Download PDF
Semin Thromb Hemost 2006; 32(2): 098-104
DOI: 10.1055/s-2006-939765
Copyright © 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

von Willebrand Factor-Cleaving Protease (ADAMTS13) in the Course of Stem Cell Transplantation

Karim Kentouche1 , Felix Zintl1 , Dorothea Angerhaus2 , Dietlinde Fuchs1 , Johann Hermann1 , Reinhard Schneppenheim3 , Ulrich Budde2
  • 1Department of Hematology, Children's Hospital, Friedrich Schiller University, Jena, Germany
  • 2Laboratory Association Prof. Arndt and Partners, Coagulation Laboratory, Hamburg, Germany
  • 3Children's University Hospital Hamburg-Eppendorf, Germany
Further Information

Publication History

Publication Date:
30 March 2006 (online)

    Permissions and Reprints

ABSTRACT

Transplantation-associated microangiopathy (TAM) is a severe complication of stem cell transplantation. Although TAM shares many features with idiopathic thrombotic thrombocytopenic purpura or hemolytic uremic syndrome, the prognosis of TAM is worse. Clinical similarities and the observation that uncleaved ultralarge von Willebrand factor (ULVWF) multimers are found in the circulation of patients suffering from TAM suggest a defect in VWF proteolysis that may be due to a deficiency in ADAMTS13 activity. In this study the course of 28 consecutive patients, who received an allogeneic stem cell transplant was correlated to ADAMTS13 activity. Before stem cell transplantation, mean ADAMTS13 activity was within normal range. Within the first 8 weeks, mean activity declined to less than half the baseline activity. Furthermore, most of the patients showed normalization of ADAMTS13 activity. Low levels of ADAMTS13 activity were not correlated with clinical signs of thrombotic microangiopathy. However, two patients with clinical TAM had the lowest activity of all patients when suffering a severe bout of microangiopathy. Plasma exchange was not able to normalize ADAMTS13 deficiency in these patients, suggesting inactivation or consumption of ADAMTS13 activity in TAM.

KEYWORDS

Stem cell transplantation - thrombotic thrombocytopenic purpura - hemolytic uremic syndrome - transplantation-associated microangiopathy - von Willebrand factor - ADAMTS13 - plasma exchange

