CURRENT CONCEPTS IN THROMBOTIC THROMBOCYTOPENIC PURPURA

24 Dec 2005 16:38 AR ANRV262-ME57-26.tex XMLPublishSM(2004/02/24) P1: KUV10.1146/annurev.med.57.061804.084505

Annu. Rev. Med. 2006. 57:419–36doi: 10.1146/annurev.med.57.061804.084505

Copyright c© 2006 by Annual Reviews. All rights reservedFirst published online as a Review in Advance on Oct. 3, 2005

CURRENT CONCEPTS IN THROMBOTIC

THROMBOCYTOPENIC PURPURA

Han-Mou TsaiDivision of Hematology, Albert Einstein College of Medicine and Montefiore MedicalCenter, Bronx, New York 10467; email: [email protected]

Key Words von Willebrand factor, ADAMTS13, shear stress, hemolytic uremicsyndrome

■ Abstract Recent advances have demonstrated that thrombotic thrombocytopenicpurpura (TTP), characterized by widespread thrombosis in the arterioles and capillaries,is caused by deficiency of a circulating zinc metalloprotease, ADAMTS13. Two types ofTTP are recognized: autoimmune TTP, caused by inhibitory antibodies of ADAMTS13,and hereditary TTP, caused by genetic mutations of ADAMTS13. This article reviewsthe characteristics and function of ADAMTS13, the mechanism by which ADAMTS13deficiency may lead to thrombosis, and the causes of ADAMTS13 deficiency. It alsodiscusses how the new knowledge may improve the diagnosis and treatment of thispreviously mysterious disorder.

INTRODUCTION

Thrombotic thrombocytopenic purpura (TTP), first described in 1924 by Mosch-cowitz, is characterized by the presence of hyaline thrombi in the arterioles andcapillaries of multiple organs. Patients typically present with weakness, pallor,petechiae, headache, or subtle mental changes (1, 2). If not treated, the diseasemay rapidly deteriorate to stupor, coma, cardiac arrest, and demise. The use ofplasma infusion and plasma exchange to treat TTP has reduced its case fatality from>90% to 10%–20% (3). Because its etiologies were unknown, its pathogenesismysterious, and its response to plasma therapy seemingly miraculous, TTP hasbeen the subject of intense interest. In the past few years, advances in elucidatingthe molecular defects behind TTP have raised new hopes of improving diagnosisand treatment.

The incidence of TTP has been estimated at 3–4 per million person-years (4,5). Blacks, and black females in particular, are affected at a disproportionatelyhigh rate. One study reported an increasing trend of the disease between 1968and 1991 (4); however, a more recent study failed to detect such a trend (5). Thesestudies were based on death certificates, insurance claims, or practice managementdatabases, whose criteria of disease classification may differ and do not necessarilyconform to the current disease definition.

0066-4219/06/0218-0419$20.00 419

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420 TSAI

CLINICAL FEATURES

Histopathologically, the changes of TTP are quite distinctive: widespread hyalinethrombi in the terminal arterioles and capillaries, which may (depending on the ageof the lesions) be accompanied by variable fibroblastic infiltration and endothelialoverlay. The thrombi are most extensive in the brain (mainly cerebral cortex),heart, spleen, pancreas, adrenal gland, and kidney, and are composed primarily ofdegranulated platelets and von Willebrand factor (6, 7). Small amounts of fibrinmay be present, surrounding or sometimes penetrating the amorphous or granularmaterials. This contrasts to the thrombi of disseminated intravascular coagulationor the hemolytic uremic syndrome (HUS), which are enriched in prominent fibrindeposits (7, 8). Endothelial or subendothelial swelling is minimal in TTP but moreprominent in shiga toxin–associated or idiopathic HUS. Glomerular thrombi in thekidney per se are not pathognomonic of TTP as they are a common feature of HUS.In contrast to HUS, TTP causes spotty rather than extensive glomerular thrombi.

Clinically, two types of TTP are recognized: a hereditary form that often presentssoon after birth and an autoimmune form that affects adolescents or adults. Mostcases of TTP are of the autoimmune type.

Autoimmune TTP

The classic features of TTP have been extensively reviewed (2). Thrombocytope-nia, microangiopathic hemolysis, and fleeting neurological deficits (triad), plusfever and renal abnormalities (pentad), are characteristic but not pathognomonicof TTP. Other complications include abdominal pain with or without evidence ofpancreatitis and EKG abnormalities. Pulmonary or liver dysfunction is rare. Aconstellation of vague symptoms may precede the onset of serious illness. Thesesymptoms may be due to a prodrome event or the early stage of the disease.Occasionally a patient may present with isolated thrombocytopenia that lasts forweeks or months and be incorrectly presumed to have immune thrombocytopenicpurpura, before developing microangiopathic hemolysis and other complications.Although hematuria and proteinuria are common, overt renal failure or oliguria israre in TTP, unless it is caused by a concurrent disorder.

Relapse of TTP occurs in 30%–60% of cases (9, 10), with most relapses occur-ring during the first month after the acute episode and less frequently thereafter.The periods between relapses may range from days to many years. Pregnancy,surgery, diarrhea, and infection are suspected to trigger relapses. However, manycases do not have obvious precipitating events. A subset of patients develop mul-tiple relapses or have persistent disease, requiring long-term plasma exchange orother therapies.

Follow-up observations in patients who survive the acute episode of TTP revealthat when the disease relapses, it often begins with a decline of the platelet countbefore hemolysis or other manifestations become apparent. The disease evolvesvariably, ranging from rapid deterioration within a few days to smoldering for

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THROMBOTIC THROMBOCYTOPENIC PURPURA 421

TABLE 1 A classification of disorders associated with microvascular thrombosis

Disorder Molecular or cellular defect

Thrombotic thrombocytopenic purpura ADAMTS13 deficiencyAutoimmune Inhibitors of ADAMTS13Idiopathic —

Secondary Ticlopidine-induced inhibitorsHereditary Mutations of ADAMTS13

Hemolytic uremic syndromeTypical Shiga toxinsAtypical Mutations of regulators of complement

activationa

Antibodies of factor HBone marrow transplantation UnknownSolid organ transplantation UnknownDrugsb UnknownLupus and related disorders Vasculitis?Intravascular procedures Unknown

Non-TTP, non-HUSMetastatic neoplasm Embolism of cancer cellsParoxysmal nocturnal hemoglobinuria Somatic mutation of phatidylinositol glycan

class A gene (PIG-A)HELLP syndrome UnknownDisseminated intravascular coagulopathy MiscellaneousRocky Mountain spotted fever, anthrax Endothelial injury?

aMutations in Factor H, membrane cofactor protein (CD46), or protein I.bExamples include cyclosporin A, gemcitabine, mitomycin C, and cocaine.

weeks or months. Occasionally, focal neurological deficits such as hemiparesis,slurred speech, or aphasia may occur early in the course. Such neurological com-plications may pose a diagnostic challenge when they precede thrombocytopeniaor microangiopathic hemolysis (11, 12).

As mentioned, the triad or pentad of manifestations is not pathognomonic ofTTP; they may be present in patients with other disorders, such as HUS, lupuserythematosus, or allogeneic bone marrow transplantation (Table 1). The trend ofmaking a diagnosis of TTP at an early stage further contributes to uncertainty orconfusion in disease classification. The introduction of the ADAMTS13 assay asa specific test of TTP has helped clarify the diagnosis in bewildering cases.

Hereditary TTP

Upshaw-Schulman syndrome, characterized by thrombocytopenia and microan-giopathic hemolysis, represents the congenital form of TTP (13, 14). Patientstypically improve swiftly following infusion of a small (10–15 ml/kg) plasmainfusion (13–15).

