thrombotic microangiopathies: towards a pathophysiology-based

Cardiovascular & Haematological Disorders-Drug Targets, 2009, 9, 000-000 1

1871-529X/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd.

Thrombotic Microangiopathies: Towards a Pathophysiology-Based Classification

Paul Coppo1,*

and Agnès Veyradier2

1Service d’Hématologie et de Thérapie Cellulaire, Hôpital Saint-Antoine, AP-HP, UPMC Univ Paris 6, Paris, France;

2Service d’Hématologie Biologique, Hôpital Antoine Béclère, AP-HP, Université Paris XI, Clamart, France

Abstract: Thrombotic microangiopathies (TMA) encompass various diseases characterized by a microangiopathic hemo-

lytic anemia, platelet clumping, and organ failure of variable severity. Thrombotic thrombocytopenic purpura (TTP) is a

particularly severe form of TMA characterized by systemic organ failure which results from a severe defect in

ADAMTS13, a plasma enzyme specifically involved in the cleavage of highly hemostatic unusually large (UL) von

Willebrand factor (VWF) multimers into smaller and less adhesive VWF forms. Failure to degrade these UL-VWF mul-

timers leads to excessive platelet aggregates and capillary occlusion. ADAMTS13 deficiency results from bi-allelic muta-

tions in hereditary TTP, whereas in acquired forms it results from autoantibodies that alter the protein function. Patients

with acquired idiopathic TTP have a trend to develop autoimmunity, since a clinical context of autoimmunity may be

found in 30p. cent of cases. Moreover, the remarkable efficiency of monoclonal antibodies directed against CD20 antigen

of B lymphocytes in refractory or chronic relapsing forms provides an additional indirect argument to consider acquired

TTP as an autoimmune disease.

Hemolytic uremic syndrome (HUS) is characterized prominently by a renal failure. In most cases, HUS is caused by en-

tero-hemorrhagic Escherichia coli (diarrhea-positive HUS). Diarrhea-negative HUS, termed atypical HUS, was associated

with a dysfunction in complement pathway involving mutations in factor H, factor I, CD46/MCP, factor B and C3 com-

ponents.

The major improvement in our understanding of TMA pathophysiology allows now a more accurate molecular classifica-

tion of TMA syndromes, which opens fascinating perspectives of targeted therapies in the forthcoming years.

Key Words : Thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, thrombotic microangiopathies, thrombocy-

topenia, ADAMTS13, autoimmune disease, complement.

INTRODUCTION

Thrombotic microangiopathies (TMA) encompass a het-

erogeneous group of disorders characterized by the associa-

tion of a microangiopathic hemolytic anemia (Fig. 1A) with

peripheral thrombocytopenia and organ injury of variable

severity, that result from microthrombi in capillaries and

arterioles (Fig. 1B). These diseases can affect people of all

classes of age, although some forms are more frequently

observed in children, while others are more likely encoun-

tered in adult population. Distinct subsets of TMA can be

distinguished depending on clinical presentation and physio-

pathological mechanisms. In 1924, Moschcowitz described

thrombotic thrombocytopenic purpura (TTP) as an acute

febrile pleiochromic anemia with hyaline thrombi in the ter-

minal arterioles and capillaries of the brain, heart, pancreas,

spleen, kidney and adrenal gland [1]. In hemolytic uremic

syndrome (HUS), severe acute renal failure with bilateral

necrosis of the renal cortex is the prominent feature, and

results from platelet-fibrin thrombi occluding predominantly

the renal circulation [2]. A TMA syndrome can also be

*Address correspondence to this author at the Service d’Hématologie et de

Thérapie Cellulaire, Hôpital Saint-Antoine, 184 rue du Fbg St Antoine

75012 Paris, France; Tel: 00*33 1 49 28 26 21; Fax: 00*33 1 49 28 32 00;

E-mail: [email protected]

observed in association with pregnancy, cancer and chemo-

therapy, human immunodeficiency (HIV) infection, malig-

nant hypertension, or following hematopoietic stem cell

transplantation.

Advances in recent years have delineated the molecular

mechanisms of some TMA syndromes, including TTP, some

atypical HUS and HELLP syndrome. These studies have

clearly revealed that TMA syndromes encompass several

distinct molecular defects, although the cause of TMA might

not be immediately apparent from the clinical presentation.

Concerning nomenclature and syndromic definitions, we use

here distinctively the terms TTP and HUS to identify TMA

syndromes fulfilling typical clinical and biological presenta-

tions of these respective entities. When the underlying cause

of disease is uncertain, the term TMA is preferred. This

work, based on the experience of the French group, aims to

present the most recent physiopathological and therapeutical

data in the field of TTP, HUS, and other TMA syndromes.

THE FRENCH REFERENCE CENTRE FOR THE

MANAGEMENT OF THROMBOTIC MICROAN-

GIOPATHIES

The French network on Thrombotic Microangiopathies is

a multidisciplinary collaborative group involving hematolo-

gists, ressuscitators, nephrologists, immunopathologists and

2 Cardiovascular & Haematological Disorders-Drug Targets, 2009, Vol. 9, No. 1 Raghupathy and Billett

biologists from more than 30 national sites, which objective

is to coordinate the management and the study of TMA at the

national level. For this aim, the French Network set up a

prospective registry which currently involves more than 650

patients exhaustively studied between 2000 and 2008. This

approach allowed improving considerably our experience in

the field of these rare diseases, which now allows drawing

consensual diagnostic and therapeutical guidelines. In 2006,

our Network was designated by the French Ministry of

Health as the official national reference center for these rare

diseases, which helped strengthening the organization at the

national level and improving the distributed information

among health actors, patients and their families.

THROMBOTIC THROMBOCYTOPENIC PURPURA

Pathophysiology

Infections and Endothelial Activation

Despite their sharp heterogeneity, TMA share some

common pathophysiological mechanisms. Particularly, endo-

thelium damage and activation may be a general phenome-

non involved in the initiation of a TMA episode [3] [4]. Fac-

tors involved in this early process may include infections,

medications, immune complexes, cancer cells, or alloreactiv-

ity. The association between TTP and infections as triggering

factors is well recognized for many years [5]. Various patho-

gens (bacterials, viruses, fungal agents or parasites) could be

evidenced at the acute phase of TTP, or within the preceding

days. TTP was also reported after administration of vaccinal

antigens. Multiple mechanisms may be involved in endothe-

lial activation by microbial-derived antigens. In vitro studies

provided evidence that bacterial structures such as lipopoly-

saccharide (LPS) act synergistically with various mediators

of inflammation to activate endothelium. These include in-

terleukin (IL)-1, IL-6, interferon- , tumor necrosis factor

(TNF)- and Fas-ligand [6] [7]. As a consequence, endothe-

lial cells acquire a proaggregant phenotype by releasing

highly adhesive von Willebrand factor (VWF) multimers and

by expressing adhesion molecules at their surface. On the

opposite, they decrease the release of prostaglandin-I2, a

strong endogenous antiplatelet agent. In patients with deter-

mined risk factors for TTP, these features lead to a persistent

platelet aggregation with thrombi formation and systemic

microvessels occlusion.