REFERENCES

  • 1 Pettitt A R, Clark R E. Thrombotic microangiopathy following bone marrow transplantation.  Bone Marrow Transplant. 1994;  14 495-504
    PubMedSearch in Google Scholar
  • 2 Ruutu T, Hermans J, Niederwieser D et al.. Thrombotic thrombocytopenic purpura after allogeneic stem cell transplantation: a survey of the European Group for Blood and Marrow Transplantation (EBMT).  Br J Haematol. 2002;  118 1112-1119
    CrossrefPubMedSearch in Google Scholar
  • 3 George J N, Li X, McMinn J R, Terrell D R, Vesley S K, Selby G B. Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome following allogeneic HPC transplantation: a diagnostic dilemma.  Transfusion. 2004;  44 294-304
    CrossrefPubMedSearch in Google Scholar
  • 4 Daly A S, Xenocostas A, Lipton J H. Transplantation-associated thrombotic microangiopathy: twenty-two years later.  Bone Marrow Transplant. 2002;  30 709-715
    CrossrefPubMedSearch in Google Scholar
  • 5 Ruutu T, Barosi G, Benjamin R J et al.. Diagnostic criteria for hematopoietic stem cell transplantation-associated microangiopathy (TAM): results of a Consensus Process by an International Working Group. Manuscript in preparation. 
    PubMed
  • 6 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
    CrossrefPubMedSearch in Google Scholar
  • 7 Kentouche K, Budde U, Furlan M, Scharfe V, Schneppenheim R, Zintl F. Remission of thrombotic thrombocytopenic purpura in a patient with compound heterozygous deficiency of von Willebrand factor-cleaving protease by infusion of solvent/detergent plasma.  Acta Paediatr. 2002;  91 1056-1059
    CrossrefPubMedSearch in Google Scholar
  • 8 Levy G G, Nichols W C, Lian E C et al.. Mutations in a member of the ADAMTS-family cause thrombotic thrombocytopenic purpura.  Nature. 2001;  413 488-494
    CrossrefPubMedSearch in Google Scholar
  • 9 Tsai H M, Lian C Y. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura.  N Engl J Med. 1998;  339 1585-1594
    CrossrefPubMedSearch in Google Scholar
  • 10 Krizek D M, Rick M E. Clinical application of a rapid method using agarose gel electrophoresis and Western blotting to evaluate von Willebrand factor protease activity.  Electrophoresis. 2001;  22 946-949
    CrossrefPubMedSearch in Google Scholar
  • 11 Ajzenberg N, Denis C V, Veyradier A, Girma J P, Meyer D, Baruch D. Complete defect in vWF-cleaving protease activity associated with increased shear-induced platelet aggregation in thrombotic microangiopathy.  Thromb Haemost. 2002;  87 808-811
    PubMedSearch in Google Scholar
  • 12 Arya M, Anvari B, Romo G M et al.. Ultralarge multimers of von Willebrand factor form spontaneous high-strength bonds with the platelet glycoprotein Ib-IX complex: studies using optical tweezers.  Blood. 2002;  99 3971-3977
    CrossrefPubMedSearch in Google Scholar
  • 13 Dong J, Moake J L, Nolasco L et al.. ADAMTS-13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions.  Blood. 2002;  100 4033-4039
    CrossrefPubMedSearch in Google Scholar
  • 14 Yagi H, Konno K, Kinoshita S et al.. Plasma of patients with Upshaw-Schulman syndrome, a congenital deficiency of von Willebrand factor-cleaving protease activity, enhances the aggregation of normal platelets under high shear stress.  Br J Haematol. 2001;  115 991-997
    CrossrefPubMedSearch in Google Scholar
  • 15 Kanamori H, Maruta A, Sasaki S et al.. Diagnostic value of hemostatic parameters in bone marrow transplant-associated thrombotic microangiopathy.  Bone Marrow Transplant. 1998;  21 705-709
    CrossrefPubMedSearch in Google Scholar
  • 16 Natazuka T, Kajimoto K, Ogawa R et al.. Coagulation abnormalities and thrombotic microangiopathy following bone marrow transplantation from HLA-matched unrelated donors in patients with hematological malignancies.  Bone Marrow Transplant. 1998;  21 815-819
    CrossrefPubMedSearch in Google Scholar
  • 17 Paquette R L, Tran L, Landaw E M. Thrombotic microangiopathy following allogeneic bone marrow transplantation is associated with intensive graft-versus-host disease prophylaxis.  Bone Marrow Transplant. 1998;  22 351-357
    CrossrefPubMedSearch in Google Scholar