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422 TSAI

Most cases of hereditary TTP are manifest soon after birth, although its presenceis not always recognized. The neonates typically develop hyperbilirubinemia andthrombocytopenia within a few hours after birth. Hemolysis with schistocytes maybe noted on blood smears. Serious complications such as seizures and mental ob-tundation may raise suspicion of intracranial hemorrhage or sepsis. Improvementoccurs promptly after simple blood transfusion or exchange transfusion. After vari-able periods ranging from weeks to years, patients relapse with thrombocytopeniaand anemia. Occasionally the disease course may be complicated with pancreatitis,focal neurological deficits, seizures, or acute renal failure. Because hereditary TTPis relatively obscure and a family history is often unremarkable for this autosomalrecessive disease, it might be mistaken as idiopathic thrombocytopenic purpura,Evan’s syndrome, or HUS. When the disease presents or relapses after the firstfew years of life, a distinction from idiopathic TTP may not be obvious.

The severity of hereditary TTP varies. Many patients require regular plasmainfusion every 2–4 weeks to prevent serious complications. These cases havebeen identified as chronic relapsing TTP in the literature. Others may maintainnormal platelet counts and only require plasma infusion intermittently. Becausesome patients have mild or subclinical disease, the hereditary form of TTP isprobably more prevalent than currently recognized (16). It is important to establishthe diagnosis in mild cases in order to facilitate appropriate management whenpatients do present with acute complications. No phenotypic abnormality has beenestablished among carriers of one mutant ADAMTS13 allele. Nevertheless, familymembers with ADAMTS13 deficiency were instrumental in the cloning of thegene and establishing its role in causing TTP (17).

The variable severity of hereditary TTP suggests that other factors affect itsmanifestation. Three types of factors appear to contribute to the variability ofTTP: the specific types of ADAMTS13 mutations, other disease-modifying genes,and environmental factors such as fever, infection, diarrhea, surgery, or pregnancy.Further studies are needed to delineate how these factors affect the phenotypicseverity of ADAMTS13 deficiency.

MOLECULAR MECHANISMS OF THROMBOSIS IN TTP

Molecular Biology and Biochemistry of ADAMTS13

The ADAMTS13 gene contains 29 exons spanning ∼37 kb on chromosome 9q34(17–19). ADAMTS13 encodes a 4.7-kb transcript that is expressed in the liver anda 2.4-kb transcript detectable in placenta, skeletal muscle, and certain tumor celllines. In the liver, ADAMTS13 is expressed primarily in the retinoid-enrichedstellate cells (also known as lipocytes, fat-storing cells, or Ito cells), which arelocated in the subendothelial space of Disse that separates the hepatocytes fromthe sinusoidal endothelium (20, 21).

The full-length transcript encodes a precursor polypeptide with 1427 amino acidresidues. ADAMTS13 is synthesized in the cells as a 185-kD protein instead of

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the calculated 145-kD protein, indicating that the protein undergoes extensive gly-cosylation and other post-translation modifications. The sequence of ADAMTS13exhibits a multidomain structure that is common for proteases of the ADAMTS(a disintegrin and metalloprotease with thrombospondin type 1 motif) family butalso contains unique domains (Figure 1).

ADAMTS13 cleaves von Willebrand factor (VWF) at the Y1605-M1606 bondof the VWF polypeptide (22). Disulfide bond–reducing agents, tetracyclines, orcation chelators such as phenanthroline inactivate the VWF cleaving activity ofADAMTS13, suggesting that the Zn2+ moiety of the metalloprotease domainand the intrachain disulfide bonds are critical for the protease activity. AlthoughADAMTS13 is stable in normal plasma, its activity may deteriorate rapidly inplasma samples obtained from patients with liver diseases or other pathologicalconditions. Thrombin, plasmin, and hemoglobin have been reported to inactivateADAMTS13 (23, 24).

Phylogenic analysis indicates that ADAMTS13 diverged early from other mem-bers of the ADAMTS family of proteases (25, 26). In particular, ADAMTS13 con-tains an unusually short (41 amino acid residues) propeptide whose cleavage doesnot appear necessary for expression of proteolytic activity (27). Enzymatic analysisof proteins expressed by mammalian cells reveals that the VWF cleaving activitydecreases precipitously when ADAMTS13 is truncated proximal to the spacer do-main (28, 29). It is possible that the sequence of the extra metalloprotease domainmodulates the expression of the protease activity, perhaps by facilitating the bind-ing between the spacer domain sequence the protease and its substrate VWF (30).

VWF, Platelet, Shear Stress, and Microvascular Thrombosis

VWF, a glycoprotein synthesized in vascular endothelial cells and megakaryocytes,exists in the circulation as a series of disulfide-bonded multimers whose molecularweights range from 1 × 106 to greater than 20 × 106 daltons. The large multimersare essential for supporting platelet aggregation under high-shear-stress conditions.Endothelial cells account for >90% of circulating VWF. Instead of being directlysecreted from vascular endothelial cells, VWF multimers derive from an ultra-large VWF polymer. This endothelial VWF and its large multimeric derivativesare cleaved in a shear-dependent manner by ADAMTS13 to become smaller forms(31–33).

The complex interaction among VWF, platelet, ADAMTS13, and shear stressis depicted in Figure 2. Three-dimensionally, VWF exists in a globular form that isconformationally flexible, and it unfolds in the direction of shear force to becomean elongated form that is most active in aggregating platelets (Figure 2a) (34).This elongated form of VWF would cause platelet thrombosis if it were allowedto accumulate in the circulation (Figure 2c). The elongated form of VWF doesnot exist in the circulation because ADAMTS13 immediately cleaves VWF at theY1605-M1606 bond whenever VWF is partially unfolded by shear stress (Figure2b). This proteolytic process is critical for keeping VWF in globular but progres-sively smaller, less flexible forms. The spectrum of VWF multimers is maintained

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424 TSAI

in balance by continual secretion of ultra-large VWF from endothelial cells. VWFmultimers as detected in the plasma represent a snapshot of a dynamic process. Adeficiency of ADAMTS13 diminishes VWF cleavage and favors the accumulationof elongated, hyperactive forms of VWF that are prone to bind platelets, causingmicrovascular thrombosis of TTP. Conformational unfolding of VWF and subse-quent platelet attachment may occur more efficiently on endothelial surfaces (34a).However, since VWF-endothelial attachment appears to occur only under extremeexperimental conditions, its role in the development of thrombosis in patients withADAMTS13 deficiency remains to be determined.

This scheme provides a basis for understanding some of the well-known peculiarfeatures of VWF:

1. In a test tube, VWF and ADAMTS13 coexist in the plasma without evidenceof ongoing cleavage, because VWF exists in a globular conformation that isresistant to cleavage by ADAMTS13.

2. VWF-platelet adhesion and aggregation do not occur in the circulation be-cause VWF is kept in globular forms that are incapable of binding plateletreceptor Ib.

3. Shear stress enhances VWF-platelet adhesion and aggregation at sites ofvessel injury because it causes rapid conformational unfolding of matrix-bound VWF, exposing its binding sites for platelet receptor Ib.

4. Large VWF multimers are hemostatically more effective than small mul-timers because large size confers higher flexibility and responsiveness toshear stress. The flexible conformation allows large VWF multimers to un-fold in response to shear stress, forming the substrate for supporting plateletadhesion and aggregation.

