art.2 trombopatias microangiopaticas

8/12/2019 Art.2 Trombopatias Microangiopaticas

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Review Article

Mechanisms of Disease

MECHANISMS OF DISEASE

N Engl J Med, Vol. 347, No. 8

August 22, 2002

www.nejm.org

589

T

HROMBOTIC

M

ICROANGIOPATHIES

J

OEL

L. M

OAKE

, M.D.

HE thrombotic microangiopathies are micro-vascular occlusive disorders characterized bysystemic or intrarenal aggregation of platelets,

thrombocytopenia, and mechanical injury to erythro-cytes. In thrombotic thrombocytopenic purpura, sys-temic microvascular aggregation of platelets causesischemia in the brain and other organs. In the hemo-lyticuremic syndrome, plateletfibrin thrombi oc-clude predominantly the renal circulation. Thrombot-ic thrombocytopenic purpura was initially describedby Moschcowitz in 1924,

1

and the hemolyticuremicsyndrome by Gasser et al.

2

in 1955. Both disordersremained mysterious until the 1980s. In 1982, un-usually large multimers of von Willebrand factor re-leased from endothelial cells were found to accumulatein the plasma of patients with chronic relapsing throm-botic thrombocytopenic purpura,

3

and a failure toprocess these multimers was proposed to explain the

disorder. In 1985, Karmali et al.

4

discovered a link be-tween the hemolyticuremic syndrome and enteric in-fections with Escherichia coli that produce Shiga toxin.These clues provoked a deluge of investigations thathave elucidated the mechanisms of thrombotic throm-bocytopenic purpura and the hemolyticuremic syn-drome. Table 1 summarizes the thrombotic microan-giopathies that will be discussed in this review.

CLINICAL PRESENTATIONS

Thrombotic microangiopathies are characterized bythrombocytopenia (with increased numbers of mar-row megakaryocytes), fragmentation of erythrocytes,and extremely elevated serum levels of lactate dehy-

drogenase. The severity of these abnormalities reflectsthe extent of the microvascular aggregation of plate-lets. Fragmented erythrocytes (schistocytes, or helmetcells) are probably produced as blood flows through

T

turbulent areas of the microcirculation that are partial-ly occluded by platelet aggregates. This process causesmicroangiopathic hemolytic anemia. The serum lac-tate dehydrogenase is largely derived from ischemic ornecrotic tissue cells rather than from lysed red cells.

5

In patients with thrombotic thrombocytopenicpurpura, the systemic clumping of platelets mediatedby unusually large multimers of von Willebrand factoroften results in platelet counts below 20,000 per cubicmillimeter during an acute episode. Ischemia of thebrain or gastrointestinal tract is common, and renaldysfunction may occur. A pentad of signs and symp-toms has been associated with thrombotic thrombo-cytopenic purpura: thrombocytopenia, microangio-

pathic hemolytic anemia, neurologic abnormalities,renal failure, and fever.

6

In actual practice, however,the triad of thrombocytopenia, schistocytosis, and el-evated lactate dehydrogenase levels is often sufficientto suggest the disorder. If severe renal failure is thepredominant feature at presentation, then the disorderis often considered to be the hemolyticuremic syn-drome.

7,8

The clinical distinction between thromboticthrombocytopenic purpura and the hemolyticuremicsyndrome is not always clear-cut, however.

4,9-11

Renalabnormalities in patients who have been given a diag-nosis of thrombotic thrombocytopenic purpura andextrarenal manifestations in some patients who havereceived a diagnosis of hemolyticuremic syndromecan obscure clinical boundaries.

12-14

Nevertheless, it isoften possible to recognize specific types of thrombot-ic microangiopathies.

Familial thrombotic thrombocytopenic purpura israre. It may appear initially in infancy or childhood

15,16

and then recur at regular intervals of about threeweeks (referred to as chronic relapsing thromboticthrombocytopenic purpura). In some patients, how-ever, a familial predisposition to the disorder may notbe clinically evident for years.

17

Acquired idiopathicthrombotic thrombocytopenic purpura occurs inadults and older children and is usually characterizedby a single acute episode. The episodes recur at irreg-ular intervals in 11 to 36 percent of patients.

