATYPICAL HUS
Treatment for HUS secondary to S. pneumoniae involves
mainly supportive care as described above. Theoretically,
because the anti-T IgM antibodies are the primary cause
THROMBOTIC THROMBOCYTOPENIC
PURPURA
TTP is generally a disorder of adults; < 10% of cases
occur in the pediatric age group.55 The original case of
TTP reported by Moschcowitz80 occurred in a 16-yearold girl. It is now recognized that TTP can occur as a
congenital disorder due to a mutation in the gene coding
for the vWF-cleaving protease (ADAMTS13), can be
caused by acquired inhibitors to that enzyme, or can be
due to other causes of endothelial cell damage.
ADAMTS13 is one of a family of currently
known 19 metalloprotease enzymes (ADAMTS) with
multiple described functions. Disorders associated with
defects in other ADAMTS enzymes include type VII C
Ehlers-Danlos syndrome (ADAMTS2)81 and WeillMarchesani syndrome (ADAMTS10).82 The gene
for ADAMTS13 has been localized to chromosome
9q3483 and codes for a 1427-amino acid protein.48
ADAMTS13 cleaves vWF released from the endothelial
cell, decreasing its multimeric size. Unlike the vWF
multimer usually found in plasma, the ultralarge
von Willebrand factor multimer (ULvWF) stored in
Weibel-Palade bodies in endothelial cells, if released
into plasma, can induce platelet thrombus formation
immediately when exposed to high shear stress. There
is increasing evidence that the presence of ULvWF in
the plasma due to defective or absent ADAMTS13 is a
key component in the pathogenesis of most cases of
TTP.
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CHRONIC RELAPSING TTP/CONGENITAL
TTP (UPSHAW-SCHULMAN SYNDROME)
In 1960, Schulman et al84 described an 8-year-old girl
with recurrent bleeding, thrombocytopenia, and hemolysis who had a clinical response to plasma infusions. In
1978, Upshaw85 described a very similar case and theorized that an absent plasma factor was the underlying
cause. Since then, there have been several reports of
similar infants and children.86
The typical presentation of chronic relapsing
TTP is that of a normal newborn who within the first
several hours or days of life develops severe hyperbilirubinemia, hemolytic anemia, and thrombocytopenia.87
Unlike in DIC, the fibrinogen level is typically not
decreased.88,89 Hyperbilirubinemia may be severe, exchange transfusion is often required, and kernicterus has
been reported with chronic relapsing TTP.90,91 These
infants usually respond rapidly to exchange transfusion
or even simple platelet transfusion.89 Because of the
response to transfusion or exchange transfusion, the
infants are often discharged home with a presumptive
diagnosis of DIC. Recurring periods of thrombocytopenia and hemolysis, with neurologic or renal abnormalities, then occur. Alternatively, thrombocytopenia may
be the only initial manifestation. Bleeding manifestations can be severe, including intracranial hemorrhage,
primarily due to the thrombocytopenia.92 Patients may
be mistakenly diagnosed with Evans syndrome. Of note,
despite the severe congenital hemolytic anemia, the
diagnosis in many of the cases reported to date is made
later in childhood or even adulthood.83
Older children can present with typical clinical
features of TTP. These include neurologic changes
(seizures, altered mental status, focal neurologic
deficits)89 renal impairment,93 schistocytic hemolytic
anemia, and thrombocytopenia. Factors that can trigger
TTP in older individuals with familial disease include
pregnancy, infection, stress, or alcohol consumption.86
Rarely, cardiac involvement has been reported.94
Genetics
Most children with familial TTP are born to asymptomatic parents, suggesting a usual autosomal recessive
pattern. However, the finding of recurrent disease presenting in successive generations of adults suggests that
for some patients there is an autosomal dominant inheritance. Consanguinity has been noted in some parents of children with congenital TTP.95–97
Laboratory Features
At presentation, children with chronic relapsing TTP
usually present with a Coombs-negative hemolytic anemia. The anemia can be quite severe, with hemoglobin
concentrations below 6 g/dL often described.98 The
2005
platelet count is also reduced, often severely so. The
coagulation profile (PT, aPTT, and fibrinogen) is usually
normal, although coagulopathy has been reported in
some cases. The lactate dehydrogenase (LDH) is elevated, the etiology of which is tissue ischemia rather than
red blood cell breakdown.99 Renal abnormalities including hematuria, proteinuria, and elevations in serum creatinine are not uncommon. The levels of vWF/
antigen (Ag) are increased in the plasma of patients
with chronic relapsing TTP; however, because vWF is
an acute phase reactant, this finding is not specific
for the disorder.100,101 The ratio of vWF/antigen to
vWF/Rco (Ristocetin cofactor) is often normal in
patients with chronic relapsing TTP and is not a reliable
marker for the presence of ULvWF multimers in the
plasma.100,102
Specialized laboratories can provide confirmatory
studies. ULvWF multimers are present in familial TTP
in remission, but decrease during relapses.103 Increased
levels of vWF propolypeptide (vWF/Ag II), a marker for
endothelial cell injury, have been shown in TTP.104
Furlan et al100 demonstrated severely deficient levels of
ADAMTS13 in four patients, including two siblings
with chronic relapsing TTP in whom they could find no
evidence of an inhibitor to the enzyme activity. Subsequently, several investigators have confirmed that there
is severe deficiency of ADAMTS13 (< .05 U/dL) in
patients with congenital TTP.83,95 Asymptomatic family
relatives have mild decreases in ADAMTS13, with
levels about averaging approximately 0.5 U/mL.83,95
The difficulty with the ADAMTS13 assay is
demonstrated by the following case. Savasan et al105
reported on a child who had recurrent schistocytic hemolytic anemia beginning in infancy with ULvWF and a
requirement for recurrent plasma infusions to maintain
clinical remission, but whose ADAMTS13 was normal.
However, the infant was subsequently shown to have a
mutation in the gene coding for ADAMTS13 and
subnormal levels when measured by the sodium dodecyl
sulfate polyacrylamide gel electrophoresis and immunoblotting technique.97 The correlation between
ADAMTS13 and ULvWF is not complete. Remuzzi
et al49 found patients who had absent ADAMTS13
activity but whose plasma did not contain ULvWF
multimers, whereas other patients with TTP or atypical
HUS had ULvWF multimers with intact ADAMTS13.