This regulation of VWF-ADAMTS13 interaction achieves immediate, effectivehemostasis in the microvasculature. This scheme ensures that large VWF is in-stantly available at sites of vessel injury for supporting platelet aggregation, whileit prevents unwarranted VWF-platelet binding in the circulation. It also takes ad-vantage of the shear-stress profile in the vascular lumen: Shear rate is highest at theendothelial surface, declining toward zero at the center. Thus, after initial cleavageat the time of release from endothelial cells, VWF is exposed to high levels ofshear stress only intermittently and very briefly during each cycle in the circula-tion, unless it is bound to a site of injury. This helps create a large safety margin:Intravascular platelet thrombosis does not occur until ADAMTS13 is decreased toa very low level (<10% of normal).

VWF Multimer Size in Diseases

The balance of VWF-ADAMTS13 interaction may be disturbed if there is anabrupt rush of VWF secretion by endothelial cells in low-shear environments,deficiency of ADAMTS13, mutant VWF with enhanced susceptibility to cleavageby ADAMTS13, or abnormal shear stress.

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Patients with ADAMTS13 deficiency are expected to have ultra-large VWFmultimers in their plasma. Indeed, ultra-large VWF multimers are present in pa-tients with low ADAMTS13 activity levels during remission (35). Paradoxically, atthe acute stage of TTP, both ultra-large and normally large multimers are missing(36, 37). The scheme depicted in Figure 2 provides a framework for understandingthe intriguing pattern of VWF multimers in TTP. In the absence of ADAMTS13,conformationally flexible large VWF multimers become progressively unfolded.These unfolded forms of VWF bind platelets, causing platelet thrombosis and adepletion of the large multimers from the circulation.

Infusion of desmopressin causes acute release of VWF from endothelial cells,resulting in the appearance of ultra-large VWF multimers (38). Although infusionof desmopressin has been reported to decrease the plasma ADAMTS13 level,the mild decrease is not sufficient to account for the appearance of ultra-largemultimers (39).

Certain mutations of the VWF gene (type 2A von Willebrand disease) enhancethe susceptibility of VWF to cleavage by ADAMTS13 (40, 41); as a consequence,VWF is continually cleaved by ADAMTS13 in the circulation to smaller multi-meric forms.

The shear-stress profile of the circulation also affects the efficiency of the cleav-age. HUS and aortic stenosis are two examples in which abnormal shear stress inthe microcirculation or at the aortic valve enhances cleavage of VWF, resulting in adecrease of large VWF multimers (8, 42). Microangiopathic hemolysis often coex-ists with loss of large VWF multimers, because abnormal shear stress contributesto the development of both conditions. The presence of ultra-large multimers inneonates or the umbilical cord may result from a lower shear-stress profile of thefetal circulation (43).

CAUSES OF ADAMTS13 DEFICIENCY

Antibodies of ADAMTS13

Inhibitory antibodies of ADAMTS13 cause a profound deficiency of the proteaseamong patients with autoimmune TTP (44, 45). The prevalence of ADAMTS13deficiency among patients with TTP varies from 13% to 100% depending onthe study’s criteria for including cases (44–50). Studies using less strict criteriaof case inclusion inevitably report the lowest prevalence rates of ADAMTS13deficiency. Since a clear distinction between TTP and HUS or other types ofmicrovascular thrombosis is not always clinically feasible, TTP case series ofteninclude patients with other types of microvascular thrombosis. However, if a setof strict criteria is applied to define patients with unequivocal idiopathic TTP, aprofound deficiency in ADAMTS13 is detected in each case (51). In our experience,inhibitory activity mediated by IgG is detectable in almost every case of TTPinvestigated. Nevertheless, this does not exclude the possibility that patients mayalso have noninhibitory antibodies (52).

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426 TSAI

The inhibitors of ADAMTS13 are generally of very low titers (<10 U/ml, usingthe same definition for factor VIII inhibitors), suggesting that the antibodies are di-rected against other targets but cross-react with ADAMTS13. Because they appearsuddenly, then decline gradually over a course of weeks to months, the inhibitorsmay represent a response to an otherwise innocuous infection or a certain exoge-nous molecule. TTP may develop within 2–6 weeks after ticlopidine is used forcardiovascular indications (53, 54). No other apparent etiologies of ADAMTS13inhibitors have been identified.

TTP may develop in patients with HIV infection. Before the introduction ofeffective antiretroviral treatment, HIV was present in up to 50% of the TTP cases ata major urban center (55). In recent years, the prevalence of HIV infection amongTTP patients has declined below 10% in some series. How HIV is related to thedevelopment of TTP remains poorly understood. Its presence can pose challengesfor management. Because immune thrombocytopenic purpura (ITP) is commonamong patients with HIV infection, persistence of thrombocytopenia in an HIVpatient with TTP may be mistaken as refractory TTP, leading to unnecessarilyprolonged plasma-exchange therapy.

When a patient is treated with plasma exchange, the rise in the platelet count isaccompanied by a decrease of the inhibitor titer and an increase of the ADAMTS13activity levels. It is believed that plasma exchange replenishes the missingADAMTS13; it may also help remove the inhibitors. The protease activity levelis usually not completely normalized, and inhibitors of the protease may remaindetectable when patients are investigated during clinical remission, suggesting thatthe autoimmune reaction against ADAMTS13 persists. In such patients, a relapseof TTP due to increased inhibitor titers might represent amnestic response to thesame or similar inciting agents, or result from a breakdown in immune regulation,allowing a resurgence of the immunocytes.

The target epitopes of the ADAMTS13 inhibitors have not been definitively de-termined. Studies of recombinant ADAMTS13 or its truncated forms revealed thatIgG molecules isolated from TTP patients react with recombinant ADAMTS13proteins that include the sequence of the spacer domain (28, 56, 57). These ob-servations suggest that the spacer domain is a potential target of TTP inhibitors.A systemic, prospective investigation is needed to further delineate the prevalenceand duration of ADAMTS13 inhibitors among patients with TTP and the natureand etiology of the autoimmune reaction against ADAMTS13.

Genetic Mutations

More than 40 different mutations of the ADAMTS13 gene have been described (17,58–60) and are shown in an extensive table available online (follow the Supplemen-tal Material link from the Annual Reviews home page at http://www.annualreviews.org). The mutations, which include missenses, nonsenses, frame-shifting deletionsor insertions, and intronic splicing mutations, distribute throughout the variousdomains of ADAMTS13. The majority of the mutations affect the sequence of

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metalloprotease-spacer domains that are critical for expression of proteolytic ac-tivity. Eight mutations have been investigated in expression studies: One mutationcreates a proteolytically inactive form, whereas the other seven impede secretionof the protein. All five intronic mutations were investigated by RT-PCR and wereconfirmed to be associated with abnormal splicing.

Mutations of ADAMTS13 have been detected in individuals of various racialdescents, including African, American Indian, Asian, and Caucasian. There areat least 17 recurrent mutations, including five mutations detected in seeminglyunrelated patients. Three reports have described the 4143insA mutation in multipleindividuals. Nevertheless, it remains to be determined whether any of the recurrentmutations occurred independently. No correlation between the types of mutationsand severity of hereditary TTP has been identified.

In addition to mutations, multiple polymorphisms of the gene are detected inindividuals from different geographic areas. Overall, each of the exons containsat least one genetic variation. The data suggest that variation in the ADAMTS13gene is not uncommon. Mutations that compromise the expression of ADAMTS13activity may persist in the population because a carrier of one mutant allele is notphenotypically disadvantaged.

DIFFERENTIAL DIAGNOSIS

TTP, HUS, or TTP/HUS?

