Correspondence

von Willebrand Factor–Cleaving Protease in Thrombotic Thrombocytopenic Purpura and the Hemolytic–Uremic Syndrome

N Engl J Med 1999; 340:1368-1369April 29, 1999

Article

To the Editor:

The study by Furlan et al. (Nov. 26 issue)1 provides evidence of an inhibitor of von Willebrand factor–cleaving protease in the pathogenesis of thrombotic thrombocytopenic purpura but not of the hemolytic–uremic syndrome. In this study, patients were classified as having either syndrome without knowledge of the results of the von Willebrand factor–cleaving protease assay. However, the authors did not describe the criteria by which the diagnosis was made. In addition, some of the distinguishing characteristics, such as disease chronicity and the likelihood of relapse, could only have been determined retrospectively.

It is remarkable that Furlan et al. were able to identify all their patients as having either thrombotic thrombocytopenic purpura or the hemolytic–uremic syndrome. Moreover, the accuracy of their assessment is supported by the concordance with results of testing for the von Willebrand factor–cleaving protease. It would be useful if the authors could discuss the criteria used to categorize patients as having thrombotic thrombocytopenic purpura or the hemolytic–uremic syndrome, since such criteria might be useful in situations in which testing for the von Willebrand factor–cleaving protease is not feasible.

Clarence Sarkodee-Adoo, M.D.
Ivana Gojo, M.D.
Meyer R. Heyman, M.D.
University of Maryland School of Medicine, Baltimore, MD 21201

1 References

1. 1

   Furlan M, Robles R, Galbusera M, et al. Von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med 1998;339:1578-1584
   Full Text | Web of Science | Medline

To the Editor:

We congratulate Furlan et al. and Tsai and Lian (Nov. 26 issue)1 on their elegant papers implicating a deficiency of and the presence of autoantibodies to von Willebrand factor–cleaving protease in the pathogenesis of thrombotic thrombocytopenic purpura, but we are not surprised that their findings do not extend to the hemolytic–uremic syndrome. We believe that nondiarrheal hemolytic–uremic syndrome is a complement-driven endotheliopathy and that in this condition, ultra-large multimers of von Willebrand factor are an epiphenomenon rather than the cause of the disease.2 Several patients have now been described with an autosomal recessive inherited deficiency of factor H. They present with either the hemolytic–uremic syndrome or, intriguingly, mesangiocapillary glomerulonephritis type II (a disease characteristically associated with C3 nephritic factor, an IgG autoantibody that stabilizes C3 convertase [C3b,Bb], thus protecting it from dissociation by factor H). Could sporadic nondiarrheal hemolytic–uremic syndrome be associated with autoantibodies directed against factor H in a fashion similar to the autoantibodies to von Willebrand factor–cleaving protease found in sporadic thrombotic thrombocytopenic purpura?

The spectrum of presentation of thrombotic microangiopathies remains complicated, but it has certainly been refined by the work of Furlan et al. and Tsai and Lian.

Paul Warwicker, M.R.C.P.
Lister Hospital, Stevenage, Hertfordshire SG1 4AB, United Kingdom

Judith A. Goodship, M.D., F.R.C.P.
Timothy H.J. Goodship, M.D., F.R.C.P.
University of Newcastle upon Tyne, Newcastle NE1 4LP, United Kingdom

2 References

1. 1

   Tsai H-M, Lian EC-Y. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med 1998;339:1585-1594
   Full Text | Web of Science | Medline

2. 2

   Warwicker P, Goodship TH, Donne RL, et al. Genetic studies into inherited and sporadic hemolytic uremic syndrome. Kidney Int 1998;53:836-844
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Warwicker and colleagues suggest an intriguing association between deficiency of the complement factor H and the nondiarrheal hemolytic–uremic syndrome. Two of our patients (Patients 44 and 45) with familial hemolytic–uremic syndrome were also found to have hypocomplementemia. The suggestion that sporadic hemolytic–uremic syndrome might be associated with autoantibodies against factor H is indeed very attractive and worth investigation.

We acknowledge the comments of Sarkodee-Adoo et al. on the difficulty of differentiating clinically between thrombotic thrombocytopenic purpura and the hemolytic–uremic syndrome. As we stated in our article, the clinical diagnosis of thrombotic thrombocytopenic purpura or the hemolytic–uremic syndrome was made by the investigators at each participating center. In virtually all patients, this differential diagnosis had been made before our multicenter study on von Willebrand factor–cleaving protease was initiated. The questionnaires were completed at participating centers after the clinical follow-up of each patient. This evaluation helped us to classify two cases (those of Patients 37 and 42) in which the initial clinical diagnosis was thrombotic thrombocytopenic purpura–hemolytic–uremic syndrome. We agree with Sarkodee-Adoo and colleagues that the laboratory data and clinical findings overlap in patients with thrombotic thrombocytopenic purpura and hemolytic–uremic syndrome.

Miha Furlan, Ph.D.
Bernhard Lämmle, M.D.
University Hospital, CH-3010 Bern, Switzerland

Citing Articles (5)

Citing Articles

1. 1

   O. Oyen, E. H. Strom, K. Midtvedt, O. Bentdal, A. Hartmann, S. Bergan, P. Pfeffer, I. B. Brekke. (2006) Calcineurin Inhibitor-Free Immunosuppression in Renal Allograft Recipients with Thrombotic Microangiopathy/Hemolytic Uremic Syndrome. American Journal of Transplantation 6:2, 412-418
   CrossRef

2. 2

   R.J.A. Murrin, J.A. Murray. (2006) Thrombotic Thrombocytopenic Purpura: aetiology, pathophysiology and treatment. Blood Reviews 20:1, 51-60
   CrossRef

3. 3

   Clarence Sarkodee-Adoo, Dan Sotirescu, Lyle Sensenbrenner, Aaron P. Rapoport, Michele Cottler-Fox, Guido Tricot, Kathy Ruehle, Barry Meisenberg. (2003) Thrombotic microangiopathy in blood and marrow transplant patients receiving tacrolimus or cyclosporine A. Transfusion 43:1, 78-84
   CrossRef

4. 4

   Jiyun Kim, Hong Wu, Lesleyann Hawthorne, Shahin Rafii, Jeffrey Laurence. (2001) Endothelial Cell Apoptotic Genes Associated with the Pathogenesis of Thrombotic Microangiopathies: An Application of Oligonucleotide Genechip Technology. Microvascular Research 62:2, 83-93
   CrossRef

5. 5

   Thomas J. Raife, Robert R. Montgomery. (2000) von Willebrand factor and thrombotic thrombocytopenic purpura. Current Opinion in Hematology 7:5, 278-283
   CrossRef