Role of Von Willebrand Factor and ADAMTS13 Defi-

ciency

VWF is a multimeric protein involved in the initiation of

platelet clumping. It is synthesized and released by endothe-

lial cells and stored in cytoplasmic organelles called Weibel-

Palade granules. The basal structure of VWF is a 200 to 300

kDa monomer. Those monomers are linked by disulfide

bonds and form multimers of 500 to 20-30000 kDa with a

globular conformation which diminishes VWF-platelet inter-

action. In high shear stress conditions, however, those high

molecular weight VWF multimers become unfolded and

display many binding sites for ligands, enhancing their he-

mostatic activity [8].

The link between VWF and TTP pathophysiology was

provided by the seminal work of Moake [9], who found that

patients with chronic relapsing TTP displayed large amounts

of circulating high molecular weight VWF at the acute phase

of the disease and during remission. Since these unusually

large VWF multimers are absent in normal plasma, Moake

hypothesized that a yet undiscovered plasma protease was

involved in the cleavage of hyper-adhesive VWF multimers.

This protein was purified in 1996 by Tsai and Furlan inde-

pendently [10] [11], and cloned in 2001 [12]. It is a specific

zinc metalloproteinase called ADAMTS13 (acronym for A

Disintegrin And Metalloproteinase with ThromboSpondin-1

motifs), that specifically cleaves unfolded, high molecular

weight VWF multimers between tyrosine 842 and methio-

nine 843 residues of A2 domain in high shear stress condi-

tion (Fig. 2). As a consequence, a dysfunction of ADAMTS13

leads to a persistent VWF-dependent platelet accumulation,

eventually causing microvascular thrombosis and TTP (Fig.

3).

The ADAMTS13 gene contains 29 exons spanning ap-

proximately 37 kb on chromosome 9q34. It encodes a 4.7-kb

transcript that is expressed primarily in the stellate cells of

the liver (Ito cells) and a 2.4-kb transcript in multiple tissues

including placenta, skeletal muscle and certain tumor cell

lines. Plasma ADAMTS13 concentration in about 1 g/ml

and its evaluated plasmatic half-life is 3 days [13]. Until

Fig. (1). (A) blood smear disclosing fragmented red cells or

schistocytes. Red cells undergo fragmentation in microvasculature,

which calibre is severely reduced by platelet thrombi. Schistocytes

may undergo multiple fragmentations. (B) Typical histopathologi-

cal features of thrombotic microangiopathy (TMA) on a renal

biopsy. Multiple thrombi are observed in glomerular capillaries and

in arterioles (red staining). Thrombi may predominantly be made of

von Willebrand factor (TTP), or either fibrin (HUS).

Thrombotic Microangiopathies Cardiovascular & Haematological Disorders-Drug Targets, 2009, Vol. 9, No. 1 3

now, ADAMTS13 remains the only enzyme involved in the

cleavage of VWF multimers. However, it is not excluded

that other proteins may act in concert with ADAMTS13 to

process VWF multimers. Indeed, thrombospondin-1 (TSP-1)

is an enzyme with reductase activity towards VWF disulfide

bonds, which may facilitate ADAMTS13 access to VWF

cleavage sites [14]. By regulating VWF multimers size,

ADAMTS13 was also reported to have a role in the regula-

tion of leukocytes rolling and adhesion on endothelial cells

and in neutrophils extravasation during inflammation [15]. In

addition, although not yet observed in humans, complete

deficiency of ADAMTS13 in mice was reported to be

prothrombotic, even in the absence of findings consistent

with TTP [16].

In normal healthy individuals, ADAMTS13 activity

ranges between 50 and 150 p. cent. ADAMTS13 activity is

often mildly decreased (20 to 40 p. cent of activity) in vari-

ous contexts such as disseminated intravascular coagulation,

liver cirrhosis, severe sepsis, idiopathic thrombocytopenic

purpura, or systemic lupus erythematosus (not associated

with TMA) [17] [18]. A low ADAMTS13 activity was also

reported in particular physiological conditions, such as eld-

erly, neonates, during pregnancy, or after a surgical proce-

dure [19] [18]. The significance of this result is still unclear;

it may result from a transient disturbance in protein synthe-

sis, and/or consumption in relation with an increase in circu-

lating VWF multimers concentrations. These results are in

sharp contrast to the extremely low levels (less than 5 p. cent

of normal values) of ADAMTS13 activity observed in 70 to

more than 90 p. cent of patients with TTP [20] [21] [22].

Moreover, ADAMTS13 activity was found normal or at least

detectable in most HUS cases [20] [23], or in other TMA

syndromes including hematopoietic stem cell transplanta-

tion-associated TMA, HELLP syndrome, or catastrophic

antiphospholipid syndrome.

Mecjmhanisms of ADAMTS13 Deficiency in TTP

The severely decreased ADAMTS13 activity observed in

TTP may result from biallelic mutations of ADAMTS13

gene (5 to 10 p. 100 of cases), which mainly involve pediat-

ric cases, or from autoantibodies directed to ADAMTS13 (90

to 95 p. 100 of cases), corresponding mostly to adult forms

[13].

ADAMTS13 Deficiency in Congenital TTP

Congenital TTP, previously known as Upshaw-Schulman

syndrome, is an autosomal recessive disease resulting from

biallelic mutations of ADAMTS13 gene. Until now, more

than 70 candidate mutations were reported, which involve

amino-acid substitutions (60 p. cent of cases), non-sense

mutations, or frameshift mutations (20 p. cent both). Half

mutations occur in the catalytic domain, the cystein-rich do-

main, and the spacer domain. These mutations have 2 func-

tional and non exclusive consequences. The first is the direct

loss of catalytic activity. In vitro experiments showed that

the deletion of the carboxy-terminal end of ADAMTS13

Fig. (2). (A) Western-blot analysis of von Willebrand factor (VWF) multimers in a patient with TTP and from normal human

plasma. VWF Multimers were separated by electrophoresis on polyacrylamide gel electrophoresis according to molecular weight and elec-

tro-transferred on a nitrocellulose membrane. Excessive levels of high molecular weight von Willebrand factor (VWF) multimers are ob-

served in the patient with TTP, as a result of severe ADAMTS13 deficiency. Those unusually high molecular weight multimers are not found

in normal human plasma (NHP). (B) Primary structure of ADAMTS13. PS: peptide signal. TSP-1: thrombospondin-1. CUB: complement

(C1r/C1s), uEGF (urchin epidermal growth factor), bone morphogenetic protein (acronym for 3 proteins harbouring these domains).


gene, including the CUB domains, the TSP-1 motifs and the

spacer domain only mildly reduced the enzyme activity,

whereas the deletion of the desintegrin-like domain results in

a severely decreased altered vWF cleavage. In patients how-

ever, mutations were found all over ADAMTS13 gene, sug-

gesting that all domains are critical for an optimal enzymatic

activity in vivo [24]. The second consequence of these muta-

tions is a defect in the release of ADAMTS13 by their secret-

ing cells, which may occur at the lateral pole of the cells

[13].