Microangiopathic hemolysis and thrombocytopenia are not pathognomonic ofTTP; instead, they are a hallmark of widespread microvascular thrombosis. Pre-viously, because the pathogenesis of microvascular thrombosis was not known,classification of microangiopathic hemolysis and thrombocytopenia was based onphenotypic manifestations: TTP was the diagnosis for patients with overt neuro-logical dysfunction, and the hemolytic uremic syndrome (HUS) for patients withprominent renal failure. This seemingly simple scheme proves to be confusingand untenable, because patients with recurrent TTP do not always present withovert neurological deficits and sometimes do have renal dysfunction. As a re-sult, it was not uncommon to encounter patients carrying both diagnoses, TTPand HUS. The development of thrombocytopenia and microangiopathic hemoly-sis in a patient with hereditary TTP after acute diarrhea may raise the suspicionof HUS. On the other hand, some cases of shiga toxin–associated thrombosis donot develop severe renal failure and consequently have been incorrectly identi-fied as TTP. Because of the overlapping manifestations, some investigators haveused the term TTP/HUS to accommodate all patients presenting with microan-giopathic hemolysis and thrombocytopenia. This approach obscures the distinctpathogenetic mechanisms or etiologies among different disorders. With advancesin our understanding of the molecular mechanisms of microvascular thrombosis,the term TTP/HUS has outlived its historic role.

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428 TSAI

Microvascular thrombosis is a pathological entity with multiple causes(Table 1). ADAMTS13 deficiency accounts for most cases of “typical” TTP, whichis characterized clinically by the absence of certain features that suggest other dis-orders: a plausible cause of microvascular thrombosis, a prodrome of diarrhea,acute renal failure, hypertension, or acute respiratory syndrome. A patient olderthan 10 years who has none of these excluding features most likely has TTP. Con-versely, the presence of any of these features favors other diagnoses, although itdoes not exclude the diagnosis of TTP.

Shiga toxin is the etiologic agent of typical HUS, which occurs after infectionwith E. coli O157:H7 or other related microorganisms (61). A defect in the reg-ulation of the complement cascade—which may be due to mutations in factor H,membrane cofactor protein (CD46), or serine protease factor I, or due to autoanti-bodies of factor H—accounts for ∼30% of cases of idiopathic atypical HUS (62,63). Table 2 summarizes some of the different features of TTP and HUS.

Thrombocytopenia and microangiopathic hemolysis occasionally occur in as-sociation with cancer chemotherapeutic agents (e.g., mitomycin, gemcitabine),bone marrow or solid organ transplantation (often in association with the use ofcalcineurin inhibitors) (64), or lupus or other related autoimmune disorders. Gen-erally, these disorders are accompanied by variable severity of renal failure anddo not feature antibody inhibitors of ADAMTS13. The molecular mechanisms ofsecondary HUS and many cases of idiopathic HUS remain unknown.

TTP and HUS do not encompass all patients that present with microangio-pathic hemolysis and thrombocytopenia. Microvascular thrombosis or occlusionmay also develop in disorders such as the HELLP (hemolysis with elevated liverenzymes and low platelet counts) syndrome of pregnancy, paroxysmal nocturnalhemoglobulinuria with widespread thrombosis in the mesenteric microvasculature,Rocky Mountain spotted fever, and metastatic cancers with widespread emboli oftumor cells. These disorders are not caused by ADAMTS13 deficiency, and withnormal renal function they do not belong in the HUS category.

LABORATORY INVESTIGATION

A thorough assessment of a patient suspected of TTP includes assay of ADAMTS13activity level, detection of ADAMTS13 inhibitors, and gel electrophoresis of VWFmultimers. When hereditary TTP is suspected, study of the parents or other familymembers, complemented by DNA sequence analysis to search for mutation ofADAMTS13, may help establish the diagnosis.

ADAMTS13 Activity

Patients presenting with thrombocytopenia due to autoimmune inhibitors ofADAMTS13 typically have a very low level of ADAMTS13 activity in theirplasma. This distinguishes TTP from shiga toxin–associated HUS, atypical HUS,and other microangiopathic disorders. Because some versions of the ADAMTS13

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TABLE 2 Different features of thrombotic thrombocytopenic purpura (TTP) and the hemolyticuremic syndrome (HUS)

FeatureAutoimmuneTTP Hereditary TTP

Shigatoxin–HUS Idiopathic HUS

Epidemiology Sporadic Sporadic Endemic areasare common

Sporadic

Age of onset Adolescent–adult Neonate–youngchild

Young child;elderly

Infant–adult

Heredity No Autosomalrecessive

No Autosomaldominant,variablepenetrance

Gastrointestinalprodromea

— — Painful, bloodydiarrhea

—

Recurrence Common Common Rare Common

Renal failure Rare Uncommon Common Common

Composition ofthrombi

VWF and platelets VWF and platelets Fibrin andplatelets

Fibrin andplatelets

VWF profile Ultra largemultimers;

Depletion of ultralarge and largemultimers atadvanced stage

Ultra largemultimers;

Depletion of ultralarge and largemultimers atadvanced stage

Increaseddegradation tosmaller forms

Increaseddegradation tosmaller forms

Diagnosis ADAMTS13activity

ADAMTS13antibodies

ADAMTS13activity

Genetic analysisof ADAMTS13

Shiga toxin +E. coli

Antibody ofO157 antigen

Genetic analysisof complementactivationregulators;

Antibodies offactor Hb

Response toplasma therapy

Yes Yes Notdemonstrated

Variablec

aAcute gastrointestinal illness may exacerbate subclinical TTP or atypical HUS.bFactor H, membrane cofactor protein (CD46), or serine protease factor I.cPatients with mutations of factor H or factor I may improve upon plasma therapy. The optimal regimen is unknown.

activity assay detect very low levels of protease activity among patients withoutTTP, the threshold value of ADAMTS13 activity for diagnosis of TTP varies andshould be established in each laboratory.

Occasionally, a patient may have concurrent ITP or other disorders that causethrombocytopenia independent of TTP. If the platelet count does not respondsatisfactorily to plasma exchange, a repeat analysis of ADAMTS13 activity mayhelp reveal that the thrombocytopenia is due to the presence of another disorder.

Current assays of ADAMTS13 activity differ in design and the range of normalvalues observed, as recently reviewed (51). The protease activity in patients with

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various pathological conditions is not stable in vitro and may be lost during stor-age or incubation. This instability may explain at least in part why some assaysdetect very low activity levels without accompanying evidence of impaired VWFproteolysis. The combination of a very low ADAMTS13 value and a normal VWFmultimer pattern should raise suspicion of the validity of the assay result.

ADAMTS13-Inhibiting Antibodies

A mixing study of patient plasma with normal plasma detects inhibitors ofADAMTS13 in most patients with acute TTP. The prevalence of ADAMTS13inhibitors depends on the sensitivity of the assay used. When a mixing study failsto detect the presence of inhibitors, IgG molecules purified from the patients’plasma or serum may bring out a positive result. Inhibitors of ADAMTS13 maypersist with fluctuating titers for months to years during periods of clinical remis-sion. Excessive increase of ADAMTS13 inhibitor titers may suppress ADAMTS13activity below the threshold level and cause relapse of TTP. An ELISA has been de-veloped to detect ADAMTS13-binding antibodies. However, the assay may yieldpositive results in patients without TTP (64a).