It also should be noted that newborns have large
vWF multimers.106–108 The ULvWF multimer appears
to occur more commonly in the premature infant
and disappears by 51 weeks gestational age.106 There
are conflicting reports regarding ADAMTS13 activity
in the neonate. Some investigators have reported that
vWF-cleaving protease activity is approximately 50% of
adult levels in the neonate.109–111 However, Tsai et al107
found that ADAMTS13 activity was normal in nearly all
newborns tested. Similarly, Schmugge et al112 found that
TTP AND HUS IN CHILDREN AND ADOLESCENTS/LOWE, WERNER
ADAMTS13 was normal in 74% of cord blood tested,
but the remainder had activity of approximately 50% of
adult normal that reached adult normal levels by 2 to 3
days. The discrepancy in results may be due to methodology, variation in the ADAMTS13 assay, or in specimen acquisition. In a small series, the levels in premature
infants correlated with gestational age and birth weight;
however, statistical difference between the preterm and
term infants was not achieved, perhaps due to the small
number of infants enrolled.109
Gene Analysis
More than 50 mutations of ADAMTS13 causing congenital TTP have been described.113 Gene abnormalities
include missense mutations leading to single amino acid
substitutions, as well as nonsense, splicing, and frameshift mutations. In most cases, the gene product leads to
greatly reduced secretion of ADAMTS13.48 Many of
these mutations have been reviewed recently.114 Most
patients with inherited TTP have compound heterozygous defects in their ADAMTS13 gene, although homozygous defects have been described.114
Diagnostic Work-Up
The diagnosis of TTP can usually be made with a
combination of clinical symptoms, schistocytic hemolytic anemia, thrombocytopenia, and elevation in serum
LDH. In their review of patients diagnosed in childhood
with TTP, Schneppenheim et al115 identified many
children previously diagnosed with ITP or Evans syndrome. In Evans syndrome, the Coombs test is usually
positive and there are prominent spherocytes on the
peripheral blood smear. Typically, coagulopathy with
hypofibrinogenemia is present in DIC. Because of
the rapid progression of symptoms, plasma infusions or
plasmapheresis should be initiated as soon as the diagnosis is entertained. Hence, the clinical response to
therapy may confirm the diagnosis.
In general, ADAMTS13 activity and inhibitor
determination are not readily available. However, given
that most of their patients eventually did have the
more serious manifestations of TTP with potentially
life-threatening effects, Schneppenheim et al115 have
proposed that vWF-cleaving protease activity be determined in children with Coombs-negative Evans
syndrome, relapsing parainfectious thrombocytopenia,
thrombocytopenia with neurologic symptoms, atypical
HUS, and even chronic thrombocytopenia.
Treatment
An ADAMTS13 threshold activity of above 0.05 U/mL
appears to be adequate to prevent formation of microthrombi.96 The half-life of vWF-cleaving protease
appears to be quite long—in excess of 2 days.96,116
Therefore, infusion of 10 cm3/kg of FFP every 2 to
3 weeks has maintained clinical remission in patients
with chronic relapsing TTP,96,98,117 although prolonged
remission with lower volumes of plasma has been
reported.96 Other products such as cryoprecipitate, cryoprecipitate supernatant,118 solvent/detergent-treated
plasma,117,119 and intermediate-purity factor VIII
(FVIII) concentrates have been used to treat children
with congenital deficiency of ADAMTS13.95 It should
be noted that there is significant variation in the
ADAMTS13 activity in plasma-derived FVIII concentrates, and that clinical failure has been noted when
concentrates, subsequently shown to have low amounts
of enzyme, were used.95 Recombinant and monoclonally
purified FVIII concentrates do not contain significant
quantities of ADAMTS13 and should not be used in
therapy for congenital TTP.95
Prognosis
If the diagnosis is made and plasma infusions are
continued, the long-term outlook appears to be related
to damage that has occurred prior to initiation of
therapy; for instance, kernicterus due to perinatal hyperbilirubinemia. Long-term neurologic sequelae from
stroke or intracranial hemorrhage can also be present.
ACQUIRED THROMBOTIC
THROMBOCYTOPENIC PURPURA
Etiology
As with adults, most cases of acquired TTP in children
and adolescents are due to the development of an inhibitor to ADAMTS13. Such antibodies may develop idiopathically or in conjunction with other autoimmune
disease. The association between acquired TTP and
systemic lupus erythematosus (SLE) may be significantly
greater in children and adolescents than in adults. Brunner et al120 found that of 35 patients identified in their
institution and in a literature review, 26% met the criteria
for SLE and an additional 23% had incipient SLE. Chak
et al121 identified 21 pediatric patients with TTP and
SLE. In four of these patients, the SLE preceded the
diagnosis of TTP by up to 5 years, in nine of the patients
the two disorders were diagnosed concurrently, and in the
remaining eight patients the diagnosis of TTP preceded
the diagnosis of SLE by 4 months to 5 years. Inhibitors to
ADAMTS13 have been documented in a 12-year-old
patient with SLE and TTP.122 Although familial TTP is
usually due to mutations in the ADAMTS13 gene, in one
case, identical twins were shown to have acquired TTP
caused by an inhibitor to ADAMTS13.123
Acquired TTP also occurs in the posttransplantation setting, especially following bone marrow
723
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SEMINARS IN THROMBOSIS AND HEMOSTASIS/VOLUME 31, NUMBER 6
transplantation (BMT). Most series of posttransplantation TTP have not separated pediatric from adult
patients. The incidence of TTP occurring in patients
undergoing allogeneic BMT has been reported at 0.5 to
8% or greater.124–126 Ruutu et al126 found the rate of
TTP to be 5.4% of 87 patients < 20 years of age
compared with 6.2% of 184 patients who were 20 to
40 years old and 8.1% of 135 patients > 40 years old
(p ¼ not significant). In a series of 22 patients with postBMT TTP, six were < 17 years of age. In this small
series, TTP was associated with increased age, female
gender, and possibly the use of unrelated donors.125
Uderzo et al86 described a very high incidence of 21%
in children undergoing BMT for leukemia. In this series,
an increased rate was noted in patients undergoing
unrelated BMT. TTP after BMT does not appear to
be due to deficiency of ADAMTS13.124,127,128 Increased
levels of vWF Ag have been noted.
Clinical Presentation
The clinical presentation of acquired TTP in childhood is
identical to that of adults. As for chronic relapsing TTP,
the presenting features include varying degrees of neurologic abnormalities, renal abnormalities, and fever. Petechiae, ecchymoses, gingival bleeding, hematuria, and
bleeding from thrombocytopenia are common. Although
acquired TTP usually occurs in older children and adolescents, it can occur in infancy.129–131 Horton et al130
identified acquired TTP as the cause of thrombocytopenia in 1.3% of nonneonates referred for evaluation of
thrombocytopenia. In the series by Horton et al, five of
seven had neurologic manifestations within 24 hours of
presentation, of which two were intracranial hemorrhage.
