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858 PART 7: Hematologic and Oncologic Disorders

CHAPTER TTP, HUS, and be superimposed. In the past decade, major progress has been made in
our understanding of the pathogenesis of TTP and HUS, as well as other
91 Other Thrombotic condition- or disease-specific thrombotic microangiopathies (TMAs), 15-18
which provide a molecular basis for the development of rapid and
Microangiopathies accurate diagnosis, as well as effective therapeutic strategies for these
potentially fatal syndromes.
X. Long Zheng
Nilam Mangalmurti
CLASSIFICATION
■
KEY POINTS TTP
• Thrombotic microangiopathy (TMA), a pathologic term, describes TTP can be classified into two major forms: hereditary TTP and
a syndrome of microangiopathic hemolytic anemia (MAHA) and acquired TTP. Hereditary TTP, also known as Upshaw-Schulman
3,4,19,20
thrombocytopenia with various degrees of organ dysfunction. syndrome, comprises only ∼5% of TTP cases, primarily seen in
• TMA includes thrombotic thrombocytopenic purpura (TTP) and neonates and young children, and occasionally in adults. In children,
acute episodes are often triggered by upper respiratory or gastro-
hemolytic uremic syndromes (HUS), as well as other related syndromes. intestinal infections. 21,22 In women, the acute episode may often be
• TTP is primarily caused by hereditary or acquired deficiency of triggered by pregnancy, and it is sometimes difficult to differentiate
plasma ADAMTS13, whereas HUS is mainly caused by Shiga TTP from pregnancy-associated complications. 21,23-26 An intermittent
toxin–producing E coli and/or abnormalities of complement acti- infusion of fresh frozen plasma (FFP) appears to be effective for treat-
vation and regulation. ment of hereditary TTP. 19,21,27 Acquired TTP is more common with an
28
• TTP should be differentiated from HUS, disseminated intravas- annual incidence rate of 3 to 10 cases per million residents or more.
cular coagulation (DIC), collagen vascular disease with vasculitis, It comprises ∼95% of cases; the etiologies of acquired TTP are quite
and Hemolytic anemia, Elevated Liver enzymes, and Low Platelets) heterogeneous. Approximately 50% of cases occur in patients without
(HELLP) syndrome, etc. evidence of a disease or a condition that is known to cause TTP, a con-
• Plasma therapy remains the mainstay of therapy for TTP and dition called idiopathic TTP. 22,27,29,30 However, the other 50% of the cases
may be associated with pregnancy/postpartum, infection (HIV),
31-33
atypical HUS (aHUS). However, the treatment for aHUS has been hematopoietic progenitor cell transplantation, 34-36 disseminated
less satisfactory. Adjunctive therapies such as corticosteroids, malignancies, 37-39 and certain drugs such as mitomycin 36,40,41 or ticlopi-
immunosuppressive agents, and anti-CD20 monoclonal antibod- dine/clopidogrel, 42-44 etc. These patients are known as having nonidio-
ies such as rituximab or anti-C5 monoclonal antibodies such as pathic TTP 45,46 or in many cases HUS 18,47-49 in the literature. Whether
eculizumab may be considered for refractory TTP or HUS cases.
these patients should be classified into TTP, a disease/condition-
specific TMA, or HUS remains a subject of controversy. Further inves-
tigation of the molecular mechanisms of these patients may provide
INTRODUCTION the basis for the classification, diagnosis, and installation of effective
treatment. Plasma exchange therapy has been offered to all patients
Thrombotic thrombocytopenic purpura (TTP) was first described by Eli
Moschcowitz in 1924. He reported a previously unrecognized case of a with MAHA and thrombocytopenia. The mortality rate has been dra-
1
11,50-53
16-year-old girl presenting with a constellation of findings including palor, matically reduced in patients with idiopathic TTP, but less so in
53,54
petechiae, fever, and hemiparesis which ultimately was fatal. Postmortem those with nonidiopathic TTP or HUS.
and capillaries. After reviewing 271 cases, Amorosi and Ultmann in 1966 ■ HUS
examination revealed numerous hyaline thrombi in the terminal arterioles
1
2
established a diagnostic pentad for TTP: thrombocytopenia, MAHA, neu- HUS may be classified into two major forms: diarrhea positive (D+) (or
rologic symptoms, renal failure, and fever without origin. Later, Schulman typical) HUS and diarrhea negative (D−) (or atypical) HUS. D+HUS
et al (1960) reported a patient with this syndrome whose symptoms were occurs 4 to 6 days after the onset of a diarrheal prodrome. 55-59 Over
dramatically improved with infusions of fresh human plasma (FFP). 70% of the cases, particularly in the pediatric population, have been
3
Again, Upshaw (I978) reported a case of 29-year-old female who had reported to have bloody diarrhea. Approximately 60% of D+HUS
4
repeated thrombocytopenia and MAHA since her childhood. However, cases are caused by E coli O157 : H7 stain. 57-59 The other strains of Shiga
her conditions were improved sometime either spontaneously or after toxin–producing organisms such as Shigella dysenteriae, citrobacter
infusion of fresh frozen plasma. Upshaw and Schulman hypothesized that freundii, and additional E coli (O104 : H4, O26, O111, and O145) are
a plasma factor that is required for platelet production or platelet and also described to cause D+ HUS. 60,61 In a recent German outbreak,
3
red blood cell survival was missing. However, the mechanism of TTP O104 : H4 was responsible for 845 cases of D+HUS. 60,61 The progno-
4
remained a mystery until 2001 when a plasma metalloprotease that cleaves sis for HUS associated with E coli O157 : H7 is usually excellent after
von Willebrand factor (VWF) was identified and cloned. 7,8 supportive care. However, complicated courses are observed in cases
5,6
Hemolytic uremic syndrome (HUS), a similar syndrome, was first of D+HUS caused by O104 : H4 and combined therapies are required
described by Gasser et al in 1955. Five children, aged 2 months to to reduce the mortality rate. 60,62 Atypical HUS (aHUS) is rare, with an
9
7 years, presented with acquired hemolytic anemia, bizarre poikilocytes, annual incidence rate of two cases per million residents. The causes
and renal insufficiency. Three had thrombocytopenia and all patients of aHUS are quite heterogeneous, but ultimately lead to complement
died. Later, Kaplan et al (1975) reported 83 siblings from 41 families activation and prothrombotic status at the site of vascular injury. In
10
15
with HUS and suggested that both genetic and environmental factors recent years, aHUS instead of D-HUS is more commonly used in the
might have contributed to the occurrence of familial cases of HUS. Since literature as some of the aHUS cases can be triggered by gastrointestinal
then, numerous HUS cases were reported. 11-14 HUS is used to describe infection. Approximately 60% of cases are associated with mutations in
a syndrome with MAHA, thrombocytopenia, and predominant renal one or several complement regulators or activators. 63-65 Plasma exchange
failure in the presence or absence of diarrheal prodrome. has been shown to reduce the severity of thrombocytopenia, but not to
While the clinical signs and symptoms of HUS appear to be indis- prevent the progression of aHUS cases to end-stage renal failure (ESRF).
tinguishable from TTP, the underlying etiologies and the molecular The risk for ESRF and death in patients with aHUS are reported to be
mechanisms of the disease may be quite different. In rare cases, they may 50% and 25%, respectively, 63-65 despite aggressive therapy.

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