Purpura, thrombotic thrombocytopenic

* Objective-To evaluate the usefulness and feasibility of measuring plasma von Willebrand factor (vWF)-cleaving metalloprotease activity (ADAMTS 13) in the differential diagnosis of thrombotic thrombocytopenic purpura (TTP), the hemolytic uremic syndrome, and other thrombotic microangiopathies.

Data Sources.-Articles published in the medical literature.

Data Extraction and Synthesis.-In TTP, a multimeric form of vWF that is larger than that ordinarily found in the plasma may cause systemic platelet aggregation under the high-shear conditions of the microcirculation. ADAMTS 13 is a divalent cation-activated, vWF-cleaving metalloprotease that converts unusually large vWF multimers derived from endothelial cells into smaller vWF forms in normal plasma. ADAMTS 13 is severely reduced or absent in most patients with TTP. The vWF-cleaving metalloprotease is present in fresh-frozen plasma, cryoprecipitate-depleted plasma (cryosupernatant), and in plasma that has been treated with solvent and detergent. The enzyme is defective in children with chronic relapsing TTP. Infusion of any of the plasma products that contain the vWF-cleaving metalloprotease stops or prevents (for about 3 weeks) TTP episodes in these patients. An immunoglobulin (Ig) G autoantibody to

the vWF-cleaving metalloprotease is found transiently in many adult patients with acquired acute idiopathic, recurrent, and ticlopidine/clopidogrel-associated TTP. Patients with acquired TTP require plasma exchange, that is, both infusion of a plasma product containing vWF-cleaving metalloprotease and removal of autoantibody and/or unusually large vWF multimers by plasmapheresis. The pathophysiology of platelet aggregation in bone marrow transplantation/chemotherapy-associated thrombotic microangiopathy, as well as in hemolytic uremic syndrome, is not established. in neither condition is there a severe decrease in plasma vWF-cleaving metalloprotease activity, as there is in TTP.

Conclusions.-The presently available lengthy and complicated procedure for estimation of plasma vWF-cleaving metalloprotease activity is not yet practical for rapid diagnostic use. This test has supplanted the equally lengthy and difficult, less specific analysis of plasma vWF multimeric pattern. If the clinical distinction between TTP and hemolytic uremic syndrome is uncertain, it is appropriate to acquire (before therapy) a citrate-plasma sample for the ultimate determination of vWF-cleaving metalloprotease activity.

(Arch Pathol Lab Med. 2002;126:1430-1433)

THROMBOTIC THROMBOCYTOPENIC PURPURA

von Willebrand Factor Multimers and von Willebrand

Factor-Cleaving Metalloprotease

After release from endothelial cells, large and "unusually large" von Willebrand factor (vWF) multimers are cleaved at Tyr842/Met843 in domain A2 of monomeric vWF subunits.1,2 This proteolysis is catalyzed by a divalent cation-activated, vWF-cleaving metalloprotease present in normal plasma and may occur optimally under high (arterial-type) shear stress.3 Unusually large vWF multimers are converted by this process into a series of somewhat smaller vWF forms. Unusually large vWF multimers are especially capable of mediating direct shear stress-induced platelet aggregation,4 which is distinct from the platelet aggregation that follows platelet-subendothelial adhesion at sites of vascular injury.

The vWF-cleaving metalloprotease has recently been partially purified and characterized as ADAMTS 13, a disintegrin and metalloprotease with 8 thrombospondin-1like domains and an Arg-Gly-Asp (RGD) segment.5-8 ADAMTS 13 is a Zn^sup 2+^ and Ca^sup 2+^requiring 190000-d glycoprotein that is encoded on chromosome 9q34. The enzyme is produced predominantly by liver cells. von Willebrand factor-cleaving metalloprotease activity in citrate plasma is reduced to about 50% of normal in patients with severe liver disease and in newborns (as a transient developmental process).9 Enzyme activity has also been reported to be somewhat decreased in disseminated malignancies.10 In contrast, patients with incipient TTP episodes have a severe reduction in plasma vWF-cleaving metalloprotease activity (to less than about 5%-10% of the level in normal citrate-pooled plasma).11-17

It is possible that reduction of some of the disulfide bonds in large and unusually large vWF multimers18 by thrombospondin-l-like domains with disulfide bond reductase/isomerase activity, is involved in vWF multimer breakdown.19 Alternatively, the thrombospondin-1 domains may be involved in attaching the ADAMTS 13 enzyme to the surface of endothelial cells, awaiting the release of unusually large vWF multimers.