Laboratory Features
The basic laboratory features of acquired TTP in childhood are essentially the same as those described for
chronic relapsing TTP. The diagnosis can be made
when the appropriate clinical features are matched
with microangiopathic hemolytic anemia, an elevated
LDH, and normal coagulation studies, and other
causes (such as drug-induced, post-bone marrow transplantation, and pregnancy-induced [hemolysis, elevated
liver enzymes, and low platelet count syndrome]
illnesses) have been excluded. As with adults, many
children with acquired TTP have antibodies against
ADAMTS13. Hence they have severe deficiency of
that enzyme with a documented inhibitor. As previously
stated, most patients with typical HUS have normal
values for ADAMTS13, hence this may help distinguish
TTP from HUS in difficult cases.132 ULvWF multimers
were not apparent and ADAMTS13 plasma levels
were normal in six patients with TTP acquired after
BMT.127
2005
Diagnostic Work-Up
The diagnostic evaluation of the patient with apparent
acquired TTP begins with the history, including current
medications and recent concomitant medical illness. Of
course, the history of prior organ transplantation, especially BMT, is especially relevant. With the exception of
cyclosporine, medications thus far implicated as causes of
TTP (including ticlopidine, quinine, and clopidogrel)
are rarely used in the pediatric population. The presence
of prosthetic cardiac devices can induce severe microangiopathic hemolytic anemia with hemoglobinuria
and decreased vWF multimers, known as the WaringBlender syndrome.
The laboratory assessment to rule out other microangiopathic disorders such as DIC is essentially the
same as for congenital relapsing TTP, including coagulation studies such as a PT, aPTT, and fibrinogen; a
Coombs test, and evaluation of the peripheral blood
smear. The LDH is usually very elevated and renal
dysfunction is variably present. Serologic studies to
evaluate the presence of SLE, other autoimmune disorders, or possible infection should be performed, especially if consideration is given to include intravenous
gamma globulin in the management.
In most patients with acquired autoimmune TTP,
the ADAMTS13 level is very low (< 0.05 U/mL). The
presence of inhibitors to ADAMTS13 is used to differentiate congenital relapsing TTP from acquired TTP.
As noted, the levels of ADAMTS13 are normal or only
slightly reduced in patients with diarrheal-associated
HUS, post-BMT TTP, and many forms of druginduced TTP.
Treatment
Plasma exchange transfusion (PET) is the only treatment to date with efficacy proven by randomized clinical
trial. In 1991, two studies both documented its efficacy.
Compared with fresh frozen plasma infusions in patients, all of whom also received antiplatelet therapy,
Rock et al133 showed a decrease in mortality at 9 days
(4 versus 16%) and 6 months (22 versus 37%). There was
also a significantly increased response rate for improved
platelet counts in the PET group. Other studies have
confirmed improved survival with PET compared with
plasma infusions.134–136 PET should be initiated as soon
as the diagnosis is considered seriously. Usually daily,
single-volume PET is used, although more frequent
exchanges may be considered for patients with refractory
disease.137 PET can be continued until clinical remission
occurs, and then gradually tapered with monitoring of
the patient for clinical and/or laboratory recurrence.
There are significant complications to TTP, including
catheter-related problems (infection, thrombosis, insertion complications), allergic reactions to plasma, and
persistent thrombocytopenia.135,138
TTP AND HUS IN CHILDREN AND ADOLESCENTS/LOWE, WERNER
FFP infusions were shown to be less effective
that PET, but could be used in the short term if PET is
not available. Coppo et al139 showed similar survival and
relapse rates in a small, nonrandomized retrospective
study comparing high-volume FFP (mean 27.5 mL/kg/
day) with PET as initial therapy; however, 42% of the
patients in the FFP group were switched to PET.
The use of additional modalities in the management of patients with TTP is less clear. In many
case series, corticosteroids and/or antiplatelet agents
have been used with PET in the initial management of
patients with TTP, but their role generally has not been
studied by randomized clinical trial. Bobbio-Pallavicini
et al140 found no significant difference in response rate,
survival, or bleeding symptoms in a study of antiplatelet
therapy when added to corticosteroids and PET. Nevertheless, there are concerns about the risk for increased
bleeding with the use of antiplatelet agents. PET has not
been proven to be efficacious for patients with posttransplantation TTP.
For patients who fail to respond adequately to
plasmapheresis or who cannot be weaned off of plasmapheresis, several other modalities have been used—
again, without the benefit of randomized controlled
clinical trials to prove efficacy. Vincristine has been
used in both adolescent and adult patients.141,142 Similarly, there are several case reports including adolescents
using cyclosporine to treat TTP,141,143 although caution
should be used because this drug can be a cause of the
disorder. Other agents include intravenous gamma globulin144 (although benefit was not seen in a small retrospective review145) and rituximab.146,147
Splenectomy has been used to treat patients
with multiply relapsing TTP or unresponsive TTP
with apparent efficacy.66,148,149 Laparoscopic splenectomy has been performed safely.150 None of these studies
has addressed the impact of splenectomy for TTP in the
pediatric age group.
For patients with drug-induced TTP, removal of
the offending agent is an important first step. Ticlopidine- and clopidogrel-induced TTP may have an autoimmune basis.
Supportive care is important in the management
of patients with TTP. Red blood cell transfusion frequently is required. Platelet transfusion should be used
only for life-threatening hemorrhage.
REFERENCES
1. Asada Y, Sumiyoshi A, Hayashi T, Suzumiya J, Kaketani K.
Immunohistochemistry of vascular lesion in thrombotic
thrombocytopenic purpura, with special reference to factor
VIII related antigen. Thromb Res 1985;38:469–479
2. Moake JL. Thrombotic microangiopathies. N Engl J Med
2002;347:589–600
3. Gasser C, Gautier E, Steck A, Siebenmann RE, Oechslin
R. Hemolytic-uremic syndrome: bilateral necrosis of the
renal cortex in acute acquired hemolytic anemia [in
German]. Schweiz Med Wochenschr 1955;85:905–909
4. Lynn RM, O’Brien SJ, Taylor CM, et al. Childhood
hemolytic uremic syndrome, United Kingdom and Ireland.