Investigation of Genetic ADAMTS13 Deficiency

In hereditary cases, inhibitors of ADAMTS13 are not detected and the parents orchildren are partially deficient in ADAMTS13 activity. Because a slight decrease inADAMTS13 activity level may be observed in patients with various types of med-ical illness, investigation of a potential carrier should be conducted in the absenceof complicating illness. Assays that have a broad normal range will not distin-guish carriers of ADAMTS13 mutant alleles from normal individuals. Nucleotidesequence analysis for ADAMTS13 mutations remains an investigational tool.

VWF Multimers

Analysis of the VWF multimers at the advanced stage of the disease usually detectsa depletion of ultra-large and large multimers. During the early stage of remission,an increase in the platelet count often coincides with the appearance of ultra-largeVWF multimers. This is because at this stage, the ADAMTS13 activity remainsvery low but is sufficient to ameliorate the binding between VWF and platelet.Ultra-large VWF multimers are detected in patients in remission with persistentlylow ADAMTS13 activity levels. Interpretation of ADAMTS13 activity levels andVWF multimers should be correlated with the disease stage.

TREATMENT

Plasma Exchange

Plasma exchange with fresh frozen plasma remains the mainstay of treatment,achieving remission in 70%–90% of patients (3, 9). Because TTP may evolve

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rapidly at its advanced stage, any delay in treatment increases the risk of adverseoutcomes. When plasma exchange is not immediately available, patients should begiven fresh frozen plasma while awaiting definitive treatment. Platelet transfusionshould be avoided. Corticosteroids and antiplatelet agents are often included in theinitial regimen, although their values have not been rigorously investigated. Whenpatients do not respond satisfactorily to plasma exchange, second-line therapiesincluding vincristine, splenectomy, cyclophosphamide, azathioprine, rituximab, orcyclosporin A may be added to the regimen. Only the efficacy of plasma therapyhas been established in a randomized controlled study.

Patients with hereditary TTP respond readily to infusion of 10–15 ml freshfrozen plasma; the platelet count rises within a few hours or by the next day.For patients who maintain normal platelet counts between episodes of relapse,the indication for chronic plasma therapy is less obvious. Patients with a historyof serious complications probably should be treated with maintenance therapy toprevent further complications.

Role of Plasma Therapy in Other Types of MicrovascularThrombosis

Because of uncertainty in diagnosis, patients with other types of microvascularthrombosis are often treated as TTP patients, i.e., with plasma therapy. With newinsights into molecular mechanisms, it is now clear that management of patientsshould be tailored to the individual diagnosis. In pediatric practice, plasma therapyis generally not used for shiga toxin–associated HUS (61). Plasma therapy may beeffective for patients with defects of circulating proteins, such as mutations of factorH or serine protease factor I. However, the optimal regimen for such patients has notbeen established. Plasma therapy is not expected to be effective for patients withmutations in membrane-anchored proteins such as the membrane cofactor protein(CD46); instead, such patients may be cured of the disease by renal transplantation.The use of plasma exchange for bone marrow transplantation–associated HUS hasgenerally produced disappointing outcomes (65, 66). Further elucidation of theunderlying mechanisms responsible for microvascular thrombosis should facilitatethe development of rationally designed targeted therapy for patients with idiopathicor secondary HUS.

Cryosupernatant Plasma

The cryosupernatant fraction of fresh frozen plasma is depleted of large VWF mul-timers. Because large VWF multimers are involved in causing platelet aggregation,cryosupernatant of fresh frozen plasma has been advocated as a more effective al-ternative to fresh frozen plasma (67, 68). Cryosupernatant plasma contains thesame amount of ADAMTS13 as fresh frozen plasma and is not expected to bemore effective in raising ADAMTS13 levels. Two randomized studies have failedto confirm the superiority of cryosupernatant plasma over fresh frozen plasma ininducing remission or reducing mortality (69, 70).

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Immunomodulation

Because autoantibody inhibitors of ADAMTS13 cause TTP, suppression of im-mune responses with immunosuppressive molecules such as cyclophosphamide,azathioprine, cyclosporin A, or rituximab, a chimeric anti-CD20 monoclonal an-tibody that depletes B cells from the circulation and lymphoid tissues, may bea rational approach. Case reports have described refractory cases that improvedwithin 2–4 weeks of rituximab therapy (71, 72). Rituximab appears to be valuablefor patients who have persistent but low inhibitor titers, but it may be inadequatefor patients with high titers of inhibitors. The role of rituximab in the acute or sub-acute setting for improving treatment outcome or preventing relapse is uncertainand will require rigorous evaluation in randomized trials.

PERSPECTIVE

Previously a perplexing disorder, TTP has been shown to be a single-moleculedisease. Future challenges include the etiologies that induce the immune responsesto ADAMTS13 among patients with TTP and the factors that affect the severityof the disease. The identification of ADAMTS13 has raised expectations thatit will soon be possible to provide molecular therapy for the treatment of TTP.This enthusiasm is hampered by the presence of ADAMTS13 inhibitors and thelack of effective measures to quickly eradicate the inhibitors. Through furtherstructure-function analysis, it may be feasible to design ADAMTS13 variantsthat are proteolytically active but are not suppressible by the inhibitors of TTP.Such nonsuppressible ADAMTS13 molecules might eliminate the need for plasmaexchange and the risk of treatment failure due to potent ADAMTS13 inhibitors.

ACKNOWLEDGMENTS

This work was supported in part by grants (R01 HL62136 and R01 HL72876) fromthe National Heart Lung and Blood Institute of the National Institutes of Health.

The Annual Review of Medicine is online at http://med.annualreviews.org

LITERATURE CITED

1. Moschcowitz E. 1924. Hyaline thrombo-sis of the terminal arterioles and capillar-ies: a hitherto undescribed disease. Proc.NY Pathol. Soc. 24:21–24

2. Bukowski RM, Hewlett JS, Reimer RR,et al. 1981. Therapy of thrombotic throm-bocytopenic purpura: an overview. Semin.Thromb. Hemost. 7:1–8

3. Rock GA, Shumak KH, Buskard NA, et al.1991. Comparison of plasma exchangewith plasma infusion in the treatmentof thrombotic thrombocytopenic purpura.Canadian Apheresis Study Group. N.Engl. J. Med. 325:393–97

4. Torok TJ, Holman RC, Chorba TL. 1995.Increasing mortality from thrombotic

Ann

u. R

ev. M

ed. 2

006.

57:4

19-4

36. D

ownl

oade

d fr

om a

rjou

rnal

s.an

nual

revi

ews.

org

by N

EW

YO

RK

UN

IVE

RSI

TY

- B

OB

ST L

IBR

AR

Y o

n 01

/21/

08. F

or p

erso

nal u

se o

nly.



thrombocytopenic purpura in the UnitedStates—analysis of national mortalitydata, 1968–1991. Am. J. Hematol. 50:84–90

5. Miller DP, Kaye JA, Shea K, et al.2004. Incidence of thrombotic thrombo-cytopenic purpura/hemolytic uremic syn-drome. Epidemiology 15:208–15

6. Asada Y, Sumiyoshi A, Hayashi T, et al.1985. Immunohistochemistry of vascu-lar lesion in thrombotic thrombocytopenicpurpura, with special reference to fac-tor VIII related antigen. Thromb. Res.38:469–79

7. Hosler GA, Cusumano AM, HutchinsGM. 2003. Thrombotic thrombocy-topenic purpura and hemolytic uremicsyndrome are distinct pathologic entities.A review of 56 autopsy cases. Arch.Pathol. Lab. Med. 127:834–39

8. Tsai HM, Chandler WL, Sarode R,et al. 2001. von Willebrand factor andvon Willebrand factor-cleaving metal-loprotease activity in Escherichia coliO157:H7-associated hemolytic uremicsyndrome. Pediatr. Res. 49:653–59