12,13,18,19

Thrombotic thrombocytopenic purpura developswithin a few weeks after the initiation of therapy ina small fraction of patients with arterial thrombosis

who receive ticlopidine, an inhibitor of one of theplatelet adenosine diphosphate (ADP) receptors,

20,21

and an even smaller fraction of those who receive thestructurally similar agent clopidogrel.

22

The disorderalso occurs occasionally during pregnancy (especial-ly the last trimester) or in the postpartum period.

23

From Baylor College of Medicine and R ice University both in Hous-ton. Address reprint requests to Dr. Moake at the HematologyOncologySection, Methodist Hospital, MS 902, Main Bldg., 6565 Fannin, Houston,TX 77030, or at [email protected].

Downloaded from www.nejm.org on October 17, 2006 . Copyright 2002 Massachusetts Medical Society. All rights reserved.


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The New England Journal of Medicine

The hemolyticuremic syndrome usually occurs asa single episode, often preceded by gastroenteritiscaused by cytotoxin-producing gram-negative bacte-ria, most commonly E. coli O157:H7.

4

A recurrent ill-

ness resembling the hemolyticuremic syndrome maybe caused by defective production of the complementcontrol protein factor H.

11,24,25

A type of thrombotic microangiopathy with eitherpredominantly renal or systemic thrombi occurs insome patients who receive mitomycin, cyclosporine,tacrolimus, quinine, a marrow or organ transplant, to-tal-body irradiation, or combinations of chemothera-peutic agents.

14

PATHOPHYSIOLOGY

Thrombotic Thrombocytopenic Purpura

Microvascular thrombi occur in most organs in pa-tients with thrombotic thrombocytopenic purpuraand consist of platelet aggregates with little or no fi-brin; there is no perivascular inflammation or overtendothelial-cell damage.

26

The platelet thrombi con-tain abundant von Willebrand factor antigen but nofibrinogen (or fibrin), whereas the platelet thrombiin disseminated intravascular coagulation contain fi-brin but not von Willebrand factor.

27

Flow-cytometricstudies demonstrate that levels of von Willebrand fac-tor antigen attached to single platelets in whole-bloodsamples are higher during episodes of thromboticthrombocytopenic purpura than during periods of re-covery or remission.

28

The results of clotting studiesduring these episodes are usually normal.

Monomers of von Willebrand factor (280 kD) arelinked by disulfide bonds to form multimers with var-ious molecular masses that range into the millions ofdaltons.

29

Multimers of von Willebrand factor are con-structed within megakaryocytes and endothelial cellsand stored within platelet a

-granules and endothelial-cell WeibelPalade bodies. Most multimers in plasmacome from endothelial cells. Both endothelial cellsand platelets produce multimers of von Willebrand

factor that are larger than those in normal plasma.

3

These unusually large multimers bind more efficientlythan the largest plasma multimers to the glycopro-tein Ib

a

component of platelet glycoprotein Ib/IX/V

receptors for von Willebrand factor.

30,31

This is prob-ably because the binding sites for glycoprotein Ib

a

in monomeric subunits of von Willebrand factor aremore effectively exposed in unusually large multimersthan in the smaller forms that are normally in circu-lation.

31

The initial attachment of only a small quan-tity of unusually large multimers of von Willebrandfactor to glycoprotein Ib

a

, and subsequently to ADP-activated platelet glycoprotein IIb/IIIa complexes,

30,32

induces platelet aggregation in vitro in the presenceof increased fluid shear stress.

A von Willebrand factorcleaving metalloproteasein plasma normally prevents the entrance into the cir-culation (or persistence) of unusually large multimersof von Willebrand factor. This enzyme degrades themultimers by cleaving peptide bonds in monomericsubunits of von Willebrand factor at position 842843(between tyrosine and methionine).

33,34

The metallo-protease is referred to as ADAMTS 13 (a disintegrinand metalloprotease, with thrombospondin-1likedomains), a member of a family of zinc- and calcium-dependent proteases. ADAMTS 13 has an arginineglycineaspartate (RGD) sequence, its gene is onchromosome 9q34, and it is produced predominantlyby hepatocytes.