Emerg Infect Dis 2005;11:590–596
5. Siegler R, Oakes R. Hemolytic uremic syndrome; pathogenesis, treatment, and outcome. Curr Opin Pediatr 2005;
17:200–204
6. Konowalchuk J, Speirs JI, Stavric S. Vero response to a
cytotoxin of Escherichia coli. Infect Immun 1977;18:775–779
7. O’Brien AO, Lively TA, Chen ME, Rothman SW, Formal
SB. Escherichia coli O157:H7 strains associated with
haemorrhagic colitis in the United States produce a Shigella
dysenteriae 1 (SHIGA) like cytotoxin. Lancet 1983;1:702
8. Banatvala N, Griffin PM, Greene KD, et al. The United
States National Prospective Hemolytic Uremic Syndrome
Study: microbiologic, serologic, clinical, and epidemiologic
findings. J Infect Dis 2001;183:1063–1070
9. Milford DV, Taylor CM, Guttridge B, et al. Haemolytic
uraemic syndromes in the British Isles 1985–8: association
with verocytotoxin producing Escherichia coli. Part 1: clinical
and epidemiological aspects. Arch Dis Child 1990;65:716–
721
10. Kleanthous H, Smith HR, Scotland SM, et al. Haemolytic
uraemic syndromes in the British Isles, 1985–8: association
with verocytotoxin producing Escherichia coli. Part 2:
microbiological aspects. Arch Dis Child 1990;65:722–
727
11. Gerber A, Karch H, Allerberger F, Verweyen HM,
Zimmerhackl LB. Clinical course and the role of shiga
toxin-producing Escherichia coli infection in the hemolyticuremic syndrome in pediatric patients, 1997–2000, in
Germany and Austria: a prospective study. J Infect Dis
2002;186:493–500
12. Tozzi AE, Caprioli A, Minelli F, et al. Shiga toxinproducing Escherichia coli infections associated with hemolytic uremic syndrome, Italy, 1988–2000. Emerg Infect Dis
2003;9:106–108
13. Elliott EJ, Robins-Browne RM, O’Loughlin EV, et al.
Nationwide study of haemolytic uraemic syndrome: clinical,
microbiological, and epidemiological features. Arch Dis
Child 2001;85:125–131
14. Haeghebaert S, Vaillant V, Decludt B, Grimont PA.
Surveillance of haemolytic uraemic syndrome in children
under 15 years of age in France in 1998. Euro Surveill
2000;5:68–73
15. Misselwitz J, Karch H, Bielazewska M, et al. Cluster
of hemolytic-uremic syndrome caused by Shiga toxinproducing Escherichia coli O26:H11. Pediatr Infect Dis J
2003;22: 349–354
16. Varma JK, Greene KD, Reller ME, et al. An outbreak of
Escherichia coli O157 infection following exposure to a
contaminated building. JAMA 2003;290:2709–2712
17. te Loo DM, Monnens LA, Der Velden TJ, et al. Binding
and transfer of verocytotoxin by polymorphonuclear leukocytes in hemolytic uremic syndrome. Blood 2000;95:3396–
3402
18. Karpman D, Papadopoulou D, Nilsson K, et al. Platelet
activation by Shiga toxin and circulatory factors as a
pathogenetic mechanism in the hemolytic uremic syndrome.
Blood 2001;97:3100–3108
725
726
SEMINARS IN THROMBOSIS AND HEMOSTASIS/VOLUME 31, NUMBER 6
19. Karch H. The role of virulence factors in enterohemorrhagic
Escherichia coli (EHEC)–associated hemolytic-uremic syndrome. Semin Thromb Hemost 2001;27:207–213
20. Hughes AK, Ergonul Z, Stricklett PK, Kohan DE.
Molecular basis for high renal cell sensitivity to the cytotoxic
effects of shigatoxin-1: upregulation of globotriaosylceramide expression. J Am Soc Nephrol 2002;13:2239–2245
21. Uchida H, Kiyokawa N, Horie H, Fujimoto J, Takeda T.
The detection of Shiga toxins in the kidney of a patient with
hemolytic uremic syndrome. Pediatr Res 1999;45:133–137
22. Chandler WL, Jelacic S, Boster DR, et al. Prothrombotic
coagulation abnormalities preceding the hemolytic-uremic
syndrome. N Engl J Med 2002;346:23–32
23. Bergstein JM, Riley M, Bang NU. Role of plasminogenactivator inhibitor type 1 in the pathogenesis and outcome
of the hemolytic uremic syndrome. N Engl J Med 1992;327:
755–759
24. Ray PE, Liu XH. Pathogenesis of Shiga toxin-induced
hemolytic uremic syndrome. Pediatr Nephrol 2001;16:823–
839
25. Tarr PI, Gordon CA, Chandler WL. Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome.
Lancet 2005;365:1073–1086
26. Sakiri R, Ramegowda B, Tesh VL. Shiga toxin type 1
activates tumor necrosis factor-alpha gene transcription and
nuclear translocation of the transcriptional activators
nuclear factor-kappa B and activator protein-1. Blood
1998;92:558–566
27. Nestoridi E, Tsukurov O, Kushak RI, Ingelfinger JR,
Grabowski EF. Shiga toxin enhances functional tissue
factor on human glomerular endothelial cells: implications
for the pathophysiology of hemolytic uremic syndrome. J
Thromb Haemost 2005;3:752–762
28. Ramegowda B, Tesh VL. Differentiation-associated toxin
receptor modulation, cytokine production, and sensitivity to
Shiga-like toxins in human monocytes and monocytic cell
lines. Infect Immun 1996;64:1173–1180
29. Hughes AK, Stricklett PK, Schmid D, Kohan DE.
Cytotoxic effect of Shiga toxin-1 on human glomerular
epithelial cells. Kidney Int 2000;57:2350–2359
30. Lesesne JB, Rothschild N, Erickson B, et al. Cancerassociated hemolytic-uremic syndrome: analysis of 85 cases
from a national registry. J Clin Oncol 1989;7:781–789
31. Dlott JS, Danielson CF, Blue-Hnidy DE, McCarthy LJ.
Drug-induced thrombotic thrombocytopenic purpura/
hemolytic uremic syndrome: a concise review. Ther Apher
Dial 2004;8:102–111
32. Ogier de Baulny H, Gerard M, Saudubray JM, Zittoun J.
Remethylation defects: guidelines for clinical diagnosis and
treatment. Eur J Pediatr 1998;157(suppl 2):S77–S83
33. Cabrera GR, Fortenberry JD, Warshaw BL, et al. Hemolytic uremic syndrome associated with invasive Streptococcus pneumoniae infection. Pediatrics 1998;101:699–703
34. Klein PJ, Bulla M, Newman RA, et al. ThomsenFriedenreich antigen in haemolytic-uraemic syndrome.
Lancet 1977;2:1024–1025
35. Feld LG, Springate JE, Darragh R, Fildes RD. Pneumococcal pneumonia and hemolytic uremic syndrome. Pediatr
Infect Dis J 1987;6:693–695
36. Huang FY, Lin DS. Pneumococcal meningitis complicated
with hemolytic uremic syndrome: report of two cases.
Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi
1998;39:58–61
2005
37. Noris M, Ruggenenti P, Perna A, et al. Hypocomplementemia discloses genetic predisposition to hemolytic uremic
syndrome and thrombotic thrombocytopenic purpura: role
of factor H abnormalities. Italian Registry of Familial
and Recurrent Hemolytic Uremic Syndrome/Thrombotic
Thrombocytopenic Purpura. J Am Soc Nephrol 1999;10:
281–293
38. Neumann HP, Salzmann M, Bohnert-Iwan B, et al.
Haemolytic uraemic syndrome and mutations of the
factor H gene: a registry-based study of German speaking
countries. J Med Genet 2003;40:676–681
39. Warwicker P, Goodship TH, Donne RL, et al. Genetic
studies into inherited and sporadic hemolytic uremic
syndrome. Kidney Int 1998;53:836–844
40. Richards A, Buddles MR, Donne RL, et al. Factor H
mutations in hemolytic uremic syndrome cluster in exons
18–20, a domain important for host cell recognition. Am J
Hum Genet 2001;68:485–490
41. Caprioli J, Bettinaglio P, Zipfel PF, et al. The molecular
basis of familial hemolytic uremic syndrome: mutation
analysis of factor H gene reveals a hot spot in short
consensus repeat 20. J Am Soc Nephrol 2001;12:297–307
42. Dragon-Durey MA, Fremeaux-Bacchi V, Loirat C, et al.
Heterozygous and homozygous factor H deficiencies
associated with hemolytic uremic syndrome or membranoproliferative glomerulonephritis: report and genetic analysis
of 16 cases. J Am Soc Nephrol 2004;15:787–795
43. Kavanagh D, Kemp EJ, Mayland E, et al. Mutations in
complement factor I predispose to development of atypical
hemolytic uremic syndrome. J Am Soc Nephrol 2005;16:
2150–2155
44. Noris M, Brioschi S, Caprioli J, et al. Familial haemolytic
uraemic syndrome and an MCP mutation. Lancet 2003;
362:1542–1547
45. Richards A, Kemp EJ, Liszewski MK, et al. Mutations in
human complement regulator, membrane cofactor protein
(CD46), predispose to development of familial hemolytic
uremic syndrome. Proc Natl Acad Sci USA 2003;100:
12966–12971
46. Dragon-Durey MA, Loirat C, Cloarec S, et al. Anti-factor
H autoantibodies associated with atypical hemolytic uremic
syndrome. J Am Soc Nephrol 2005;16:555–563
47. Moake JL. Thrombotic thrombocytopenic purpura and the
hemolytic uremic syndrome. Arch Pathol Lab Med 2002;
126:1430–1433
48. Levy GG, Motto DG, Ginsburg D. ADAMTS13 turns 3.
Blood 2005;106:11–17
49. Remuzzi G, Galbusera M, Noris M, et al. von Willebrand
factor cleaving protease (ADAMTS13) is deficient in
recurrent and familial thrombotic thrombocytopenic purpura
and hemolytic uremic syndrome. Blood 2002;100:778–785
50. Veyradier A, Obert B, Haddad E, et al. Severe deficiency of
the specific von Willebrand factor-cleaving protease
(ADAMTS 13) activity in a subgroup of children with
atypical hemolytic uremic syndrome. J Pediatr 2003;142:
310–317
51. Moghal NE, Brocklebank JT, Meadow SR. A review of
acute renal failure in children: incidence, etiology and
outcome. Clin Nephrol 1998;49:91–95
52. Verweyen HM, Karch H, Allerberger F, Zimmerhackl
LB. Enterohemorrhagic Escherichia coli (EHEC) in pediatric hemolytic-uremic syndrome: a prospective study in
Germany and Austria. Infection 1999;27:341–347
TTP AND HUS IN CHILDREN AND ADOLESCENTS/LOWE, WERNER
53. Brandt JR, Fouser LS, Watkins SL, et al. Escherichia coli O
157:H7-associated hemolytic-uremic syndrome after ingestion of contaminated hamburgers. J Pediatr 1994;125:
519–526
54. Tarr PI, Fouser LS, Stapleton AE, et al. Hemolytic-uremic
syndrome in a six-year-old girl after a urinary tract infection
with Shiga-toxin-producing Escherichia coli O103:H2.
N Engl J Med 1996;335:635–638
55. Miller DP, Kaye JA, Shea K, et al. Incidence of thrombotic
thrombocytopenic purpura/hemolytic uremic syndrome.
Epidemiology 2004;15:208–215
56. Rangel JM, Sparling PH, Crowe C, Griffin PM, Swerdlow
DL. Epidemiology of Escherichia coli O157:H7 outbreaks,
United States, 1982–2002. Emerg Infect Dis 2005;11:
603–609
57. Wong CS, Jelacic S, Habeeb RL, Watkins SL, Tarr PI. The
risk of the hemolytic-uremic syndrome after antibiotic
treatment of Escherichia coli O157:H7 infections. N Engl J
Med 2000;342:1930–1936
58. Bell BP, Griffin PM, Lozano P, et al. Predictors of
hemolytic uremic syndrome in children during a large
outbreak of Escherichia coli O157:H7 infections. Pediatrics
1997;100:E12
59. Lopez EL, Contrini MM, Devoto S, et al. Incomplete
hemolytic-uremic syndrome in Argentinean children with
bloody diarrhea. J Pediatr 1995;127:364–367
60. Brandt J, Wong C, Mihm S, et al. Invasive pneumococcal
disease and hemolytic uremic syndrome. Pediatrics 2002;
110:371–376
61. Brandt JR, Joseph MW, Fouser LS, et al. Cholelithiasis
following Escherichia coli O157:H7-associated hemolytic
uremic syndrome. Pediatr Nephrol 1998;12:222–225
62. Constantinescu AR, Bitzan M, Weiss LS, et al. Nonenteropathic hemolytic uremic syndrome: causes and shortterm course. Am J Kidney Dis 2004;43:976–982
63. Siegler RL. Spectrum of extrarenal involvement in postdiarrheal hemolytic-uremic syndrome. J Pediatr 1994;125:511–
518
64. Trompeter RS, Schwartz R, Chantler C, et al. Haemolyticuraemic syndrome: an analysis of prognostic features. Arch
Dis Child 1983;58:101–105
65. Siegler RL, Pavia AT, Hansen FL, Christofferson RD,
Cook JB. Atypical hemolytic-uremic syndrome: a comparison with postdiarrheal disease. J Pediatr 1996;128:505–511