9. Bell WR. 1997. Thrombotic thrombocy-topenic purpura/hemolytic uremic syn-drome relapse: frequency, pathogenesis,and meaning. Semin. Hematol. 34:134–39

10. Shumak KH, Rock GA, Nair RC. 1995.Late relapses in patients successfullytreated for thrombotic thrombocytopenicpurpura. Canadian Apheresis Group. Ann.Intern. Med. 122:569–72

11. Tsai HM, Shulman K. 2003. Rituximabinduces remission of cerebral ischemiacaused by thrombotic thrombocytopenicpurpura. Eur. J. Haematol. 70:183–85

12. Downes KA, Yomtovian R, Tsai HM,et al. 2004. Relapsed thrombotic thrombo-cytopenic purpura presenting as an acutecerebrovascular accident. J. Clin. Aphere-sis 19:86–89

13. Schulman I, Pierce M, Lukens A, et al.1960. Studies on thrombopoiesis. I. Afactor in normal human plasma required

for platelet production. Chronic throm-bocytopenia due to its deficiency. Blood16:943–57

14. Upshaw JD Jr. 1978. Congenital defi-ciency of a factor in normal plasma thatreverses microangiopathic hemolysis andthrombocytopenia. N. Engl. J. Med. 298:1350–52

15. Furlan M, Robles R, Morselli B, et al.1999. Recovery and half-life of vonWillebrand factor-cleaving protease afterplasma therapy in patients with throm-botic thrombocytopenic purpura. Thromb.Haemost. 81:8–13

16. Jubinsky PT, Moraille R, Tsai HM. 2003.Thrombotic thrombocytopenic purpura ina newborn. J. Perinatol. 23:85–87

17. Levy GG, Nichols WC, Lian EC, et al.2001. Mutations in a member of theADAMTS gene family cause thromboticthrombocytopenic purpura. Nature 413:488–94

18. Soejima K, Mimura N, Hirashima M,et al. 2001. A novel human metallopro-tease synthesized in the liver and se-creted into the blood: possibly, the vonWillebrand factor-cleaving protease? J.Biochem. (Tokyo) 130:475–80

19. Zheng X, Chung D, Takayama TK, et al.2001. Structure of von Willebrand factor-cleaving protease (ADAMTS13), a metal-loprotease involved in thrombotic throm-bocytopenic purpura. J. Biol. Chem. 276:41059–63

20. Zhou W, Inada M, Lee TP, et al. 2005.ADAMTS13 is expressed in hepatic stel-late cells. Lab. Invest. 85:780–88

21. Uemura M, Tatsumi K, Matsumoto M,et al. 2005. Localization of ADAMTS13to the stellate cells of human liver. Blood43:319–24

22. Dent JA, Berkowitz SD, Ware J, et al.1990. Identification of a cleavage site di-recting the immunochemical detection ofmolecular abnormalities in type IIA vonWillebrand factor. Proc. Natl. Acad. Sci.USA 87:6306–10

23. Crawley JT, Lam JK, Rance JB,

Ann

u. R

ev. M

ed. 2

006.

57:4

19-4

36. D

ownl

oade

d fr

om a

rjou

rnal

s.an

nual

revi

ews.

org

by N

EW

YO

RK

UN

IVE

RSI

TY

- B

OB

ST L

IBR

AR

Y o

n 01

/21/

08. F

or p

erso

nal u

se o

nly.


434 TSAI

et al. 2005. Proteolytic inactivation ofADAMTS13 by thrombin and plasmin.Blood 105:1085–93

24. Studt JD, Hovinga JA, Antoine G,et al. 2005. Fatal congenital thromboticthrombocytopenic purpura with apparentADAMTS13 inhibitor: in vitro inhibitionof ADAMTS13 activity by hemoglobin.Blood 105:542–44

25. Apte SS. 2004. A disintegrin-like andmetalloprotease (reprolysin type) withthrombospondin type 1 motifs: theADAMTS family. Int. J. Biochem. CellBiol. 36:981–85

26. Nicholson AC, Malik SB, Logsdon JMJr. et al. 2005. Functional evolution ofADAMTS genes: evidence from analysesof phylogeny and gene organization. BMCEvol. Biol. 5:11

27. Majerus EM, Zheng X, Tuley EA,et al. 2003. Cleavage of the ADAMTS13propeptide is not required for protease ac-tivity. J. Biol. Chem. 278:46643–48

28. Soejima K, Matsumoto M, KokameK, et al. 2003. ADAMTS-13 cysteine-rich/spacer domains are functionally es-sential for von Willebrand factor cleavage.Blood 102:3232–37

29. Zheng X, Nishio K, Majerus EM, et al.2003. Cleavage of von Willebrand factorrequires the spacer domain of the metal-loprotease ADAMTS13. J. Biol. Chem.278:30136–41

30. Majerus EM, Anderson PJ, Sadler JE.2005. Binding of ADAMTS13 to vonWillebrand factor. J. Biol. Chem. 280:21773–78

31. Tsai HM, Nagel RL, Hatcher VB,et al. 1989. Endothelial cell-derived highmolecular weight von Willebrand factor isconverted into the plasma multimer pat-tern by granulocyte proteases. Biochem.Biophys. Res. Commun. 158:980–85

32. Tsai HM. 1996. Physiologic cleavage ofvon Willebrand factor by a plasma pro-tease is dependent on its conformation andrequires calcium ion. Blood 87:4235–44

33. Tsai HM, Sussman II, Nagel RL. 1994.

Shear stress enhances the proteolysis ofvon Willebrand factor in normal plasma.Blood 83:2171–79

34. Siedlecki CA, Lestini BJ, Kottke-Marchant KK, et al. 1996. Shear-depen-dent changes in the three-dimensionalstructure of human von Willebrand factor.Blood 88:2939–50

34a. Dong JF, Moake JL, Nolasco L, et al.2002. ADAMTS-13 rapidly cleavesnewly secreted ultralarge von Willebrandfactor multimers on the endothelial sur-face under flowing conditions. Blood 100:4033–39

35. Moake JL, Rudy CK, Troll JH, et al. 1982.Unusually large plasma factor VIII:vonWillebrand factor multimers in chronicrelapsing thrombotic thrombocytopenicpurpura. N. Engl. J. Med. 307:1432–35

36. Moake JL, McPherson PD. 1989. Abnor-malities of von Willebrand factor mul-timers in thrombotic thrombocytopenicpurpura and the hemolytic-uremic syn-drome. Am. J. Med. 87:9N–15N

37. Tsai HM. 2000. High titers of inhibitorsof von Willebrand factor-cleaving metal-loproteinase in a fatal case of acute throm-botic thrombocytopenic purpura. Am. J.Hematol. 65:251–55

38. Mannucci PM. 2003. Desmopressin(DDAVP) and factor VIII: the tale asviewed from Milan (and Malmo). J. Thr-omb. Haemost. 1:622–24

39. Reiter RA, Knobl P, Varadi K, et al.2003. Changes in von Willebrand factor-cleaving protease (ADAMTS13) activ-ity after infusion of desmopressin. Blood101:946–48

40. Tsai HM, Sussman II, Ginsburg D, et al.1997. Proteolytic cleavage of recombi-nant type 2A von Willebrand factor mu-tants R834W and R834Q: inhibition bydoxycycline and by monoclonal antibodyVP-1. Blood 89:1954–62

41. O’Brien LA, Sutherland JJ, Hegadorn C,et al. 2004. A novel type 2A (Group II) vonWillebrand disease mutation (L1503Q)associated with loss of the highest

Ann

u. R

ev. M

ed. 2

006.