So far, no clear correlation could be established between

ADAMTS13 mutations and clinical presentation, suggesting

the involvement of additional factors in TTP pathophysiol-

ogy. These may include infectious processes (extrinsic fac-

tors), but also yet unknown “modifying genes” (intrinsic

factors) which may act in concert with ADAMTS13 in vari-

ous processes such as platelets aggregation, endothelial acti-

vation, or vascular homeostasis. This view was strongly sup-

ported by the analysis of ADAMTS13-deficient mice, in

which intravenous injection of a microbe-derived toxin de-

rived from bacterial pathogens associated with HUS resulted

in a striking syndrome closely resembling human TTP. Im-

portantly, this syndrome only occurred in Casa/Rk strain

mice, which harbor 5 to 10 times higher circulating VWF

multimers. Moreover, the absence of correlation between

circulating VWF multimers concentration and the severity of

TTP led the authors to conclude that additional genes may be

involved in this process [25]. Interestingly, this relevant

model of congenital TTP also allowed demonstrating the

crucial role of VWF in TTP since CASA/Rk/Adamts13-/-

mice in which VWF gene was also invalidated did not de-

velop TTP after shigatoxin administration [26].

ADAMTS13 Deficiency in Acquired TTP

In acquired TTP, ADAMTS13 deficiency usually results

from autoantibodies altering the protein activity, leading to

consider acquired TTP as an autoimmune disease. The effi-

ciency of immunomodulating agents such as rituximab in the

prevention of relapses in patients with persistent anti-

ADAMTS13 antibodies further comforted this view. In 38 to

95 p. cent of cases, anti-ADAMTS13 antibodies display an

inhibitory activity against the enzyme in vitro, as evidenced

by mixing the plasma of a patient with acquired TTP with

normal human plasma, thereby neutralizing the enzyme ac-

tivity of this latter [23] [27]. The wide range of these results

probably reflects the lack of standardization and reproduci-

bility of the assays for ADAMTS13 functional assays. In

patients with no detectable inhibitory anti-ADAMTS13 anti-

bodies, ADAMTS13 deficiency may be related to inhibitory

antibodies which concentration is below the detection

threshold of the current assays, or either to non-neutralizing

Fig. (3). Pathophysiological mechanisms leading to microthrombi formation in TTP. Endothelial cells may be activated by triggering

factors, mostly infections. Bacterial lipopolysaccharide, various cytokines and Fas-ligand may act in concert to activate endothelial cells.

Damaged endothelial cells release high molecular weight VWF multimers, as well as PAF, and express adhesion molecules at their surface.

In patients with a severe ADAMTS13 deficiency, high molecular weight VWF accumulate, which results in platelet hyperadhesiveness and

platelet clumping within microvasculature of various organs including brain, kidneys, digestive tract and heart. LPS: lipopolysaccharide;

TNF: tumor necrosis factor; IL: interleukin; PAF: platelet activating factor; VWF: von Willebrand factor.


antibodies, which are identified by ELISA [28]. In most

cases, anti-ADAMTS13 antibodies (either inhibitory or non-

inhibitory) are of IgG type. In rare cases, IgA and/or IgM

isotypes were associated with antibodies of IgG isotype, and

may worsen the prognosis [28] [29]. Anti-ADAMTS13 anti-

bodies may decrease ADAMTS13 activity by directly inhib-

iting the catalytic activity, or by decreasing protein concen-

trations through an opsonization process [29]. The inhibition

of ADAMTS13 binding to its endothelium receptor CD36 is

a tempting possible mechanism that still remains to be dem-

onstrated. Anti-ADAMTS13 may recognize various epitopes

among the protein. Antibodies directed against the cystein-

rich and the spacer domains are the most frequently ob-

served. These may be associated with antibodies directed

against CUB domains, the first thrombospondin-1 (TSP-1)

motif, or the region including the catalytic domain, the desin-

tegrin-like domain, and the first TSP-1 domain. More rarely,

these antibodies recognize the TSP-1 motifs 2 to 8, or the

propeptide domain [30]. Anti-ADAMTS13 IgG, as detected

by ELISA, were found in a majority of patients with severe

ADAMTS13 deficiency (35/36 patients, 97 p. 100), but also

in 3 patients with TTP showing a detectable ADAMTS13

activity (11 to 16 p. 100 of normal activity), which suggests

that ELISA sensitivity may be higher than this of functional

ADAMTS13 assays [31]. On the opposite, these antibodies

were not found in 4 patients with a diagnosis of HUS [31].

Those promising results, suggesting a specificity of anti-

ADAMTS13 for acquired TTP, need however confirmation

on larger series of patients.

Clinical Presentation

TTP is a specific subset of TMA usually characterized by

a microangiopathic hemolytic anemia with a profound pe-

ripheral thrombocytopenia, fever, central nervous system

manifestations, and renal failure [5]. However, these features

are complete only in 40 p. cent of cases; in other instances,

TTP may be revealed by only a bicytopenia without organ

involvement. Indeed, the only association of a microan-

giopathic hemolytic anemia with a peripheral thrombocy-

topenia should alert clinicians for this diagnosis. Importantly,

reports clearly emphasized that TTP may be underestimated

and under-recognized, particularly in children. As a general

rule, TTP should be systematically suspected in children

with a diagnosis of peripheral cytopenia, particularly if asso-

ciated with any organ involvement. In patients with an ap-

parent diagnosis of idiopathic thrombocytopenic purpura or

Evan’s syndrome not responding to usual therapies, the iden-

tification of schistocytes on repeated blood smears, in asso-

ciation with a severe ADAMTS13 deficiency may allow

revisiting the diagnosis [32].

Central nervous system involvement occurs in 84 to 92 p.

cent of cases and was shown to be associated with a worse

prognosis by some groups [33]. It may result in confusion,

obnubilation, headache, somnolence, coma and seizure. A

focal sensitive or motor deficiency, dysarthria, or aphasia

may also be observed. Brain magnetic resonance imagery

may disclose punctiform images in white matter resulting

from ischemia. Thrombosis or hemorrhage may also be ob-

served. Fever is observed in 59 to 98 p. cent of cases. Renal

failure is usually mild and is observed in half of cases. A

mild proteinuria and/or hematuria may also be observed.

Heart involvement may be characterized by thoracic pain,

repolarization or conduction changes, and elevated troponin

Ic, which may reflect left ventricular dysfunction [34]. Di-

gestive involvement, associating vomiting and abdominal

pain with sometimes pancreatitis, or more rarely, lung and

ocular injury, may occur.

Histopathologically, TTP is characterized by the presence

of widespread hyaline thrombi in the terminal arterioles and

capillaries, accounting for organ failure. The high levels of

shear stress in the arterioles and capillaries are believed to be

a critical factor in determining the distribution of thrombosis

in TTP. Autopsic studies revealed that thrombi involved

most organs, including the brain (mainly cerebral cortex),

heart, spleen, pancreas, adrenal gland and kidney. Thrombi

are composed primarily of platelets and VWF, which con-

trasts with the thrombi of disseminated intravascular coagu-

lopathy or the HUS, which are rather characterized by

prominent fibrin deposits [35].