66. Onundarson PT, Rowe JM, Heal JM, Francis CW.
Response to plasma exchange and splenectomy in thrombotic thrombocytopenic purpura. A 10-year experience at a
single institution. Arch Intern Med 1992;152:791–796
67. Karch H, Bielaszewska M. Sorbitol-fermenting Shiga toxinproducing Escherichia coli O157:H(-) strains: epidemiology,
phenotypic and molecular characteristics, and microbiological diagnosis. J Clin Microbiol 2001;39:2043–2049
68. Zipfel PF, Neumann HP, Jozsi M. Genetic screening in
haemolytic uraemic syndrome. Curr Opin Nephrol Hypertens 2003;12:653–657
69. Fenton W, Rosenberg L. Disorders of propionate and
methylmalonate metabolism. In: Scriver C, Baudet A, Sly W,
Valle D, eds. Metaboloic and Molecular Basis of Inherited
Disease. New York: McGraw-Hill; 2001:2165–2193
70. Ake JA, Jelacic S, Ciol MA, et al. Relative nephroprotection
during Escherichia coli O157:H7 infections: association with
intravenous volume expansion. Pediatrics 2005;115:e673–
e680
71. Dowling TC, Chavaillaz PA, Young DG, et al. Phase 1
safety and pharmacokinetic study of chimeric murinehuman monoclonal antibody c alpha Stx2 administered
intravenously to healthy adult volunteers. Antimicrob
Agents Chemother 2005;49:1808–1812
72. Karmali MA. Prospects for preventing serious systemic
toxemic complications of Shiga toxin-producing Escherichia
coli infections using Shiga toxin receptor analogues. J Infect
Dis 2004;189:355–359
73. Bell BP, Goldoft M, Griffin PM, et al. A multistate
outbreak of Escherichia coli O157:H7-associated bloody
diarrhea and hemolytic uremic syndrome from hamburgers.
The Washington experience. JAMA 1994;272:1349–1353
74. Licht C, Weyersberg A, Heinen S, et al. Successful plasma
therapy for atypical hemolytic uremic syndrome caused
by factor H deficiency owing to a novel mutation in the
complement cofactor protein domain 15. Am J Kidney Dis
2005;45:415–421
75. Nathanson S, Fremeaux-Bacchi V, Deschenes G. Successful
plasma therapy in hemolytic uremic syndrome with factor H
deficiency. Pediatr Nephrol 2001;16:554–556
76. Loirat C, Niaudet P. The risk of recurrence of hemolytic
uremic syndrome after renal transplantation in children.
Pediatr Nephrol 2003;18:1095–1101
77. Ducloux D, Rebibou JM, Semhoun-Ducloux S, et al.
Recurrence of hemolytic-uremic syndrome in renal transplant recipients: a meta-analysis. Transplantation 1998;65:
1405–1407
78. Quan A, Sullivan EK, Alexander SR. Recurrence of
hemolytic uremic syndrome after renal transplantation in
children: a report of the North American Pediatric Renal
Transplant Cooperative Study. Transplantation 2001;72:
742–745
79. Cheong HI, Lee BS, Kang HG, et al. Attempted treatment
of factor H deficiency by liver transplantation. Pediatr
Nephrol 2004;19:454–458
80. Moschcowitz E. Hyaline thrombosis of the terminal
arterioles and capillaries: a hitherto undescribed disease.
Proc NY Pathol Soc 1924;24:21–24
81. Colige A, Sieron AL, Li SW, et al. Human Ehlers-Danlos
syndrome type VII C and bovine dermatosparaxis are caused
by mutations in the procollagen I N-proteinase gene. Am J
Hum Genet 1999;65:308–317
82. Dagoneau N, Benoist-Lasselin C, Huber C, et al.
ADAMTS10 mutations in autosomal recessive WeillMarchesani syndrome. Am J Hum Genet 2004;75:801–806
83. Levy GG, Nichols WC, Lian EC, et al. Mutations in a
member of the ADAMTS gene family cause thrombotic
thrombocytopenic purpura. Nature 2001;413:488–494
84. Schulman I, Pierce M, Lukens A, Currimbhoy Z. Studies
on thrombopoiesis, I: a factor in normal human plasma
required for platelet production; chronic thrombocytopenia
due to its deficiency. Blood 1960;16:943–957
85. Upshaw JD Jr. Congenital deficiency of a factor in normal
plasma that reverses microangiopathic hemolysis and
thrombocytopenia. N Engl J Med 1978;298:1350–1352
86. Schneppenheim R, Budde U, Oyen F, et al. von Willebrand
factor cleaving protease and ADAMTS13 mutations in
childhood TTP. Blood 2003;101:1845–1850
87. Jubinsky PT, Moraille R, Tsai HM. Thrombotic thrombocytopenic purpura in a newborn. J Perinatol 2003;23:85–87
88. Kinoshita S, Yoshioka A, Park YD, et al. UpshawSchulman syndrome revisited: a concept of congenital
727
728
SEMINARS IN THROMBOSIS AND HEMOSTASIS/VOLUME 31, NUMBER 6
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
thrombotic thrombocytopenic purpura. Int J Hematol
2001;74:101–108
Chintagumpala MM, Hurwitz RL, Moake JL, Mahoney
DH, Steuber CP. Chronic relapsing thrombotic thrombocytopenic purpura in infants with large von Willebrand factor
multimers during remission. J Pediatr 1992;120:49–53
Matsumoto M, Kokame K, Soejima K, et al. Molecular
characterization of ADAMTS13 gene mutations in Japanese patients with Upshaw-Schulman syndrome. Blood
2004; 103:1305–1310
Schiff DE, Roberts WD, Willert J, Tsai HM. Thrombocytopenia and severe hyperbilirubinemia in the neonatal
period secondary to congenital thrombotic thrombocytopenic purpura and ADAMTS13 deficiency. J Pediatr Hematol
Oncol 2004;26:535–538
Burle S, Passi GR, Salgia P, Modi A. Thrombotic
thrombocytopenic purpura. Indian Pediatr 2004;41:277–
279
Elias M, Horowitz J, Tal I, Kohn D, Flatau E. Thrombotic
thrombocytopenic purpura and haemolytic uraemic syndrome in three siblings. Arch Dis Child 1988;63:644–
646
Buyukavci M, Olgun H, Kertmen B, Tan H, Ceviz N.