33-39

Unusually large multimers of von Willebrand fac-tor are probably cleaved by ADAMTS 13 directly onthe surface of endothelial cells (Fig. 1).

40

The throm-bospondin-1like domains in ADAMTS 13 may bindthe enzyme to thrombospondin receptors on the sur-face of endothelial cells. Partial unfolding of emergingunusually large multimers as a result of fluid shearstress

39,40

may increase the efficiency of cleavage byADAMTS 13 (Fig. 2).

41,42

Table 2 summarizes the re-lation between defects in ADAMTS 13 and the var-ious clinical presentations of thrombotic thrombocy-topenic purpura.

T

ABLE

1. T

HROMBOTIC

M

ICROANGIOPATHIES

.

T

YPE

OF

M

ICROANGIOPATHY

C

AUSE

C

LINICAL

P

RESENTATION

Systemic platelet thrombi Failure to degrade unusually large multi-mers of von Willebrand factor Thrombotic thrombocytopenic purpura

Predominantly renal plateletfibrin thrombi

Exposure to Shiga toxin Classic, childhood, or Escherichia coli

associated hemolyticuremic syndromeDefect in plasma factor H Familial (or recurrent) hemolyticuremic

syndrome

Renal or systemic thrombi Transplantation or drugs (mitomycin,cyclosporine, tacrolimus, quinine)

Hemolyticuremic syndrome or throm-botic thrombocytopenic purpura



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In most patients with familial or acquired typesof thrombotic thrombocytopenic purpura, plasma

ADAMTS 13 activity is less than 5 percent of nor-mal.

16,21,22,43-45

A severe deficiency of ADAMTS 13activity in plasma from patients with familial or ac-quired thrombotic thrombocytopenic purpura cor-relates with deficient ADAMTS 13 activity on the sur-face of endothelial cells (Fig. 1). As a consequence, theunusually large multimers of von Willebrand factorare not cleaved after they are secreted from endothe-lial cells and instead remain anchored to the cells inlong strings (Fig. 1 and 2).

40

Passing platelets adhereby means of their glycoprotein Ib

a

receptors to theselong multimers. (Platelets do not adhere to the small-er von Willebrand factor forms produced by cleavage

of unusually large multimers.

29

) Many additional plate-lets subsequently aggregate by means of their activatedglycoprotein IIb/IIIa complexes onto the unusuallylarge multimeric strings. As a result, large, potentiallyocclusive platelet thrombi are formed (Fig. 2). An ad-ditional event intense stimulation of secretion ofunusually large multimers by endothelial cells mayprovoke episodes of thrombotic thrombocytopenicpurpura in some patients.

Patients with familial thrombotic thrombocytope-nic purpura frequently have unusually large multimersof von Willebrand factor in their plasma.

3,46

Theirplasma ADAMTS 13 activity is zero (or barely detect-able)

16,43,47

as a consequence of homozygous (or dou-ble heterozygous) mutations in each of the two 9q34

Figure 1.

Cleavage of Unusually Large Multimers of von Willebrand Factor on Endothelial Cells by the von Willebrand Fac-torCleaving Metalloprotease, ADAMTS 13.

In vivo, the von Willebrand factorcleaving metalloprotease, ADAMTS 13, may cleave unusually large multimers of von

Willebrand factor as they exit endothelial cells. When washed, fluorescently labeled platelets from a normal subject aresuspended in buffer, they adhere by means of glycoprotein Ib

a

to long strings of these unusually large multimers thathave been secreted from, and remain attached to, histamine-stimulated endothelial cells (Panel A).

40

The phenomenon

occurs under conditions of both venous and arterial flow (2 to 60 dyn per square centimeter). In the presence of normalplasma containing partially purified von Willebrand factorcleaving metalloprotease, the unusually large multimers ofvon Willebrand factor are cleaved within seconds to a few minutes as they are secreted by endothelial cells (Panel B).

The secreted, attached unusually large multimers on endothelial cells are not cleaved during more than 10 minutes offlow in the presence of plasma from a patient with thrombotic thrombocytopenic purpura (TTP), indicating that thereis no metalloprotease activity (Panel C).