Acquired TTP

Acquired TTP occurs more frequently in females (3 fe-

males for 2 males), within the fourth decade. The onset of

disease is typically sudden. However, prodromic manifesta-

tions including fatigue, arthralgias, myalgias, abdominal or

lumbar pain, suggesting a flu-like episode are frequently

observed. The incidence of TTP was reported to be of 4

cases per million hab. per year. Acquired TTP could be asso-

ciated with various autoimmune diseases, especially SLE (4

p. 100 of SLE cases) [36]. More generally, acquired TTP is

associated in one third of cases with various manifestations

suggesting an underlying autoimmune process. Antinuclear

antibodies or antibodies directed against CD36 are observed

in up to two third of cases [37] [38]. Finally, questioning the

patients with an acquired TTP allow sometimes evidencing a

history of autoimmune disease in other family members.

These observations, arising from series of adult patients or

either from more limited series of pediatric cases [39], highly

suggest that patients with acquired TTP have a trend to de-

velop autoimmune manifestations. In addition, multiple stud-

ies focused on the higher prevalence of acquired TTP in par-

ticular ethnical groups, such as Afro-Caribbeans [27] [38]

[40], suggesting the existence of susceptibility genes in-

volved in the loss of tolerance of the immune system towards

ADAMTS13. The report of acquired TTP in two twin sisters

at 23 and 24-year old further supports this hypothesis [41].

Whether anti-ADAMTS13 antibodies have a prognostic

value in TTP is the matter of intensive research. The identifi-

cation of inhibitory anti-ADAMTS13 antibodies was associ-

ated with a longer time to platelet count recovery and larger

volumes of plasma, in relation with more frequent early re-

lapses during intensive treatment or during the decrease of

plasma exchange sessions [42] [43] [44]. In addition, a high

titre of anti-ADAMTS13 antibodies (either inhibitory or non-


inhibitory) as evidenced by ELISA was correlated with a

persistently decreased ADAMTS13 activity. Interestingly,

this latter condition could be associated with a relapse risk of

50 p. cent, whereas patients who normalize ADAMTS13

activity may relapse in less than 10 p. cent of cases [29] [45].

Indeed, the study of ADAMTS13 activity after complete

remission achievement may have an important prognostic

value in evaluating the probability of relapse [46] [45]. Mul-

ticentre, large prospective studies with standardized assays

should further clarify the prognostic value of neutralizing

and non-neutralizing anti-ADAMTS13 antibodies and draw-

ing definitive conclusions.

Congenital TTP

Congenital TTP, previously termed Upshaw-Schulman

syndrome, is an autosomal recessive disorder usually ob-

served in children and newborns. Consequently, probands

may be either male or female and parents (who may be con-

sanguineous) are healthy with a mild decrease in ADAMTS13

activity. Congenital TTP may be revealed by cytopenias or

jaundice in the neonatal period (about 75 p. cent of cases) or

later, usually in the first decade [24]. Some congenital TTP

may be revealed in adulthood [47], particularly within a con-

text of pregnancy. Clinical manifestations typically include

anemia, thrombocytopenia, and organ involvement of vari-

able severity. In neonates, unexplained hemolysis and throm-

bocytopenia sometimes result in exsanguino-trans-fusion

sessions. Patients frequently experience repeated relapses at

varying intervals that are frequently triggered by non specific

infectious processes, including flu-like episodes. Initially,

TTP episodes may resolve completely; however, when mul-

tiple relapses occur, those patients with a chronic relapsing

form may develop a chronic renal failure or ischemic lesions

in brain. In other instances, patients may present with mod-

erate chronic hemolysis and thrombocytopenia. A history of

hemolysis or thrombocytopenia may be found in other fam-

ily members.

Treatment and Outcome

Plasmatherapy

Without treatment, acquired TTP is almost always fatal,

whereas under rigorous management, up to 80 p. cent of pa-

tients recover. Treatment is based on therapeutical plasma

exchanges [48] [49], which have to be started as soon as the

diagnosis is established or even suspected. If plasma ex-

changes cannot be performed immediately, high dose plasma

infusions should be started in emergency until plasma ex-

change availability [50]. Plasma exchanges allow bringing

large volumes of plasma that will supply ADAMTS13 defi-

ciency. Plasma exchanges may have additional therapeutical

effects such as removal of anti-ADAMTS13 antibodies or of

high molecular weight VWF from plasma; however, the im-

portance of these latter in patients’ improvement remains

elusive. Plasma exchanges are performed daily until durable

platelet recovery. The rapid or progressive decrease in

plasma exchanges sessions remains a matter of debate. In 30

to 40 p. cent of cases, patients experience one or multiple

relapses after the initial episode, which require to resume

intensive plasmatherapy. The period between relapses may

range from days to many years. In 10 p. cent of cases, TTP is

unresponsive to plasma exchanges and requires more inten-

sive plasmatherapy and/or immunomodulatory therapies.

Patients with congenital TTP are efficiently treated with

plasma infusions. In patients with chronic relapsing forms or

persistent hemolysis and thrombocytopenia, prophylactic

infusions every 2 to 3 weeks may efficiently control the dis-

ease and prevent serious complications. Other patients may

maintain normal or mildly subnormal platelet counts and

require plasma infusion only during intermittent acute exac-

erbations.

Immunomodulatory Therapies

The view that acquired TTP is an autoimmune dis-

ease incites the use of immunomodulatory therapies. Steroids

are frequently proposed at the acute phase of the disease, in

association with plasma exchanges, but their efficacy was

not evaluated on controlled studies. Other immunomodula-

tory agents such as cyclosporin A, azathioprine, or vincris-

tine were also used efficiently in single cases or small series

of patients. Patients with a refractory, threatening disease

may be efficiently treated with pulses of cyclophosphamide

[51].

These last years, the chimeric monoclonal antibody ri-

tuximab, directed against CD20 antigen on B lymphocytes,

became the most frequently used immunomodulatory agent.

Indeed, patients with a refractory disease or showing inter-

mittent relapses were reported to be be efficiently treated

with high response rates, along with an increase in

ADAMTS13 activity and a decrease in anti-ADAMTS13

antibodies [52] [53]. However, the use of rituximab may not

systematically hamper long term relapses. Ongoing large,

prospective studies are attempting to specify the schedule of

rituximab administration in an order to reduce the number of

plasma exchanges, which are associated with significant

side-effects.

HEMOLYTIC UREMIC SYNDROME

Two forms of HUS are classically identified. The first

occurs after an intestinal infection resulting from a shiga-

toxin-producing Escherichia coli (STEC) strain; it is there-

fore termed STEC-associated HUS or diarrhea-associated

HUS (D+ HUS), and represents the most common form of

HUS (for an extensive review, see [54]). The second form,

termed atypical HUS, occurs out of a context of STEC infec-

tion and accounts for 5 to 10 p. cent of all cases of the disor-

der. It was associated with congenital or, more rarely, ac-

quired complement pathway dysfunctions [55]. TMA with

features of atypical HUS were also reported in patients with

abnormalities in cobalamins metabolism, or either in associa-

tion with various conditions such as HIV infection, autoim-

mune diseases, cancers and pregnancy. These latter are

thought to act as triggers causing endothelial cell activation

and injury, probably within a context of genetic susceptibil-

ity [55].