Ventricular tachycardia as a presenting symptom in a
child with thrombotic thrombocytopenic purpura. Thromb
Haemost 2004;91:198–200
Allford SL, Harrison P, Lawrie AS, et al. Von Willebrand
factor–cleaving protease activity in congenital thrombotic
thrombocytopenic purpura. Br J Haematol 2000;111:1215–
1222
Barbot J, Costa E, Guerra M, et al. Ten years of
prophylactic treatment with fresh-frozen plasma in a child
with chronic relapsing thrombotic thrombocytopenic purpura as a result of a congenital deficiency of von Willebrand
factor-cleaving protease. Br J Haematol 2001;113:649–651
Savasan S, Lee SK, Ginsburg D, Tsai HM. ADAMTS13
gene mutation in congenital thrombotic thrombocytopenic
purpura with previously reported normal VWF cleaving
protease activity. Blood 2003;101:4449–4451
Haberle J, Kehrel B, Ritter J, et al. New strategies in
diagnosis and treatment of thrombotic thrombocytopenic
purpura: case report and review. Eur J Pediatr 1999;158:
883–887
Cohen JA, Brecher ME, Bandarenko N. Cellular source of
serum lactate dehydrogenase elevation in patients with
thrombotic thrombocytopenic purpura. J Clin Apher 1998;
13:16–19
Furlan M, Robles R, Galbusera M, et al. von Willebrand
factor-cleaving protease in thrombotic thrombocytopenic
purpura and the hemolytic-uremic syndrome. N Engl J Med
1998;339:1578–1584
Furlan M, Robles R, Solenthaler M, et al. Deficient activity
of von Willebrand factor-cleaving protease in chronic
relapsing thrombotic thrombocytopenic purpura. Blood
1997;89:3097–3103
Mannucci PM, Lombardi R, Lattuada A, et al. Enhanced
proteolysis of plasma von Willebrand factor in thrombotic
thrombocytopenic purpura and the hemolytic uremic
syndrome. Blood 1989;74:978–983
Moake JL, Rudy CK, Troll JH, et al. Unusually large plasma
factor VIII:von Willebrand factor multimers in chronic
relapsing thrombotic thrombocytopenic purpura. N Engl J
Med 1982;307:1432–1435
2005
104. van Mourik JA, Boertjes R, Huisveld IA, et al. von
Willebrand factor propeptide in vascular disorders: A tool
to distinguish between acute and chronic endothelial cell
perturbation. Blood 1999;94:179–185
105. Savasan S, Taub JW, Buck S, et al. Congenital microangiopathic hemolytic anemia and thrombocytopenia with
unusually large von Willebrand factor multimers and von
Willebrand factor-cleaving protease. J Pediatr Hematol
Oncol 2001;23:364–367
106. Katz JA, Moake JL, McPherson PD, et al. Relationship
between human development and disappearance of unusually large von Willebrand factor multimers from plasma.
Blood 1989;73:1851–1858
107. Tsai HM, Sarode R, Downes KA. Ultralarge von Willebrand factor multimers and normal ADAMTS13 activity
in the umbilical cord blood. Thromb Res 2002;108:121–125
108. Weinstein MJ, Blanchard R, Moake JL, Vosburgh E, Moise
K. Fetal and neonatal von Willebrand factor (vWF) is
unusually large and similar to the vWF in patients with
thrombotic thrombocytopenic purpura. Br J Haematol
1989; 72:68–72
109. Hellstrom-Westas L, Ley D, Berg AC, Kristoffersson AC,
Holmberg L. VWF-cleaving protease (ADAMTS13) in
premature infants. Acta Paediatr 2005;94:205–210
110. Kavakli K, Canciani MT, Mannucci PM. Plasma levels of
the von Willebrand factor-cleaving protease in physiological
and pathological conditions in children. Pediatr Hematol
Oncol 2002;19:467–473
111. Mannucci PM, Canciani MT, Forza I, et al. Changes in
health and disease of the metalloprotease that cleaves von
Willebrand factor. Blood 2001;98:2730–2735
112. Schmugge M, Dunn MS, Amankwah KS, et al. The activity
of the von Willebrand factor cleaving protease ADAMTS13 in newborn infants. J Thromb Haemost 2004;2:228–
233
113. Assink K, Schiphorst R, Allford S, et al. Mutation analysis
and clinical implications of von Willebrand factor-cleaving
protease deficiency. Kidney Int 2003;63:1995–1999
114. Kokame K, Miyata T. Genetic defects leading to hereditary
thrombotic thrombocytopenic purpura. Semin Hematol
2004;41:34–40
115. Schneppenheim R, Budde U, Hassenpflug W, Obser T.
Severe ADAMTS-13 deficiency in childhood. Semin
Hematol 2004;41:83–89
116. Furlan M, Robles R, Morselli B, Sandoz P, Lämmle B.
Recovery and half-life of von Willebrand factor-cleaving
protease after plasma therapy in patients with thrombotic
thrombocytopenic purpura. Thromb Haemost 1999;81:8–13
117. Kentouche K, Budde U, Furlan M, et al. Remission of
thrombotic thrombocytopenic purpura in a patient with
compound heterozygous deficiency of von Willebrand
factor-cleaving protease by infusion of solvent/detergent
plasma. Acta Paediatr 2002;91:1056–1059
118. Moake JL, Byrnes JJ, Troll JH, et al. Effects of fresh-frozen
plasma and its cryosupernatant fraction on von Willebrand
factor multimeric forms in chronic relapsing thrombotic
thrombocytopenic purpura. Blood 1985;65:1232–1236
119. Moake J, Chintagumpala M, Turner N, et al. Solvent/
detergent-treated plasma suppresses shear-induced platelet
aggregation and prevents episodes of thrombotic thrombocytopenic purpura. Blood 1994;84:490–497
120. Brunner HI, Freedman M, Silverman ED. Close relationship between systemic lupus erythematosus and thrombotic
TTP AND HUS IN CHILDREN AND ADOLESCENTS/LOWE, WERNER
121.
122.
123.
124.
125.
126.
126a.
127.
128.
129.
130.
131.
132.
133.
134.
thrombocytopenic purpura in childhood. Arthritis Rheum
1999;42:2346–2355
Chak WK, Lam DS, Lo WH, Hui CM, Wong SN.
Thrombotic thrombocytopenic purpura as a rare complication in childhood systemic lupus erythematosus: case report
and literature review. Hong Kong Med J 2003;9:363–368
Gungor T, Furlan M, Lämmle B, Kuhn F, Seger RA.