A B C

Normal washedplatelets in

normal plasma


plasma froma patientwith TTP


buffer

Flow



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genes that encode ADAMTS 13.

37

In most patientswith a severe familial deficiency of ADAMTS 13 ac-tivity, episodes of thrombotic thrombocytopenic pur-pura begin in infancy or childhood. In others, how-ever, the disease does not develop for years (perhapsduring a first pregnancy), and a few may never havean episode. In the occasional patient with severe fa-milial deficiency of plasma ADAMTS 13 activity whoeither has a delayed onset of thrombotic thrombocy-topenic purpura or has not had any episodes, the phys-iologic ADAMTS 13 activity on the surface of endo-thelial cells may exceed estimates of enzyme activityobtained with in vitro fluid-phase plasma assays.

During an episode of acquired idiopathic throm-botic thrombocytopenic purpura or any recurrence,patients usually have undetectable or barely detectableplasma levels of ADAMTS 13.

21,43,44

The activity isnormal after recovery. IgG antibodies (presumably au-toantibodies) that inhibit enzyme activity in plasmaare found in 48 to 80 percent of these patients,

43-45,48

suggesting the presence of a transient (or intermittent)defect of immune regulation. Antibodies that inhibitthe plasma metalloprotease have also been demon-strated in a few patients with thrombotic thrombocy-topenic purpura associated with ticlopidine (or clo-pidogrel) use.

21,22

It is not known whether there is a

Figure 2.

Proposed Relation among the Absence of ADAMTS 13 Activity in Vivo, Excessive Adhesion and Aggregation of Platelets,and Thrombotic Thrombocytopenic Purpura.

In Panel A, in normal subjects, ADAMTS 13 (von Willebrand factorcleaving metalloprotease) molecules attach to binding sites on

endothelial-cell surfaces and cleave unusually large multimers of von Willebrand factor as they are secreted by stimulated endo-

thelial cells. The smaller von Willebrand factor forms that circulate after cleavage do not induce the adhesion and aggregation ofplatelets during normal blood flow. ADAMTS 13 may use one of its thrombospondin-1like domains or its arginineglycineaspartate

(RGD) sequence to attach to the surface of endothelial cells. In Panel B, absent or severely reduced activity of ADAMTS 13 in patientswith thrombotic thrombocytopenic purpura prevents timely cleavage of unusually large multimers of von Willebrand factor as theyare secreted by endothelial cells. The uncleaved multimers induce the adhesion and aggregation of platelets in flowing blood. A

congenital deficiency of ADAMTS 13 activity, or an acquired defect of ADAMTS 13 (such as that caused by autoantibodies or by achange in the production or survival of the protein) can lead to thrombotic thrombocytopenic purpura. Interference with the attach-ment of ADAMTS 13 to endothelial cells in vivo (for example, as a result of ADAMTS 13receptor blockade by other types of auto-

antibodies) may also cause thrombotic thrombocytopenic purpura in patients with normal ADAMTS 13 activity in plasma.

Normal Subject

Cleaved unusuallylarge multimers of von

Willebrand factor Uncleaved unusuallylarge multimers of von

Willebrand factor

ADAMTS 13

Secretion ofmultimers from

WeibelPalade body

Patient with ThromboticThrombocytopenic Purpura

ADAMTS 13

Endothelialcell

Bindingsite

Endothelialcell

Bindingsite

Secretion ofmultimers from

WeibelPalade body

Adhesion andaggregation of platelets

A B



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transient, severe defect of metalloprotease productionor survival in patients with acquired idiopathic throm-botic thrombocytopenic purpura who do not have de-tectable autoantibodies against ADAMTS 13 with theuse of in vitro assays.

Plasma ADAMTS 13 activity in healthy adults rang-es from about 50 to 178 percent of normal. The levelof activity is often below normal in patients with liverdisease, disseminated cancers,

49

and chronic metabol-ic and inflammatory conditions; pregnant women; andnewborns.

50

These moderately reduced levels are incontrast to the extremely low levels (less than 5 per-cent of normal values) in most patients with episodesof familial or acquired thrombotic thrombocytopenicpurpura.