Pathophysiology

STEC-Associated HUS

Toxins released by shigatoxin-producing microorgan-

isms, most commonly Escherichia coli O157:H7 (shigatox-

ins 1 and 2) and Shigella dysenteriae serotype 1 (shigatoxin)

strains, are directly involved in D+ HUS pathophysiology

since their injection to non human primate leads to manifes-

tations mimicking HUS in a dose-dependent manner [56].

Shigatoxin is composed of one A subunit of 33 kDa and 5 B

subunits of 7.7 kDa each. Most E. coli O157:H7 carry the

gene encoding shigatoxin 2, and about two-thirds have the

gene encoding shigatoxin 1. Other strains have also been

involved: E. coli O111: H-, O26: H11 and O103: H2. Bacte-

rial agents ingested from contaminating sources proliferate in

the intestinal lumen and adhere to mucosal epithelial cells of

the colon. Shigatoxins damage the underlying tissue and

vasculature and cause bloody diarrhea. The lesions are po-

tentiated by neutrophils, which are recruited into the dam-

aged colon and activated by IL-8 and other chemokines. Shi-

gatoxins cross the intestinal barrier and are transported by

neutrophils, monocytes and platelets in blood flow onto renal

microcirculation. The toxins stimulate the release of TNF- ,

IL-1 and IL-6 from monocytes and renal glomerular and

tubular epithelial cells, which up-regulate the expression of

shigatoxins receptors called globotriaosylceramide and gal-

abiosylceramide.

Shigatoxins bind to their receptors through B subunits on

glomerular capillary endothelial cells, mesangial cells, and

glomerular and tubular epithelial cells. After internalization,

subunit A of shigatoxins inhibits 28S ribosomal subunit,

thereby inhibiting protein synthesis machinery. This process

leads to endothelial cell apoptosis and endothelial injury.

This damage is potentiated by the monocytes and neutrophils

that infiltrate the glomeruli in response to the secreted

chemokines such as IL-8 and fractalkine and the production

of monocyte chemoattractant protein 1 by renal cells. Renal

endothelial cell injury results in the expression of high mo-

lecular weight VWF multimers and adhesion molecules,

such as P-selectin, PECAM-1 (platelet-endothelial-cell adhe-

sion molecule 1) and vitronectin ( V 3 integrin) receptors.

Damaged endothelial cells also express high levels of tissue

factor, plasma activator inhibitor type 1 (PAI-1) and D-

dimers. All these features lead to a local prothrombotic state

resulting in increased platelet adhesiveness with fibrin-rich

microthrombi (Fig. 4).

It is estimated that only 5 to 15 p. cent of patients with

STEC-associated gastro-enteritis develop a full-blown HUS,

suggesting the involvement of yet unknown additional fac-

tors. These may include mutations or polymorphisms in pu-

tative susceptibility genes including shigatoxin receptor,

TNF and IL-1, as well as their receptors.

Atypical HUS

In children, as well as in adults, atypical HUS was asso-

ciated in up to 50 p. cent of cases with genetic changes in

genes involved in key regulators of alternative complement

pathway. Familial occurrence of atypical HUS has been rec-

ognized for many years. Inheritance is now thought to be

dominant with a global 50 p. cent penetrance. In 1998, War-

wicker et al. could show a segregation of the disease to the

q32 region of chromosome 1 [57], which contains genes in-

volved in the regulation of complement activation.

The complement system is an ancient innate immune

network of plasma proteins that began evolutionary as a host

defense system of hemolymph. The oldest cascade, the alter-

native pathway, allows to rapidly coat invading microbes

with large quantities of the opsonic complement fragment

Fig. (4). Pathophysiological mechanisms leading to microthrombi formation in diarrhea-associated HUS. Shigatoxins are transported

in blood flow by neutrophils, platelets and monocytes, and bind their receptors (globotriaosyl ceramide) at the surface of renal endothelial

cells. IL-1, IL-6 and TNF- up-regulate expression of shigatoxins receptors on endothelial cells surface. After internalization, they interfere

with protein traduction machinery and thereby induce endothelial cell apoptosis. Damaged cells express surface high molecular weight VWF,

which initiates platelet clumping through interaction with glycoprotein Ib. Shigatoxins also induce tissue factor expression on endothelial

cells, leading to factor VII activation and fibrin formation. VWF: von Willebrand factor.


C3b (Fig. 5). This process is facilitated by an amplification

loop that results in the deposition of several million mole-

cules of C3b on bacteria within a few seconds. Complement

activation may also occur on altered self-tissues, such as on

cells undergoing apoptosis and at sites of injury and infec-

tion. To prevent excessive production and deposits of C3b,

the alternative pathway is finely regulated by proteins that

prevent C3 activation. Indeed, heterozygous mutations (hap-

loinsufficiency) in these regulators predisposes humans to

HUS [58].

Complement Proteins Implicated in Atypical HUS

The first complement protein associated with atypical

HUS was factor H, a 150-kDa plasma protein composed of

20 short consensus repeats of 60 amino-acids each. Factor H

normally protects host cells from accidental damage by the

alternative complement pathway by displacing Bb from C3b,

thereby exposing C3b to cleavage and inactivation by factor

I. Mutations in the factor H gene in atypical HUS have now

been widely described. More than 100 disease-associated

mutations are reported in the factor H-HUS mutations data-

base (http://www.FH-HUS.org). Twenty to 30 p. cent of pa-

tients with atypical HUS were reported to harbour heterozy-

gous mutations in factor H [59]. Missense mutations, dele-

tions and frame shifts in the factor H gene have been identi-

fied in patients and their relatives. Most mutations cluster in

short consensus repeat number 20 of factor H gene in the C-

terminal end of the protein, which disrupts a heparine-

binding site involved in factor H binding to host surfaces. In

most cases, they consist in missense mutations and are asso-

ciated with normal levels of circulating factor H. In the re-

maining cases, they result in either a truncated protein or

impaired secretion of the protein and thus cause a 50 p. cent

reduction in plasma levels of factor H. A mouse model of

HUS designed to mirror human mutations in factor H con-

firmed that the binding of factor H in anionic targets such as

heparine on endothelial cells surface had a crucial impor-

tance since suppression of this function resulted in the occur-

rence of HUS features [60]. Of note, mutations were also

observed in genes harbouring sequence homologies with

factor H gene (CFHR [complement factor H-related]1 and

CFHR3), as well as fusion genes between factor H and

CFHR1. An acquired dysfunction in factor H related to anti-

factor H antibodies of IgG type was also reported in 3 pediat-

ric cases of atypical HUS [61]. Those antibodies are usually

associated with mutations of CFHR1.