The ADAMTS 13 vWF-cleaving metalloprotease is functionally defective in patients who have congenital chronic relapsing TTP. These patients also have unusually large vWF multimers in their plasma, which may account for the periodic platelet aggregation in their high-shear microcirculation.20-22 The microvascular platelet thrombi in TTP patients have been demonstrated by immunohistochemical techniques to be vWF positive and fibrinogen negative (the opposite of thrombi in disseminated intravascular coagulation).23 Using flow cytometry, it has been shown that the single platelets of patients with chronic relapsing, acute idiopathic, intermittently recurrent, and ticlopidine- or clopidogrel-associated types of TTP have increased vWF on their surfaces at the onset of TTP episodes.24 This platelet-vWF binding is sometimes associated with disappearance of the largest plasma vWF multimers.25 The divalent cation-activated, vWF-cleaving metalloprotease that proteolyzes unusually large vWF multimers to plasma-type vWF forms in normal plasma is severely reduced or absent in most TTP patients as the episodes commence.11-13,15,17,26,27 The enzyme activity is absent or barely detectable at all times in the plasma of patients with chronic relapsing TTP11,12,14

The vWF-cleaving metalloprotease activity in vitro is accentuated by low-ionic-strength buffer, the partial unfolding of large or unusually large vWF multimers by shear stress3 or denaturing chemicals (guanidine or urea),1,2 and the presence of Ca^sup 2+^ or Ba^sup 2+^. Detection of activity in vitro requires many hours of enzyme-vWF incubation at 37 deg C and is inhibited by EDTA.1-3 Although these conditions are predominantly artificial, cleavage in vitro of vWF and unusually large vWF multimers results in the generation of 176-kd and 140-kd vWF fragments that are identical to those found in normal plasma.1,2

Transfusion with a plasma product containing vWFcleaving metalloprotease results in a transient decline in platelet-vWF binding in chronic relapsing TTP.24 Although the plasma t^sub 1/2^ of the transfused vWF-cleaving metalloprotease is 2 to 4 days,14 TTP episodes do not recur for about 3 weeks in these patients.20,22 An inhibitor of the vWFcleaving metalloprotease is found in some,12,13,16 but not all, patients with acquired, idiopathic acute TTP The inhibitor, if present, is usually an IgG autoantibody. 16 Replacement of the inhibited (or otherwise inactive) vWF-cleaving metalloprotease by plasma infusion, as well as removal of unusually large vWF multimers by plasmapheresis, may explain the effectiveness of plasma exchange. Disappearance of the autoantibodies against the vWF-cleaving metalloprotease, along with reappearance of the enzyme activity, eventually leads to remission.12,13,16 A decrease in vWF-cleaving metalloprotease autoantibody titers has not, however, been demonstrated consistently during plasma exchange procedures.14 The binding of vWF to single platelets also reverts to normal as remission is achieved.24 In patients who have recovered from an initial acute idiopathic TTP episode associated with autoantibodies, reappearance of the autoantibody against the vWF-cleaving metalloprotease is associated with recurrence.13

Plasma exchange is also effective therapy for TTP associated with ticlopidine (Ticlid)17,28 and clopidogrel (Plavix)15(after discontinuation of the drug). These patients have ticlopidine- or clopidogrel-induced antibodies against the vWF-cleaving metalloprotease.

von Willebrand factor-cleaving metalloprotease activity is present in fresh-frozen plasma, cryoprecipitate-depleted plasma (cryosupernatant), and in plasma treated with solvent-detergent.12,16 Cryosupernatant and solvent-detergent plasma lack the largest plasma-type vWF multimers.22,29,so Cryosupernatant may be effective in episodes of refractory TTP in adults who do not respond to exchange with fresh-frozen plasma.29