16,21,22,43-45,47,48

Some patients with acquired idiopathic thromboticthrombocytopenic purpura have unusually large mul-timers of von Willebrand factor in their plasma in theabsence of severely reduced levels of plasma metallo-protease activity in vitro.

48,51

Another mechanism mustexplain the inadequate in vivo function of ADAMTS13 in these patients. They might, for example, pro-duce autoantibodies that prevent the attachment of

ADAMTS 13 to endothelial-cellbinding sites with-out interfering with the active site of the metallopro-tease. It may be relevant that autoantibodies againstglycoprotein IV (CD36),

52

a cell-surface thrombo-spondin receptor, appear in the plasma of some pa-tients during episodes of thrombotic thrombocyto-penic purpura. Whether these antibodies interfere

with the attachment of ADAMTS 13, through oneof its thrombospondin-1like domains, to CD36thrombospondin receptors on the surface of endothe-lial cells is unknown.

The HemolyticUremic Syndrome

The hemolyticuremic syndrome occurs in 9 to 30percent of infected children about a week after an ep-isode of bloody diarrhea caused by E. coli O157:H7.

4,10,53

Infections with other E. coli serotypes, Shi-gella dysenteriae, and (occasionally) other microbesalso cause the hemolyticuremic syndrome in childrenand adults. In Buenos Aires, Argentina, and Calgary,Canada, enterohemorrhagic E. coli infections are en-demic and the hemolyticuremic syndrome is a com-mon cause of acute renal failure in children.

10

Shiga toxin is a 70-kD protein exotoxin encodedby S. dysenteriae DNA,

54

whereas Shiga toxins 1 and2 are encoded by bacteriophage DNA, which can bepresent in several E. coli serotypes.

54

Shiga toxin con-sists of one A subunit (33 kD) and five B, or bind-ing, subunits (7.7 kD each) (Fig. 3A).

54

Each B sub-unit binds with high affinity to terminal galactose

a

1,4

b

galactose disaccharides in globotriaosylcera-mide receptors

54,55 (Fig. 3A) in the membranes of glo-merular, colonic, and cerebral epithelial or microvas-cular endothelial cells; renal mesangial and tubularcells; and monocytes and platelets.54,56-59

Strains of S. dysenteriae that are capable of produc-ing Shiga toxin and E. coli serotypes that produceShiga toxin 1 or 2 can contaminate meat, milk, cheese,and other types of insufficiently cooked or pasteur-ized food.10,60Cattle are a major reservoir of E. coliO157:H7, but they remain well because their vascularendothelial cells lack the globotriaosylceramide recep-tors necessary to bind Shiga toxins 1 and 2.61

In humans, the enterohemorrhagic bacteria ad-here to mucosal epithelial cells of the colon and invade,replicate, and destroy the cells. The Shiga exotoxins

*Cases associated with clopidogrel, which is structurally similar to ticlopidine, have been reported.

This possibility has yet to be proved.

TABLE2. RELATIONBETWEENDEFECTSINPLASMAVONWILLEBRANDFACTORCLEAVINGMETALLOPROTEASE, ADAMTS 13, ANDTHROMBOTICTHROMBOCYTOPENIC

PURPURA(TTP).

DEFECT CLINICALPRESENTATION

ADAMTS 13 plasma activity


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Figure 3.Role of Shiga Toxin, Cytokines, Unusually Large Multimers of von Willebrand Factor, and Cellular Injury.

The B subunits of polymeric Shiga toxin molecules attach to specific disaccharides of globotriaosylceramide receptors in the mem-branes of colonic epithelial cells, monocytes, platelets, glomerular and tubular epithelial cells, renal mesangial cells, and glomerularand cerebrovascular endothelial cells. This action stimulates epithelial cells and monocytes to secrete cytokines and chemokines,

stimulates endothelial cells to secrete unusually large multimers of von Willebrand factor, and activates platelets. The binding ofShiga toxin to globotriaosylceramide receptors may also increase tissue factor on endothelial cells and epithelial-cell surfaces. Oncethe A subunit of Shiga toxin is internalized, it is converted to a glycosidase whose actions ultimately result in cell death. The glo-

botriaosylceramide receptors associate with cholesterol and ganglioside to form lipid rafts that float in plasma membranes. TNF- a

denotes tumor necrosis factor a.