57:4

19-4

36. D

ownl

oade

d fr

om a

rjou

rnal

s.an

nual

revi

ews.

org

by N

EW

YO

RK

UN

IVE

RSI

TY

- B

OB

ST L

IBR

AR

Y o

n 01

/21/

08. F

or p

erso

nal u

se o

nly.



molecular weight von Willebrand factormultimers. J. Thromb. Haemost. 2:1135–42

42. Vincentelli A, Susen S, Le TT, et al. 2003.Acquired von Willebrand syndrome inaortic stenosis. N. Engl. J. Med. 349:343–49

43. Tsai HM, Sarode R, Downes KA. 2002.Ultralarge von Willebrand factor multi-mers and normal ADAMTS13 activity inthe umbilical cord blood. Thromb. Res.108:121–25

44. Furlan M, Robles R, Galbusera M, et al.1998. von Willebrand factor-cleaving pro-tease in thrombotic thrombocytopenicpurpura and the hemolytic-uremic syn-drome. N. Engl. J. Med. 339:1578–84

45. Tsai HM, Lian EC. 1998. Antibodies tovon Willebrand factor-cleaving proteasein acute thrombotic thrombocytopenicpurpura. N. Engl. J. Med. 339:1585–94

46. Tsai HM, Li A, Rock G. 2001. In-hibitors of von Willebrand factor-cleavingprotease in thrombotic thrombocytopenicpurpura. Clin. Lab. 47:387–92

47. Veyradier A, Obert B, Houllier A, et al.2001. Specific von Willebrand factor-cleaving protease in thrombotic microan-giopathies: a study of 111 cases. Blood98:1765–72

48. Vesely SK, George JN, Lammle B,et al. 2003. ADAMTS13 activity inthrombotic thrombocytopenic purpura-hemolytic uremic syndrome: relation topresenting features and clinical outcomesin a prospective cohort of 142 patients.Blood 102:60–68

49. Bianchi V, Robles R, Alberio L, et al.2002. Von Willebrand factor-cleavingprotease (ADAMTS13) in thrombocy-topenic disorders: a severely deficient ac-tivity is specific for thrombotic throm-bocytopenic purpura. Blood 100:710–13

50. Peyvandi F, Ferrari S, Lavoretano S, et al.2004. von Willebrand factor cleaving pro-tease (ADAMTS-13) and ADAMTS-13neutralizing autoantibodies in 100 pa-

tients with thrombotic thrombocytopenicpurpura. Br. J. Haematol. 127:433–39

51. Tsai HM. 2003. Advances in the patho-genesis, diagnosis, and treatment ofthrombotic thrombocytopenic purpura. J.Am. Soc. Nephrol. 14:1072–81

52. Scheiflinger F, Knobl P, Trattner B,et al. 2003. Nonneutralizing IgM andIgG antibodies to von Willebrand factor-cleaving protease (ADAMTS-13) in a pa-tient with thrombotic thrombocytopenicpurpura. Blood 102:3241–43

53. Bennett CL, Weinberg PD, Rozenberg-Ben-Dror K, et al. 1998. Throm-botic thrombocytopenic purpura associ-ated with ticlopidine. A review of 60cases. Ann. Intern. Med. 128:541–44

54. Tsai HM, Rice L, Sarode R, et al. 2000.Antibody inhibitors to von Willebrandfactor metalloproteinase and increasedbinding of von Willebrand factor toplatelets in ticlopidine-associated throm-botic thrombocytopenic purpura. Ann. In-tern. Med. 132:794–99

55. Hymes KB, Karpatkin S. 1997. Hu-man immunodeficiency virus infectionand thrombotic microangiopathy. Semin.Hematol. 34:117–25

56. Klaus C, Plaimauer B, Studt JD, et al.2004. Epitope mapping of ADAMTS13autoantibodies in acquired thromboticthrombocytopenic purpura. Blood 103:4514–19

57. Luken BM, Turenhout EA, HulsteinJJ, et al. 2005. The spacer domain ofADAMTS13 contains a major bindingsite for antibodies in patients with throm-botic thrombocytopenic purpura. Thromb.Haemost. 93:267–74

58. Kokame K, Miyata T. 2004. Genetic de-fects leading to hereditary thromboticthrombocytopenic purpura. Semin. Hema-tol. 41:34–40

59. Licht C, Stapenhorst L, Simon T,et al. 2004. Two novel ADAMTS13gene mutations in thrombotic throm-bocytopenic purpura/hemolytic-uremic

Ann

u. R

ev. M

ed. 2

006.

57:4

19-4

36. D

ownl

oade

d fr

om a

rjou

rnal

s.an

nual

revi

ews.

org

by N

EW

YO

RK

UN

IVE

RSI

TY

- B

OB

ST L

IBR

AR

Y o

n 01

/21/

08. F

or p

erso

nal u

se o

nly.


436 TSAI

syndrome (TTP/HUS). Kidney Int. 66:955–58

60. Noris M, Bucchioni S, Galbusera M,et al. 2005. Complement factor H mu-tation in familial thrombotic thrombocy-topenic purpura with ADAMTS13 defi-ciency and renal involvement. J. Am. Soc.Nephrol. 16:1177–83

61. Tarr PI, Gordon CA, Chandler WL.2005. Shiga-toxin-producing Escherichiacoli and haemolytic uraemic syndrome.Lancet 365:1073–86

62. Goodship T. 2004. Inherited dysregula-tion of the complement system. Bull.Mem. Acad. R. Med. Belg. 159:195–98

63. Dragon-Durey MA, Loirat C, Cloarec S,et al. 2005. Anti-Factor H autoantibodiesassociated with atypical hemolytic uremicsyndrome. J. Am. Soc. Nephrol. 16:555–63

64. Arai S, Allan C, Streiff M, et al. 2001. VonWillebrand factor-cleaving protease activ-ity and proteolysis of von Willebrand fac-tor in bone marrow transplant-associatedthrombotic microangiopathy. Hematol. J.2:292–99

64a. Rieger M, Mannucci PM, Kremer Hov-inga JA, et al. 2005. ADAMTS13 au-toantibodies in patients with thromboticmicroangiopathies and other immunome-diated diseases. Blood 106:1262–67

65. Fortin MC, Raymond MA, Madore F,et al. 2004. Increased risk of thromboticmicroangiopathy in patients receiving acyclosporin-sirolimus combination. Am.J. Transplant. 4:946–52

66. Daly AS, Hasegawa WS, Lipton JH,et al. 2002. Transplantation-associated

thrombotic microangiopathy is associ-ated with transplantation from unrelateddonors, acute graft-versus-host diseaseand venoocclusive disease of the liver.Transfus. Apheresis. Sci. 27:3–12

67. Byrnes JJ, Moake JL, Klug P, et al. 1990.Effectiveness of the cryosupernatant frac-tion of plasma in the treatment of refrac-tory thrombotic thrombocytopenic pur-pura. Am. J. Hematol. 34:169–74

68. Rock G, Shumak KH, Sutton DM, et al.1996. Cryosupernatant as replacementfluid for plasma exchange in thromboticthrombocytopenic purpura. Members ofthe Canadian Apheresis Group. Br. J.Haematol. 94:383–86

69. Zeigler ZR, Shadduck RK, Gryn JF, et al.2001. Cryoprecipitate poor plasma doesnot improve early response in primaryadult thrombotic thrombocytopenic pur-pura (TTP). J. Clin. Apheresis 16:19–22