Further proteins involved in complement regulation, such

as factor I or CD46/MCP (membrane cofactor protein) were

also found mutated in atypical HUS [62] [63] [64] [65]. Mu-

tations in factor I were reported in < 4 p. cent to 13 p. cent of

cases. In 30 p. cent of cases, this latter is associated with

additional mutations of complement components or with

anti-factor H antibodies. Mutations in CD46/MCP were re-

ported in 13 p. cent of cases [59]. Mutations in the gene en-

coding factor B were found to enhance formation of the al-

ternative C3 convertase C3bBb or increase resistance to in-

activation [66]. More recently, heterozygous mutations in

complement C3 were identified in 11 patients and 3 relatives

with atypical HUS. These were heterozygous missense or

nonsense mutations, which resulted in most cases in a gain of

function of complement activation through a reduced interac-

tion with MCP or factor H (the major inhibitors of the alter-

native complement pathway) [67].

The specific role of these abnormalities in the occurrence

of HUS features still remains hypothetical. They could result

Fig. (5). Key regulators of alternative complement pathway involved in atypical HUS. Mutations in factor H, factor I, CD46/MCP

(membrane cofactor protein), as well as auto-activating mutations in complement factor B and C3 were reported. Factor H dysfunction may

also involve autoantibodies. It is hypothesized that those mutations result in excessive complement activation, with renal endothelial cells

damage and hyperexpression of tissue factor, fibrin formation and thrombi formation. : mutated protein.


in an excessive activation of complement pathway mediated

by infectious agents or immune complexes, with a subse-

quent release of excessive amounts of complement compo-

nents such as C5 and membrane attack complex. As a conse-

quence, damaged renal endothelial cells may express pro-

coagulant proteins including local tissue factor with factor

VIII binding and activation, leading to the generation of

thrombin and fibrin polymers (Fig. 5). Noteworthy, results

obtained from patients and analysis of animal models clearly

emphasize that atypical HUS appears more and more as a

multigenic disease involving multiple complement genes in

an individual patient. Therefore, those mutations must be

considered to be predisposing rather than causative, as a

trigger factor (such as infections or a pregnancy) is necessary

to initiate the disease [58].

Interestingly, factor H dysfunctions were also reported in

other diseases in which this protein may have a role in pro-

tecting cells against various insults. Indeed, age-related

macular degeneration was associated with a polymorphism

in short consensus repeat 7 of factor H [68], whereas mem-

branoproliferative glomerulopathies were associated with a

complete deficiency in factor H. Mutations in factor H, but

also in factor I and CD46/MCP were reported in HELLP

syndrome [69], suggesting that this disorder may be an addi-

tional form of TMA with complement dysfunction as risk

factors.

Streptococcus Pneumoniae-Associated HUS

HUS associated with a pneumococcal infection is a spe-

cific form of HUS, resulting from the expression of Thom-

sen-Friedenreich antigen at the surface of erythrocytes, endo-

thelial cells, and glomerules. This antigen, which is normally

covered by sialic acid, is exposed by the pneumococcal-

secreted neuraminidase, and subsequently recognized by

circulating IgM, leading to platelet aggregation with endo-

thelial and glomerular lesions. Consequently, plasmatherapy

is usually contra-indicated in this form of HUS since IgM

provided by plasma infusions may exacerbate the disease.

HUS Associated with Cobalamin Disorders

Atypical HUS was associated with dysfunctions of

cobalamin metabolism disorders. Cobalamin (vitamin B12)

derivatives, methylcobalamin and adenosylcobalamin, par-

ticipate as cofactors for the enzymes 5-methyltetrahydro-

folate-homocysteine methyltransferase and methylmalonyl-

CoA mutase. These enzymes are involved in the remethyla-

tion of homocysteine to methionine and in the conversion of

L-methylmalonyl-CoA to succinate, respectively. Comple-

mentation studies subgroup Cbl disorders from cblA to cblH.

CblC complementation group is the principal inborn error of

Cbl metabolism associated with atypical HUS. Renal com-

plications of CblC disease are thought to be mainly due to

hyperhomocysteinemia-induced damage to glomerular endo-

thelium [70].

Clinical Presentation

D+ HUS represents more than 90 p. cent of HUS cases in

children before 3 year-old; therefore, any child presenting for

the first time with a TMA syndrome, but who does not have

diarrhea, could still be infected with an STEC. Those pa-

tients should thus be investigated for the presence of an

STEC by microbiological analysis of the stools and urines.

The incidence of diagnosed E. coli O157:H7 infections is

greater among rural than urban populations, probably be-

cause of greater exposure to animals excreta. Transmission

from cattle to people might be airborne. D+ HUS may occur

within an epidemic context, mostly in the summer and

autumn. In Buenos-Aires (Argentina) where STEC infections

are endemic, HUS has a very high incidence. Bacterial

strains can contaminate unpasteurized milk or dairy prod-

ucts, ground beef, insufficiently cooked food, as well as mu-

nicipal or swimming water. Diarrhea occurs 2 to 12 days

later, and becomes bloody after 1 to 3 days. Abdominal pain

may be intense and greater than is generally observed in

other forms of bacterial gastroenteritis. Defecation may also

be painful.

Cerebral manifestations are important determinants of

morbidity and mortality. They can be observed in 50 p. cent

of cases. Analysis of blood pressure and metabolic parame-

ters on admission did not predict which child would exhibit

cerebral signs. During the course of the illness however,

children with cerebral involvement had more severe azote-

mia, lower minimum sodium concentrations and required

more dialysis [71]. Cerebral magnetic resonance imaging

(MRI) and computerized tomography may evidence features

of cerebral oedema within parieto-occipital white matter,

suggestive of posterior leuko-encephalopathy. These features

were more frequently observed in patients with severe high

blood pressure. Patients with seizure and/or coma may dis-

play ischemic lesions of basal ganglia with hemorrhagic in-

farction [72].

Other non-renal complications such as cardiac dysfunc-

tion, intestinal complications including perforation and ne-

crosis, and pancreatitis have been reported more rarely.

Treatment and Outcome

HUS management systematically requires a symptomatic

treatment, including haemodialysis, control of renin-depen-

dent high blood pressure with angiotensin convertase inhibi-

tors or angiotensin receptors antagonists. In D+ HUS, intra-

venous rehydratation with isotonic crystalloid and mainte-

nance fluid provide optimum nephroprotection. Plasmather-

apy does not seem to modify the prognosis, which remains

good under symptomatic treatment. Antibiotics, antimotility

agents or narcotics were associated with a worsening of the

disease, and should thus be avoided. Non-steroidal anti-

inflammatory agents, by diminishing renal blood flow,

should not be used either. Prognosis of D+ HUS is usually

good, and end stage renal failure or death are observed in up

to 12 p. cent of cases, with 25 p. cent of survivors demon-

strating long term renal sequelae [73].

Atypical HUS is typically characterized by a high mortal-

ity rate (54 p. cent). About half of survivors experience re-

lapses, and over one third require long-term dialysis. From

pediatric series, children with factor H or factor I mutations


develop relapses leading rapidly to end-stage renal failure

and/or death. Factor H mutations were associated with the

most severe prognosis, since 60 p. cent of patients reached

end stage renal failure or died within <1 year. Half of pa-

tients with factor I mutation have a rapid evolution to end

stage renal failure, and half recover. Patients with factor H or

factor I mutations usually relapse after renal transplantation.

