Correspondence

Thrombotic Microangiopathies

N Engl J Med 2002; 347:2171-2173December 26, 2002

Article

To the Editor:

We write to address several statements in Dr. Moake's review of thrombotic microangiopathies (Aug. 22 issue).1 First, assays of the activity of the metalloprotease ADAMTS 13 differ in design; the normal range of activity is assay-specific.2 The use of an assay for which the normal range is 79 to 127 percent, rather than 50 to 178 percent, as cited by Moake, permitted the identification of carriers of ADAMTS 13 mutations (45 to 68 percent activity) and linked the defect to the ADAMTS 13 gene.3 We urge caution in comparing the results of different assays.

Also, the identity of the liver cell that synthesizes ADAMTS 13 remains unknown. Evidence is lacking that a von Willebrand factor transmembrane domain anchors ADAMTS 13 to endothelial cells, that Shiga toxins impair ADAMTS 13 activity, or that von Willebrand factor platelet binding initiates thrombogenesis in the hemolytic–uremic syndrome. In fact, in the hemolytic–uremic syndrome associated with Escherichia coli O157:H7, cleavage of von Willebrand factor by ADAMTS 13 is increased, and pathologically large plasma forms are absent.4 Prothrombotic abnormalities preceding the hemolytic–uremic syndrome5 raise the possibility that platelet trapping in fibrin thrombi, not aggregation, causes thrombocytopenia.

We agree that patients with possible thrombotic thrombocytopenic purpura should undergo plasmapheresis to restore ADAMTS 13 activity. However, in the literature and in our experience, E. coli O157:H7 infections and the associated hemolytic–uremic syndrome are similar and recognizable at all ages: thrombocytopenia, hemolytic anemia, and azotemia develop 5 to 10 days after the onset of acute, painful, afebrile, and usually bloody diarrhea. In such cases, plasma exchange cannot be justified on the basis of our current understanding of thrombotic microangiopathies.

Phillip I. Tarr, M.D.
Children's Hospital and Regional Medical Center, Seattle, WA 98105
tarr@u.washington.edu

Han-Mou Tsai, M.D.
Montefiore Medical Center, Bronx, NY 10467

Wayne L. Chandler, M.D.
University of Washington, Seattle, WA 98195

5 References

1. 1

   Moake JL. Thrombotic microangiopathies. N Engl J Med 2002;347:589-600
   Full Text | Web of Science | Medline

2. 2

   Tsai HM. Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. J Mol Med 2002;80:639-647
   CrossRef | Web of Science | Medline

3. 3

   Levy GG, Nichols WC, Lian EC, et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 2001;413:488-494
   CrossRef | Web of Science | Medline

4. 4

   Tsai HM, Chandler WL, Sarode R, et al. Von Willebrand factor and von Willebrand factor-cleaving metalloprotease activity in Escherichia coli O157:H7-associated hemolytic uremic syndrome. Pediatr Res 2001;49:653-659
   CrossRef | Web of Science | Medline

5. 5

   Chandler WL, Jelacic S, Boster DR, et al. Prothrombotic coagulation abnormalities preceding the hemolytic-uremic syndrome. N Engl J Med 2002;346:23-32[Erratum, N Engl J Med 2002;346:715.]
   Full Text | Web of Science | Medline

To the Editor:

Moake emphasizes the role of von Willebrand factor–cleaving protease in the pathogenesis of thrombotic microangiopathies, as well as differences between the hemolytic–uremic syndrome and thrombotic thrombocytopenic purpura. However, other data suggest that the hemolytic–uremic syndrome and thrombotic thrombocytopenic purpura may be different expressions of the same disease process.1 In some familial cases with a known specific genetic abnormality, the disease has been classified as thrombotic thrombocytopenic purpura or the hemolytic–uremic syndrome in different family members. Furthermore, recurrent episodes of the microangiopathic syndrome in the same patient have been variously classified as thrombotic thrombocytopenic purpura or the hemolytic–uremic syndrome, even when the same genetic defect was implicated.2 Finally, in secondary cases of thrombotic microangiopathy due to drugs, the critical roles of shear stress and direct endothelial injury or activation cannot be ignored.3,4 Such stress may enhance platelet activation and the breakdown of von Willebrand factor multimers, thus favoring the cascade of microangiopathy. In these cases, shear stress, vasoconstriction, and endothelial injury or activation may have more important roles than alterations of von Willebrand factor–cleaving protease activity itself.