B

B

B

B

A

A

Gal

Gal

Stimulation

of glomerular

endothelial cells

to secrete unusually

large multimers of

von Willebrand factor

CH2

CH2

OBindingof Shiga toxin toglobotriaosylceramidereceptor

Endocytosis of a subunit of Shiga

toxin and conversion to N-glycosidase

Globotriaosylceramide

Cell death

Cellmembrane

Inhibition of peptide-chain elongation

HOCH

Stimulation of

colonic epithelial

cells to release

interleukin-8,

chemokines

Elimination of 1 adenine from

28S ribosomal RNA

C

Stimulation of

monocytes and

renal epithelial

cells to secrete

TNF-a, interleukin-1,

interleukin-6

Glc

HC

CH2

NHC

O

B



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Figure 4.Proposed Mechanisms of PlateletFibrin Formation in the HemolyticUremic Syndrome.

In Panel A, platelets activated by Shiga toxin may adhere by means of the glycoprotein Ibacomponents of glycoprotein Ib/IX/V

complexes to unusually large multimers of von Willebrand factor that are secreted from toxin-stimulated renal endothelial cells.The adherence of platelets to endothelial cells is especially likely if the cleavage of multimers extruding from endothelial cells byvon Willebrand factorcleaving metalloprotease, ADAMTS 13, is impaired by the interactions of Shiga toxin with globotriaosylcer-

amide (Gb3) receptors on endothelial-cell surfaces. The activation of platelets that is mediated by Shiga toxin may contribute to theaggregation of additional platelets. In Panel B, endocytosis and activation of the A subunits of Shiga toxin may cause the death anddesquamation of endothelial cells, exposing unusually large multimers of von Willebrand factor entwined with collagen in the sub-

endothelium. Platelets from flowing blood in the renal microcirculation may then adhere and aggregate on the exposed multimersand collagen. Local exposure of tissue factor and binding and activation of factor VII may occur on fibroblasts, invading phagocyticcells, and injured renal endothelial and epithelial cells. These actions may, in turn, induce the activation of factors IX and X, cleavageof prothrombin to thrombin by the complex of activated factor X and activated factor V, and the thrombin-induced formation of

fibrin polymers, thus potentiating renal microvascular thrombosis.

Gb3

Gb3

Platelets

Platelets

Unusually large

multimers of von

Willebrand factor

Unusually large multimers

of von Willebrand factor

WeibelPalade

body

Shiga toxinShiga toxin

A

B

GlycoproteinIba

Glomerular

endothelial

cell

Glomerular

endothelial

cell

Fibrin

Thrombin

Tissue

factor

Tissue

factor

Activatedfactor VII

Collagen Fibroblast



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Point mutations, deletions, and frame shifts in thefactor H gene have been identified in patients andtheir relatives. Most mutations occur in short-consen-sus-repeat number 20 of the factor H gene,87,88whichincludes one of the domains that enables factor H to

attach to C3b.86-88Both autosomal recessive and au-tosomal dominant forms of inheritance have been de-scribed.86,88,89Recessive inheritance is associated withfactor H levels that are 10 to 50 percent of normalas a result of aberrant protein folding and decreasedsecretion. The serum C3 level is low, and the hemo-lyticuremic syndrome develops at a young age.88,90

Dominant inheritance is associated with a function-ally abnormal factor H protein with a normal serumantigenic value, normal serum C3 levels, and delayedonset of the hemolyticuremic syndrome, which maybe precipitated by infection or pregnancy.88,89

Renal or Systemic Thrombotic Microangiopathiesof Unknown Causes

Thrombotic microangiopathy has been associatedwith mitomycin, cyclosporine, tacrolimus, combina-tions of chemotherapeutic agents, and total-body ir-radiation weeks or months after exposure to theseagents.71Thrombi may be predominantly renal or sys-temic and have been reported after allogeneic bonemarrow, kidney, liver, heart, or lung transplanta-tion.91,92In the type of thrombotic microangiopathythat is associated with bone marrow transplantation,the activity of ADAMTS 13 in plasma is not usuallyreduced.74 The mechanism of these microangiopa-thies is unknown.