Patients with CD46/MCP mutations have a better prognosis

characterized by a relapsing course without end stage renal

failure. Moreover, the rate of relapse after kidney transplan-

tation is low in this group [74].

Plasma exchanges were reported to have a beneficial

effect in one third of children from all groups except for pa-

tients harbouring MCP mutations [74]. In atypical HUS with

factor H mutations, kidney and liver transplantations were

intended, but this procedure is associated with a significant

mortality risk [75]. Targeted therapies aimed at supplying the

abnormal proteins or inhibiting complement pathway should

be evaluated in the forthcoming years.

HUS associated with cobalamin disorders require par-

enteral administration of hydroxocobalamin [70].

OTHER TMA SYNDROMES

Pregnancy and Post-Partum

TMA occurring in the setting of pregnancy and post-

partum may display features of acquired or congenital TTP,

as well as HUS or HELLP syndrome. Indeed, pregnancy

may reveal ADAMTS13 or complement dysfunctions result-

ing from gene mutations [69]. HELLP syndrome needs to be

identified since it implies a foetal extraction, whereas TTP

may be efficiently treated with only plasma exchanges. Liver

involvement disseminated intravascular coagulation and de-

tectable ADAMTS13 activity, usually higher than 20 p. cent,

which are typical features in HELLP syndrome but not in

TTP, may help to distinguish both diseases. Severe eclamp-

sia and HELLP syndrome may result from a maternal endo-

thelium dysfunction mediated by an excessive release of

both placenta-derived soluble VEGF (vascular-endothelium

growth factor) receptor and endoglin. This latter is a circulat-

ing transforming growth factor (TGF)- 1 co-receptor which

impairs binding of TGF- 1 to its receptor. In concert with

soluble VEGF receptor, endoglin may inhibit downstream

signalling including effects on activation of eNOS (endothe-

lial nitric oxyde synthetase) and vasodilatation, and thereby

induce placental hypoperfusion.

Hematopoietic Stem Cell Transplantation

Hematopoietic stem cell transplantation (HSCT)-

associated TMA was initially considered as a particular form

of TTP with a worse prognosis due to treatment refractori-

ness. ADAMTS13 activity was found consistently normal in

this form of TMA. Consequently, this latter now tends to be

individualized as a specific form of TMA with specific

pathophysiology and prognosis. HSCT-associated TMA is

favoured by numerous initiating factors, which include total

body irradiation in transplant conditioning, infections, medi-

cations such as calcineurin inhibitors, as well as graft versus

host disease grade 2 to 4 [76]. The response to plasma ex-

change is disappointing, and the management should include

as much as possible the treatment of triggering factors. Vari-

ous studies have reported the efficiency of defibrotide, which

is a single strand polyribonucleotide obtained from mammal

DNA. This latter may protect endothelial cells from TNF- -

associated cell death.

Cancers

Stomach, breast and prostate cancers are the most typical

malignancies providing a TMA syndrome. Cancer-associated

TMA onset is usually insidious. Dyspnea, wasting, severe

disseminated intravascular coagulopathy with dacryocytes

and massive erythromyelemia are specific features [77].

Bone marrow investigations frequently display extrahema-

topoietic, metastatic cells. TMA pathophysiology still re-

mains unclear. Metastatic micro-emboli may be involved in

the occlusion of microvessels, thereby inducing erythrocytes

fragmentation and platelet activation. Cytokines such as

TNF may also participate to endothelial agression. In this

context, ADAMTS13 activity is usually measurable and

higher than 20 p. cent. Rare cases of severe acquired

ADAMTS13 deficiency were observed; these latter may

correspond to a paraneoplastic form of TTP (Oberic et al.,

submitted). Prognosis of cancer-associated TMA is very

poor, and depends on treatment responsiveness of the under-

lying malignancy.

Medications

A large number of drugs were associated with TMA,

including antiplatelet agents, antineoplastic drugs and qui-

nine.

TTP with a documented antibody-mediated severe

ADAMTS13 deficiency was reported in a small fraction of

patients treated with ticlopidine, an inhibitor of one of the

platelet adenosine diphosphate receptors, and clopidogrel,

the structurally similar agent [78] [79]. The estimated inci-

dence of ticlopidin-associated TTP is 1 per 1600 to 5000

patients treated, with a disease onset that ranged from 2 to 12

weeks following treatment initiation [80]. Though no clopi-

dogrel-associated cases were initially observed among

20,000 closely monitored patients treated in phase 3 clinical

trials and cohort studies, patients were found to develop ac-

quired TTP within the first two weeks following drug intake,

suggesting a possible causal relationship. The mechanism

leading to anti-ADAMTS13 antibodies production remains

unknown. It is not excluded however that ticlopidin may

induce the development of anti-ADAMTS13 autoimmune

reaction against ADAMTS13 in a mode analogous to the

development of anti-red cell antibodies in association with

the use of alpha-methyldopa. Additionally, ticlopidin was

reported to disrupt production of extracellular matrix com-

ponents critical for microvascular endothelial cell integrity

with induction of apoptosis [81]. Treatment with plasma

exchange usually allows obtaining resolution of TTP in 77 to

84 p. cent of cases [80]. Relapses may occur in clopidogrel-

associated TTP [79].


Table 1. To a molecular-based classification of TMA syn-

dromes

Severe ADAMTS13 deficiency (TTP)*:

1. TTP + ADAMTS13 mutations

2. Autoimmune TTP :

+ HIV

+ Antiplatelet agents

+ Cancers

+ Pregnancy

“Idiopathic”

Detectable ADAMTS13 activity (HUS):

1. HUS + enteropathogenic bacteria

2. Atypical HUS + complement dysfunction :

Mutations: factor H, CFHR, FI, MCP/CD46, factor B, C3

Fusion genes between factor H and CFHR1

Auto-Abs: Anti-factor H antibodies

3. Atypical HUS + S. pneumoniae

4. Atypical HUS + Cobalamin metabolism disorders

Detectable ADAMTS13 activity (others):

1. Other TMA syndromes:

+ HIV (often AIDS)

+ Cancer (often disseminated)

+ Connective tissue disease

+ Medications

« Idiopathic »

2. HELLP Syndrome

+ sVEGF-R1, sEndoglin and/or complement dysfunction

3. Malignant AHT, CAPS, type II HIT, VOD, severe DIC

* includes rare cases of TTP with decreased but detectable (10-20%) ADAMTS13

activity and anti-ADAMTS13 antibodies [31]. CFHR : complement factor H-related

genes ; HIV: human immunodeficiency virus ; AIDS: acquired immunodeficiency

syndrome. HELLP: hemolysis, elevated liver enzymes, low platelet count. AHT: arte-

rial hypertension. sVEGF: soluble form of VEGF (vascular-endothelium growth fac-

tor); sEndoglin: soluble endoglin; CAPS: catastrophic antiphospholipid syndrome ;

HIT: heparine-induced thrombocytopenia; VOD: veno-occlusive disease; DIC : dis-

seminated intravascular coagulation.