Chike Magnus Nzerue, M.D.
University of Rochester, Rochester, NY 14642
chike_nzerue@urmc.rochester.edu

4 References

1. 1

   Kaplan BS, Kaplan P. Hemolytic uremic syndrome in families. In: Kaplan BS, Trompeter RS, Moake JL, eds. Hemolytic uremic syndrome and thrombotic thrombocytopenic purpura. New York: Marcel Dekker, 1992: 213-25.
   

2. 2

   Meroni M, Volpi A, Battini G, et al. Recurrent hemolytic uremic syndrome: case report. Nephron 1986;44:263-264
   CrossRef | Medline

3. 3

   Galbusera M, Remuzzi A, Benigni A, Rossi C, Remuzzi G. A novel interpretation of the role of von Willebrand factor in thrombotic microangiopathies based on platelet adhesion studies at high shear rate flow. Am J Kidney Dis 2000;36:695-702
   CrossRef | Web of Science | Medline

4. 4

   Gallego MJ, Zoja C, Morigi M, et al. Cyclosporine enhances leukocyte adhesion to vascular endothelium under physiologic flow conditions. Am J Kidney Dis 1996;28:23-31
   CrossRef | Web of Science | Medline

Author/Editor Response

Dr. Moake replies:

To the Editor: Nzerue emphasizes two points discussed in my review: the difficulty in categorizing thrombotic microangiopathies on the basis of the clinical phenotype, and the incompletely defined pathogenesis of thrombotic microangiopathies associated with allogeneic transplantation or exposure to drugs (other than ticlopidine and clopidogrel).

I agree with Tarr and colleagues that the normal range is not identical when different procedures are used to quantify plasma ADAMTS 13 activity and that the predominant type of hepatic cell producing ADAMTS 13 remains imprecisely defined. I also agree that plasma exchange is not appropriate in patients (especially children) with an unequivocal diagnosis of the hemolytic–uremic syndrome associated with E. coli O157:H7. As I state in my review, however, plasma exchange is prudent when patients have “an acquired syndrome that could be either thrombotic thrombocytopenic purpura or the hemolytic–uremic syndrome.”

In response to the other comments by Tarr and colleagues, I offer the following observations and interpretations. Preliminary data reported by Padilla et al.1 indicate that unusually large von Willebrand factor multimers secreted from Weibel–Palade bodies are transiently anchored to the endothelial cell surfaces (in preparation for ADAMTS 13 cleavage) through P-selectin molecules, which are also secreted from Weibel–Palade bodies. Shiga toxin 1 binds to globotriaosylceramide receptors on endothelial cells and stimulates the rapid secretion of unusually large von Willebrand factor multimers.2 Experiments by Morigi et al.3 suggest that the secreted von Willebrand factor can avoid cleavage by ADAMTS 13 on Shiga toxin 1–treated endothelial cell surfaces long enough to initiate the adhesion and aggregation of platelets from perfused normal human whole blood. One interpretation of their findings is that exposure to Shiga toxin 1 interferes with ADAMTS 13 activity on endothelial cell surfaces and thereby delays (perhaps only transiently) the cleavage of emerging, unusually large von Willebrand factor multimers. Proteolytic fragments of von Willebrand factor would nonetheless be expected to accumulate under these conditions in the plasma of patients with the hemolytic–uremic syndrome.4 The reason for this is that even modestly impaired ADAMTS 13 activity on endothelial cell surfaces should be capable of generating within minutes many cleavage products from the excessive quantities of unusually large von Willebrand factor multimers secreted by Shiga toxin 1–stimulated endothelial cells.2

Joel L. Moake, M.D.
Baylor College of Medicine, Houston, TX 77030
jmoake@rice.edu

4 References

1. 1

   Padilla A, Bernardo A, Nolasco L, Moake J, López J, Dong J-F. A potential role for P-selectin in anchoring ultra-large von Willebrand factor multimers onto the endothelial cell surface. Blood (in press). abstract.
   

2. 2

   Moake JL. Haemolytic-uraemic syndrome: basic science. Lancet 1994;343:393-397
   CrossRef | Web of Science | Medline

3. 3

   Morigi M, Galbusera M, Binda E, et al. Verotoxin-1-induced up-regulation of adhesive molecules renders microvascular endothelial cells thrombogenic at high shear stress. Blood 2001;98:1828-1835
   CrossRef | Web of Science | Medline

4. 4

   Mannucci PM, Lombardi R, Lattuada A, et al. Enhanced proteolysis of plasma von Willebrand factor in thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome. Blood 1989;74:978-983
   Web of Science | Medline

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1. 1

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