Acquired deficiency of von Willebrand factor-cleaving
protease in a patient suffering from acute systemic
lupus erythematosus. Rheumatology (Oxford) 2001;40:
940–942
Studt JD, Hovinga JA, Radonic R, et al. Familial acquired
thrombotic thrombocytopenic purpura: ADAMTS13 inhibitory autoantibodies in identical twins. Blood 2004;103:
4195–4197
Elliott MA, Nichols WL Jr, Plumhoff EA, et al. Posttransplantation thrombotic thrombocytopenic purpura: a
single-center experience and a contemporary review. Mayo
Clin Proc 2003;78:421–430
Fuge R, Bird JM, Fraser A, et al. The clinical features, risk
factors and outcome of thrombotic thrombocytopenic
purpura occurring after bone marrow transplantation. Br J
Haematol 2001;113:58–64
Ruutu T, Hermans J, Niederwieser D, et al. Thrombotic
thrombocytopenic purpura after allogeneic stem cell transplantation: a survey of the European Group for Blood and
Marrow Transplantation (EBMT). Br J Haematol 2002;
118:1112–1119
Uderzo C, Funagalii M, DeLorenzo P, et al. Impact of
thrombotic thrombocytopenic purpura on leukemic children
undergoing bone marrow transplantation. Bone Marrow
Transplant 2000;26:1005–1009
Arai S, Allan C, Streiff M, et al. Von Willebrand factorcleaving protease activity and proteolysis of von Willebrand
factor in bone marrow transplant-associated thrombotic
microangiopathy. Hematol J 2001;2:292–299
van der Plas RM, Schiphorst ME, Huizinga EG, et al. von
Willebrand factor proteolysis is deficient in classic, but not
in bone marrow transplantation-associated, thrombotic
thrombocytopenic purpura. Blood 1999;93:3798–3802
Ashida A, Nakamura H, Yoden A, et al. Successful
treatment of a young infant who developed high-titer
inhibitors against VWF-cleaving protease (ADAMTS-13):
important discrimination from Upshaw-Schulman syndrome. Am J Hematol 2002;71:318–322
Horton TM, Stone JD, Yee D, et al. Case series of
thrombotic thrombocytopenic purpura in children and
adolescents. J Pediatr Hematol Oncol 2003;25:336–339
Robson WL, Tsai HM. Thrombotic thrombocytopenic
purpura attributable to von Willebrand factor-cleaving
protease inhibitor in an 8-year-old boy. Pediatrics 2002;
109:322–325
Hunt BJ, Lämmle B, Nevard CH, Haycock GB, von Furlan
M. Willebrand factor-cleaving protease in childhood
diarrhoea-associated haemolytic uraemic syndrome.
Thromb Haemost 2001;85:975–978
Rock G, Shumak K, Nair R. A study of plasma exchange in
TTP. The Canadian Apheresis Study Group. Prog Clin
Biol Res 1990;337:125–127
Bell WR, Braine HG, Ness PM, Kickler TS. Improved
survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Clinical experience in 108 patients.
N Engl J Med 1991;325:398–403
135. George JN. How I treat patients with thrombotic
thrombocytopenic purpura-hemolytic uremic syndrome.
Blood 2000; 96:1223–1229
136. Lara PN Jr, Coe TL, Zhou H, et al. Improved survival with
plasma exchange in patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Am J Med
1999; 107:573–579
137. George JN, Sadler JE, Lämmle B. Platelets: thrombotic
thrombocytopenic purpura. Hematology (Am Soc Hematol
Educ Program) 2002:315–334
138. Perdue JJ, Chandler LK, Vesely SK, et al. Unintentional
platelet removal by plasmapheresis. J Clin Apher 2001;16:
55–60
139. Coppo P, Bussel A, Charrier S, et al. High-dose plasma
infusion versus plasma exchange as early treatment of
thrombotic thrombocytopenic purpura/hemolytic-uremic
syndrome. Medicine (Baltimore) 2003;82:27–38
140. Bobbio-Pallavicini E, Gugliotta L, Centurioni R, et al.
Antiplatelet agents in thrombotic thrombocytopenic purpura (TTP). Results of a randomized multicenter trial by the
Italian Cooperative Group for TTP. Haematologica 1997;
82:429–435
141. Jayabose S, Levendoglu-Tugal O, Ozkayanak MF, et al.
Use of vincristine and cyclosporine in childhood thrombotic
thrombocytopenic purpura. J Pediatr Hematol Oncol 2003;
25:421–425
142. Welborn JL, Emrick P, Acevedo M. Rapid improvement of
thrombotic thrombocytopenic purpura with vincristine and
plasmapheresis. Am J Hematol 1990;35:18–21
143. Hand JP, Lawlor ER, Yong CK, Davis JH. Successful use of
cyclosporine A in the treatment of refractory thrombotic
thrombocytopenic purpura. Br J Haematol 1998;100:597–
599
144. Kondo H, Imamura T. Effects of intravenous immunoglobulin in a patient with intermittent thrombotic thrombocytopenic purpura. Br J Haematol 2000;108:880–882
145. Dervenoulas J, Tsirigotis P, Bollas G, et al. Efficacy of
intravenous immunoglobulin in the treatment of thrombotic
thrombocytopaenic purpura. A study of 44 cases. Acta
Haematol 2001;105:204–208
146. Koulova L, Alexandrescu D, Dutcher JP, et al. Rituximab
for the treatment of refractory idiopathic thrombocytopenic
purpura (ITP) and thrombotic thrombocytopenic purpura
(TTP): report of three cases. Am J Hematol 2005;78:
49–54
147. Fakhouri F, Vernant JP, Veyradier A, et al. Efficiency of
curative and prophylactic treatment with rituximab in
ADAMTS13 deficient-thrombotic thrombocytopenic purpura: a study of 11 cases. Blood 2005. In press
148. Crowther MA, Heddle N, Hayward CP, Warkentin T,
Kelton JG. Splenectomy done during hematologic remission to prevent relapse in patients with thrombotic
thrombocytopenic purpura. Ann Intern Med 1996;125:
294–296
149. Thompson CE, Damon LE, Ries CA, Linker CA.
Thrombotic microangiopathies in the 1980s: clinical
features, response to treatment, and the impact of the
human immunodeficiency virus epidemic. Blood 1992;80:
1890–1895
150. Schwartz J, Eldor A, Szold A. Laparoscopic splenectomy
in patients with refractory or relapsing thrombotic
thrombocytopenic purpura. Arch Surg 2001;136:1236–
1238
729