LABORATORY ASSESSMENT OF vWF-CLEAVING

METALLOPROTEASE

Many metalloproteases are found in humans.31 The metalloprotease responsible for cleavage of large and unusually large vWF multimers has been partially purified. For activity in vitro, the enzyme requires either Ba^sup 2-^ or Ca^sup 2+^, plus urea or guanidine, and is inhibited by EDTA.1-3 In vitro, the vWF-cleaving metalloprotease cleaves large and unusually large vWF multimers and diminishes the selective binding of these largest vWF multimeric forms to collagen.32 von Willebrand factor-cleaving metalloprotease activity can be estimated in dilutions of plasma using an assay based on this principle.

In another assay, enzyme activity is estimated by incubating large vWF multimers purified from normal cryoprecipitate, or cultured endothelial cell supernatant containing unusually large vWF forms, with plasma dilutions in the presence of urea and Ba^sup 2-^1,11-14 One of the following reactions is then observed: (1) disappearance of the largest vWF forms on unreduced sodium dodecyl sulfate-agarose gels,1-3,11-14,16,17 or (2) appearance of vWF fragments generated on either side of the 842-843 cleavage site in the vWF subunits that comprise vWF multimers.2,3,16,17 These latter fragments are dimers (176-176 kd and 140-140 kd) detectable on unreduced sodium dodecyl sulfate-acrylamide gels. In vitro, vWF-cleaving metalloprotease assays require long incubation times (up to 24 hours), in addition to denaturation of large or unusually large vWF multimers by urea or guanidine and the presence of Ca^sup 2+^ or nonphysiologic Ba^sup 2+^. The mechanism of action of the vWFcleaving metalloprotease in vivo is not yet known.

HEMOLYTIC UREMIC SYNDROME

The hemolytic uremic syndrome (HUS) is thrombocytopenia, microangiopathic hemolysis, and acute renal failure. Hemolytic uremic syndrome typically occurs in young children following hemorrhagic colitis caused by Shigella-like toxin-producing strains of Escherichia coli (eg, 0157:H7).33 In contrast to TT, neither HUS after E coli enterocolitis nor HUS unassociated with diarrhea is associated with a severe deficiency in plasma ADAMTS 13 vWF-cleaving metalloprotease activity.12

In diarrhea-associated HUS, both Shigella-like toxin and lipopolysaccharides are absorbed from the inflamed gastrointestinal tract. Shigella-like toxin binds to glycolipid (Gb^sub 3^) receptors in renal glomerular endothelial cells, enters the glomerular endothelial cell cytoplasm, and inhibits protein synthesis. The results are endothelial cell damage, swelling, death, and detachment. Platelet adhesion and aggregation on exposed subendothelium may culminate in HUS.34,35 The glomerular endothelial cell response to Shigella-like toxin may be amplified by lipopolysaccharides stimulation of tumor necrosis factor-(alpha) production, which up-regulates endothelial cell Gb^sub 3^ receptors.

The complement control protein, factor H, is reduced in the plasma of some patients who have congenital recurrent HUS as a consequence of chromosome lq32 mutations.36 Factor H normally suppresses the activity of the C3bBb C3 convertase in the alternative complement pathway. These patients (often children) may be predisposed to excessive activation of C3 via the alternative complement pathway. Measurement of serum factor H or C3 antigen levels by immunodiffusion or nephelometry may contribute to the diagnosis of congenital HUS in some of these patients.

OTHER THROMBOTIC MICROANGIOPATHIES

The pathophysiology of microvascular platelet aggregation in transplantation/chemotherapy-associated thrombotic microangiopathy is not known. As in HUS, most patients studied to date with this type of thrombotic microangiopathy do not have a severe reduction in plasma ADAMTS 13 vWF-cleaving metalloprotease activity.37 The possible importance of microvascular endothelial cell apoptosis,311 as well as Bartonella infections,39 in subgroups of patients with thrombotic microangiopathic disorders has not been established.