70. Rock G, Anderson D, Clark W, et al.2005. Does cryosupernatant plasma im-prove outcome in thrombotic thrombocy-topenic purpura? No answer yet. Br. J.Haematol. 129:79–86

71. Yomtovian R, Niklinski W, Silver B, et al.2004. Rituximab for chronic recurringthrombotic thrombocytopenic purpura: acase report and review of the literatures.Br. J. Haematol. 124:787–95

72. Fakhouri F, Vernant JP, Veyradier A,et al. 2005. Efficiency of curative andprophylactic treatment with rituximab inADAMTS13-deficient thrombotic throm-bocytopenic purpura: a study of 11 cases.Blood 106:1932–37

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THROMBOTIC THROMBOCYTOPENIC PURPURA C-1

Figure 1 Schematic depiction of the homologous domain structure of ADAMTS13.The sequence of ADAMTS13 consists of a signal peptide, a propeptide that endswith a consensus RQRR sequence, a metalloprotease domain with zinc-bindingcatalytic sequence motif (HExGHxxGxxHD), a disintegrin-like domain, a centralthrombospondin type 1 repeat (TSR-1), a cysteine-rich domain, a cysteine-free spacer region, seven additional TSR-1s, and two unique CUB (complement, uEGF,and bone morphogenesis) domains. The metalloprotease domain is essential for vonWillebrand factor cleaving activity. The cysteine-rich and spacer domain sequencemarkedly enhances the potency of the protease.

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Figure 2 Schematic depiction of the critical role of shear stress in enhancing VWF-platelet aggregation as well as in cleavage of VWF by ADAMTS13. (a) At a site ofvessel injury, VWF binds to extracellular ligands and quickly becomes unfolded byhigh levels of shear stress in the arterioles and capillaries. (b) In normal circulation,ADAMTS13 cleaves partially unfolded VWF. This process progressively decreasesthe size of VWF but maintains the VWF molecules in a globular, inactive conforma-tion. (c) When ADAMTS13 is missing, VWF becomes unfolded to elongated forms,causing platelet aggregation and intravascular thrombosis characteristic of TTP.

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P1: JRX

December 16, 2005 20:57 Annual Reviews AR262-FM

Annual Review of MedicineVolume 57, 2006

CONTENTS

ANGIOGENESIS, Judah Folkman 1

ADVANCES IN RADIATION ONCOLOGY, Mohamed Elshaikh,Mats Ljungman, Randall Ten Haken, and Allen S. Lichter 19

BORTEZOMIB: PROTEASOME INHIBITION AS AN EFFECTIVEANTICANCER THERAPY, Paul G. Richardson, Constantine Mitsiades,Teru Hideshima, and Kenneth C. Anderson 33

CHEMOPREVENTION OF PROSTATE CANCER, Eric A. Klein 49

EFFECTIVE CANCER THERAPY THROUGH IMMUNOMODULATION,Thomas A. Waldmann 65

MOLECULAR APPROACHES IN PEDIATRIC ONCOLOGY, Chand Khannaand Lee J. Helman 83

MOLECULAR IMAGING IN THE DEVELOPMENT OF CANCERTHERAPEUTICS, Johannes Czernin, Wolfgang A. Weber,and Harvey R. Herschman 99

PHARMACOGENOMICS AND INDIVIDUALIZED DRUG THERAPY,Michel Eichelbaum, Magnus Ingelman-Sundberg,and William E. Evans 119

AVIAN FLU TO HUMAN INFLUENZA, David B. Lewis 139

EMERGING THERAPEUTICS FOR CHRONIC HEPATITIS B,Mark E. Mailliard and John L. Gollan 155

THE ROTAVIRUS VACCINE SAGA, Alan R. Shaw 167

WEST NILE VIRUS: EPIDEMIOLOGY AND CLINICAL FEATURES OF ANEMERGING EPIDEMIC IN THE UNITED STATES, Edward B. Hayesand Duane J. Gubler 181

PROSTATITIS/CHRONIC PELVIC PAIN SYNDROME,Geoffrey M. Habermacher, Judd T. Chason, and Anthony J. Schaeffer 195

CELIAC DISEASE, Peter H.R. Green and Bana Jabri 207

AMYLOIDOSIS, Mark B. Pepys 223

SURGICAL TREATMENT OF MORBID OBESITY, Peter F. Crookes 243

THERAPEUTIC APPROACHES TO PRESERVE ISLET MASS IN TYPE 2DIABETES, Laurie L. Baggio and Daniel J. Drucker 265

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December 16, 2005 20:57 Annual Reviews AR262-FM

vi CONTENTS

ENZYME REPLACEMENT FOR LYSOSOMAL DISEASES,Roscoe O. Brady 283

GENETIC BASIS OF LIPODYSTROPHIES AND MANAGEMENT OFMETABOLIC COMPLICATIONS, Anil K. Agarwal and Abhimanyu Garg 297

NUCLEAR RECEPTORS IN LIPID METABOLISM: TARGETING THE HEARTOF DYSLIPIDEMIA, Simon W. Beaven and Peter Tontonoz 313

HEMOCHROMATOSIS: GENETICS AND PATHOPHYSIOLOGY,Ernest Beutler 331

THERAPEUTIC USE OF CALCIMIMETICS, Steven C. Hebert 349

TOWARD A UNIFIED THEORY OF RENAL PROGRESSION,Raymond C. Harris and Eric G. Neilson 365

CD4+CD25+ REGULATORY T CELLS AND THEIR THERAPEUTICPOTENTIAL, David A. Randolph and C. Garrison Fathman 381

UMBILICAL CORD BLOOD TRANSPLANTATION AND BANKING,Claudio G. Brunstein and John E. Wagner 403

CURRENT CONCEPTS IN THROMBOTIC THROMBOCYTOPENICPURPURA, Han-Mou Tsai 419

USE OF STENTS TO TREAT EXTRACRANIAL CEREBROVASCULARDISEASE, Philip M. Meyers, H. Christian Schumacher,Randall T. Higashida, Megan C. Leary, and Louis R. Caplan 437

NEW DIRECTIONS IN CARDIAC TRANSPLANTATION, Abdulaziz Al-khaldiand Robert C. Robbins 455

EXERCISE-INDUCED VENTRICULAR ARRHYTHMIAS IN PATIENTS WITHNO STRUCTURAL CARDIAC DISEASE, Melvin M. Scheinmanand Jason Lam 273

CARDIOTOXICITY INDUCED BY CHEMOTHERAPY AND ANTIBODYTHERAPY, Edward T.H. Yeh 485

“SUNDOWNING” AND OTHER TEMPORALLY ASSOCIATED AGITATIONSTATES IN DEMENTIA PATIENTS, David Bachman and Peter Rabins 499

CURRENT PHARMACOTHERAPY FOR ALZHEIMER’S DISEASE,A. Lleo, S.M. Greenberg, and J.H. Growdon 513

NEW TREATMENTS FOR NEUROPATHIC PAIN, Andrew S.C. Riceand Raymond G. Hill 535

PLANT, SYNTHETIC, AND ENDOGENOUS CANNABINOIDS IN MEDICINE,Vincenzo Di Marzo and Luciano De Petrocellis 553

THE HEALTH INSURANCE PORTABILITY AND ACCOUNTABILITY ACT OF1996 (HIPAA) PRIVACY RULE: IMPLICATIONS FOR CLINICALRESEARCH, Rachel Nosowsky and Thomas J. Giordano 575

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CURRENT CONCEPTS IN THROMBOTIC THROMBOCYTOPENIC PURPURA

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