In quinine-induced immune thrombocytopenia,

patients produce antibodies against epitopes of plate-let glycoprotein Ib/IX/V or IIb/IIIa complexes thathave been antigenically altered by the attachment ofquinine. In some of these patients, thrombotic micro-angiopathy also develops,93,94 possibly because theantibodies cross-react with quinine-altered glycopro-tein IIIa molecules on endothelial-cell membranes.

THERAPY

Thrombotic Thrombocytopenic Purpura

Infants or young children with familial thromboticthrombocytopenic purpura produce a functionally de-fective ADAMTS 13.16,37,47Their episodes of throm-botic thrombocytopenic purpura are reversed or pre-

vented by the infusion of platelet-poor fresh-frozenplasma, cryoprecipitate-poor plasma (cryosuperna-tant), or plasma that has been treated with a mixtureof an organic solvent and detergent.15Plasmapheresisis not required.15Fresh-frozen plasma, cryosuperna-tant, and plasma treated with a mixture of solvent anddetergent all contain the active metalloprotease. It isnot known why infusion of the metalloprotease is re-quired only about every three weeks. The plasma half-

life of the infused enzyme is about two days,47and thehalf-life of the enzyme once it is attached to the endo-thelial-cell surface may be even longer.

The sequence of ADAMTS 13 has been deter-mined, and the enzyme has been partially purified

from normal human plasma.35,36These advances maymake purified metalloprotease products available foruse in thrombotic thrombocytopenic purpura. Sincea plasma level of only about 5 percent is sufficient toprevent or shorten episodes of thrombotic thrombo-cytopenic purpura,95,96gene therapy may induce last-ing remissions in children with the chronic relapsingform of the disease.

Adults and older children with acquired acute id-iopathic thrombotic thrombocytopenic purpura re-quire daily plasma exchange.13,18Plasma exchange isthe combination of plasmapheresis (which may removeunusually large multimers of von Willebrand factorand autoantibodies against ADAMTS 13) and infu-

sion of fresh-frozen plasma or cryosupernatant (con-taining additional metalloprotease). Plasma exchangeallows about 90 percent of these patients to survivean episode of thrombotic thrombocytopenic purpu-ra,12,13usually without permanent organ damage.12

Some patients with acquired acute idiopathic throm-botic thrombocytopenic purpura and high titers ofantibodies against ADAMTS 1397do not respond toplasma exchange alone. It may be possible to interfere

with autoantibody production through treatment withglucocorticoids12or splenectomy98,99or to depolymer-ize platelet microtubules and alter exposure of surfacereceptors by infusing vincristine.100Rituximab, themonoclonal antibody against CD20 on B-lympho-

cytes, is under investigation. In the absence of life-threatening hemorrhage or intracranial bleeding, it isprudent to avoid platelet transfusions, which can ex-acerbate microvascular thrombosis.12,26Aspirin mayprovoke hemorrhagic complications in patients withsevere thrombocytopenia.101

The HemolyticUremic Syndrome

In mildly affected children with the hemolyticuremic syndrome who have had oligoanuria for lessthan 24 hours, appropriate management of fluid andelectrolyte levels is usually sufficient. Otherwise, theduration of anuria and attendant dialysis support cor-relates inversely with the likelihood of full recovery.

Acute renal failure is often more severe in adults. Ul-timately, care for end-stage renal disease may be re-quired.

Plasma infusion or exchange has been tried, withequivocal results.102,103Even the infusion of normalfresh-frozen plasma (containing factor H) in patients

with familial hemolyticuremic syndrome has not suc-ceeded in preventing relapses or progressive renal dis-ease.24,25,84,85 Purified or recombinant factor H may



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73. Ray PE, Liu XH. Pathogenesis of Shiga toxin-induced hemolytic ure-mic syndrome. Pediatr Nephrol 2001;16:823-39.74. van der Plas RM, Schiphorst ME, Huizinga EG, et al. Von Willebrandfactor proteolysis is deficient in classic, but not in bone marrow transplan-tation-associated, thrombotic thrombocytopenic purpura. Blood 1999;93:3798-802.75. Tsai H-M, Chandler WL, Sarode R, et al. Von Willebrand factor and

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