THERAPY

Plasma infusion or exchange is not unequivocally effective in either HUS or transplantation/chemotherapy-associated thrombotic microangiopathy.40,41 Although these conditions are not characterized by severe deficiency of plasma vWF-cleaving metalloprotease,12,37 it is not currently possible to obtain emergency vWF-cleaving metalloprotease levels on plasma samples from acutely ill patients. Consequently, any distinction between acute TTP and HUS in adults based on pretreatment vWF-cleaving metalloprotease levels in plasma has, thus far, been attempted only in retrospect.12

The clinical presentations of acute TTP and HUS in adults are often indistinguishable. The widespread use of plasma exchange has improved survival in adult acquired, acute idiopathic TTP from near 0% to 75%-92%.42,43 It is, therefore, prudent to presume that most acutely ill adult patients with the differential diagnosis of "TTP vs HUS" have TTP and to initiate emergency plasma exchange.44 There has not yet been a prospective clinical trial in adults with acute episodes of TTP/HUS correlating clinical responsiveness with serial vWF-cleaving metalloprotease levels obtained before, during, and after plasma exchange.

It is not known if suppression of autoantibody accounts for the possible usefulness of glucocorticoids in TTP patients.42 Some patients with acute idiopathic TTP who have responded poorly to glucocorticoids and plasma exchange (using fresh-frozen plasma or cryosupernatant) have achieved clinical remission following splenectomy.45 This beneficial effect may result from the removal of a large mass of immune cells that produce autoantibodies against the vWF-cleaving metalloprotease.

CONCLUSIONS

Thrombotic Thrombocytopenic Purpura.-von Willebrand factor-leaving metalloprotease (ADAMTS 13) activity in citrate-patient plasma is usually less than 5% to 10% of the activity in normal citrate-pooled plasma.

Hemolytic Uremic Syndrome and Other Thrombotic Microangiopathies.-ADAMTS 13 activity varies over a broad range, but is not less than 5% to 10% of normal.

Chronic Relapsing TTP-ADAMTS 13 gene mutations (chromosome 9q34) cause activity levels that are chronically less than 5% to 10% of normal.

Acquired TTP-ADAMTS 13 activity is usually transiently less than 5% to 10% of normal as a result of transient antibody inhibition of enzyme activity (or of enzyme binding to endothelial cell surfaces) or some other unidentified transient defect in enzyme production or survival.

* Familial or recurrent HUS may be caused by deficient plasma levels of factor H, as a consequence of chromosome 1q32 mutations. Factor H normally suppresses the activity of the C3bBb C3 convertase in the alternative complement pathway.

* The procedures for estimation of vWF-cleaving metalloprotease activity (ADAWS 13) using citrate-plasma are either lengthy or developmental.

* The presently available tests are not capable of rapidly confirming the clinical diagnosis of TTP (or distinguishing between TTP and HUS) and are only available in specialized reference laboratories.

RECOMMENDATIONS

* The diagnosis of TTP remains clinicopathologic. However, if the diagnosis is uncertain, it may be appropriate to collect (before plasma infusion or exchange) a citrateplasma sample for the later determination of vWF-cleaving metalloprotease activity (ADAMTS 13) in a reference laboratory. The activity level may influence subsequent therapeutic decisions.* Level I

* Hemolytic uremic syndrome remains a clinicopathologic diagnosis; however, measurements of serum factor H and C3 in familial or recurrent HUS may be appropriate.36 Level 1

For an explanation of the levels cited in this article, refer to Olson.46

* References 7,8, 11-13, 15-17, 26, 27, 37.

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Joel L. Moake, MD

Accepted for publication May 20, 2002.

From Baylor College of Medicine and Rice University, Houston, Tex.

Presented at the College of American Pathologists Consensus Conference XXXVI: Diagnostic Issues in Thrombophilia, Atlanta, Ga, November 9-11, 2001.

Reprints: Joel L. Moake, MD, Department of Medicine, Baylor College of Medicine, The Methodist Hospital, Mail Station 902, 6565 Fannin, Houston, TX 77030 (e-mail: jmoake@rice.edu).

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