Multiple antineoplastic drugs were associated with TMA.

Particularly, mitomycin C induces TMA with a frequency

that ranges from less than 2 p. cent of cases to 10 p. cent, and

may be dose-dependent. The specific pathophysiological

mechanisms may involve a drug-mediated endothelial injury.

Mitomycin-associated TMA typically associates high blood

pressure with lung oedema. By contrast, central nervous in-

volvement and fever are rarely observed. Response to plasma

exchanges is usually poor. More recently, inhibitors of

VEGF, aimed at inhibiting tumor vascularization, were asso-

ciated with nephritic-range proteinuria, high blood pressure

and TMA [82], suggesting a major role for VEGF in vascular

homeostasis.

HIV Infection

TMA is more frequently observed in HIV-infected pa-

tients than in non-infected individuals [83]. However, HIV-

associated TMA incidence decreased from 1.4 to 0.3 p. cent

since the era of antiretroviral therapies [84] [85]. When

compared to HIV-positive patients without TMA, patients

with HIV-associated TMA have a lower CD4+ T cell count, a

higher HIV RNA viral load and a higher frequency of oppor-

tunistic infections. TMA may result from distinct patho-

physiological mechanisms. HIV-associated TMA with se-

vere ADAMTS13 deficiency usually have less AIDS-related

complications and their median CD4+ T cell count is higher

than in patients with a detectable ADAMTS13 activity. In

the former, prognosis is comparable to this of non-HIV pa-

tients, whereas in the latter, prognosis is poor despite adapted

treatment [86-89].

CONCLUDING REMARKS

These last years, our knowledge in TMA pathophysiol-

ogy outstandingly improved. Indeed, the evidence of a defi-

ciency in ADAMTS13 in TTP allowed understanding the effi-

ciency of plasmatherapy, which opens perspectives of tar-

geted therapies based on recombinant or plasma-purified

ADAMTS13. In addition, to consider acquired idiopathic

TTP as an autoimmune disease incites to introduce immu-

nomodulatory drugs aimed at reducing the number of plasma

exchange sessions. Atypical HUS may also be treated effi-

ciently with purified proteins or complement pathway modu-

lators. Among these latter, eculizumab is a monoclonal anti-

body directed against C5 component of complement, that was

used efficiently in paroxystical nocturnal hemoglobinuria,

where a deficiency in GPI-anchored proteins lead to an ex-

cessive, complement-mediated, intravascular hemolysis [90].

Altogether, these findings should now allow drawing a

rigorous, pathophysiologically-based, TMA classification

(Table 1), and defining more homogeneous groups of pa-

tients. Obviously, these findings open fascinating perspec-

tives of targeted therapies in the forthcoming years.

THE MEMBERS OF THE REFERENCE CENTRE

FOR THE MANAGEMENT OF THROMBOTIC MI-

CROANGIOPATHIES ARE:

Azoulay Elie = Service de Réanimation Médicale,

Hôpital Saint-Louis, Paris

Bordessoule = Service d’Hématologie, Hôpital

Dominique Dupuytren, Limoges

Buffet Marc = Service d’Hématologie clinique et

de Thérapie Cellulaire, Hôpital

Saint-Antoine, Paris

Bussel Annette = Unité de Clinique Transfusion-

nelle, Hôpital Cochin, Paris

Choukroun Gabriel = Service de Néphrologie, Hôpital

Sud, Amiens

Clabault Karine = Service de Réanimation, CHU de

Rouen


Coppo Paul = Service d’Hématologie clinique et

de Thérapie Cellulaire, Hôpital

Saint-Antoine, Paris

Daubin Cédric = Service de Réanimation Médicale,

Hôpital de Caen

Devaux Edouard = Service de Néphrologie, Centre

Hospitalier de Pontoise

Frémeaux-Bacchi = Laboratoire d’Immunologie, Hôpi-

Véronique tal Européen Georges Pompidou,

Paris

Galicier Lionel = Service d’Immunopathologie,


Gruson Didier = Service de néphrologie, CHU de

Bordeaux

Guidet Bertrand = Service de Réanimation Médicale,

Hôpital Saint-Antoine, Paris

Hamidou Mohamed = Service de Médecine Interne,

Hôpital Hôtel-Dieu, Nantes

Heshmati Farhad = Unité de Clinique Transfusion-

nelle, Hôpital Cochin, Paris

Ifrah Norbert = Service d’Hématologie, CHU Lar-

rey, Angers

Korach Jean-Michel = Service de Réanimation Médicale,

Hôpital Châlons-en-Champagne

Mira Jean-Paul = Service de Réanimation Médicale,

Hôpital Cochin

Monge Matthieu = Service de Néphrologie, Hôpital

Sud, Amiens

Moulin Bruno = Service de Néphrologie, Hôpital

civil, Strasbourg

Mousson Christiane = Service de Néphrologie, CHU de

Dijon

Nivet Hubert = Hôpital Bretonneau, Service de

Néphrologie et Immunologie,

Tours

Ojeda-Uribe Mario = Service de Néphrologie, Hôpital

Emile Muller, Mulhouse

Palcoux = Service de Pédiatrie, CHU de

Jean-Bernard Clermont-Ferrand

Poullin Pascale = Service d’hémaphérèse et

d’autotransfusion, Hôpital la Con-

ception, Marseille

Pourrat Jacques = Service de Néphrologie et Immu-

nologie Clinique, CHU Rangueil,

Toulouse

Pouteilnoble Claire = Service de Néphrologie, Centre

Hospitalier Lyon-Sud, Lyon

Provôt François = Service de Néphrologie, Hôpital

Albert Calmette, Lille

Ramakers Michel = Service de Réanimation Médicale,

Hôpital de Caen

Ribeil Jean-Antoine = Service de Thérapie Cellulaire,

Hôpital Necker-Enfants Malades,

Paris

Ronco Pierre = Service de Néphrologie et de

Dialyses, Hôpital Tenon, Paris

Rondeau Eric = Service de Néphrologie et de

Transplantation, Hôpital Tenon,

Paris

Rossi Jean-François = Service Hématologie et Oncologie

Médicale, Hôpital Lapeyronie,

Montpellier

Saheb Samir = Unité de Thérapie Cellulaire et

d’Hémaphérèse, Hôpital la Pitié-

Salpétrière, Paris

Schlemmer Benoît = Service de Réanimation Médicale,


Vernant Jean-Paul = Service d’Hématologie, Hôpital la

Pitié-Salpétrière, Paris

Veyradier Agnès = Service d’Hématologie Bi-

ologique, Hôpital Antoine Béclère,

Clamart

Vigneau Cécile = Service de Néphrologie, Hôpital

Pontchaillou, Rennes

Vincent François = Service de Réanimation Médicale,

Hôpital Avicenne, Bobigny

Winckel Alain = Service de Néphrologie, CHU de

Reims

Wolf Martine = Service d’Hématologie Bi-

ologique, Hôpital Antoine Béclère,

Clamart

Zunic Patricia = Service d’Hématologie, Groupe

Hospitalier Sud-Réunion, la Réun-

ion

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