  • 18 Takatsuka H, Takemoto Y, Okamoto T et al.. Thrombotic microangiopathy following allogeneic bone marrow transplantation.  Bone Marrow Transplant. 1999;  24 303-306
    CrossrefPubMedSearch in Google Scholar
  • 19 Takatsuka H, Takemoto Y, Yamada S et al.. Complications after bone marrow transplantation are manifestations of systemic inflammatory response syndrome.  Bone Marrow Transplant. 2000;  26 419-426
    CrossrefPubMedSearch in Google Scholar
  • 20 Wang F Z, Larsson K, Linde A, Ljungman P. Human herpes virus 6 infection and cytomegalovirus-specific lymphoproliferative responses in allogeneic stem cell transplant recipients.  Bone Marrow Transplant. 2002;  30 521-526
    CrossrefPubMedSearch in Google Scholar
  • 21 Gerritsen H E, Turecek P L, Schwarz H P, Lämmle B, Furlan M. Assay of von Willebrand factor (vWF)-cleaving protease based on decreased collagen binding affinity of degraded vWF.  Thromb Haemost. 1999;  82 1386-1389
    PubMedSearch in Google Scholar
  • 22 Schneppenheim R, Budde U, Oyen F, Angerhaus D, Aumann V, Drewke E. VonWillebrand factor cleaving protease and ADAMTS13 mutations in childhood TTP.  Blood. 2003;  101 1845-1850
    CrossrefPubMedSearch in Google Scholar
  • 23 Kondo M, Kojima S, Horibe K, Kato K, Matsuyama T. Hemolytic uremic syndrome after allogeneic or autologous hematopoetic stem cell transplantation for childhood malignancies.  Bone Marrow Transplant. 1998;  21 281-286
    CrossrefPubMedSearch in Google Scholar
  • 24 Uderzo C, Fumagalli M, De Lorenzo P et al.. Impact of thrombotic thrombocytopenic purpura on leukemic children undergoing bone marrow transplantation.  Bone Marrow Transplant. 2000;  26 1005-1009
    CrossrefPubMedSearch in Google Scholar
  • 25 Park Y D, Yoshioka A, Kawa K et al.. Impaired activity of plasma von Willebrand factor-cleaving protease may predict the occurrence of hepatic veno-occlusive disease after stem cell transplantation.  Bone Marrow Transplant. 2002;  29 789-794
    CrossrefPubMedSearch in Google Scholar
  • 26 Bianchi V, Robles R, Alberio L, Furlan M, Lämmle B. Von Willebrand factor-cleaving protease (ADAMTS13) in thrombocytopenic disorders: a severely deficient activity is specific for thrombotic thrombocytopenic purpura.  Blood. 2002;  100 710-713
    CrossrefPubMedSearch in Google Scholar
  • 27 Fontana S, Gerritsen H E, Kremer Hovinga J, Furlan M, Lämmle B. Microangiopathic haemolytic anaemia in metastasizing malignant tumours is not associated with a severe deficiency of the von Willebrand factor-cleaving protease.  Br J Haematol. 2001;  113 100-102
    CrossrefPubMedSearch in Google Scholar
  • 28 Loof A H, Van Vliet H HDM, Kappers-Klunne M C. Low activity of von Willebrand factor-cleaving protease is not restricted to patients suffering from thrombotic thrombocytopenic purpura.  Br J Haematol. 2001;  112 1087-1090
    CrossrefPubMedSearch in Google Scholar
  • 29 Mannucci P M, Canciani M T, Forza I, Lussana F, Lattuada A, Rossi E. Changes in health and disease of the metalloprotease that cleaves von Willebrand factor.  Blood. 2001;  98 2730-2735
    CrossrefPubMedSearch in Google Scholar
  • 30 Moore J C, Hayward C PM, Warkentin T E, Kelton J G. Decreased von Willebrand factor-cleaving protease activity associated with thrombocytopenic disorders.  Blood. 2001;  98 1842-1846
    CrossrefPubMedSearch in Google Scholar
  • 31 Remuzzi G, Galbusera M, Noris M et al.. von Willebrand factor cleaving protease (ADAMTS13) is deficient in recurrent and familial thrombotic thrombocytopenic purpura and hemolytic uremic syndrome.  Blood. 2002;  100 778-785
    CrossrefPubMedSearch in Google Scholar
  • 32 Vesely S K, George J N, Lämmle B et al.. ADAMTS13 activity in thrombotic thrombocytopenic purpura hemolytic uremic syndrome: relation to presenting features and clinical outcomes in a prospective cohort of 142 patients.  Blood. 2003;  102 60-68
    CrossrefPubMedSearch in Google Scholar
  • 33 Veyradier A, Obert B, Houllier A, Meyer D, Girma J P. Specific von Willebrand factor-cleaving protease in thrombotic microangiopathies: a study of111 cases.  Blood. 2001;  98 1765-1772
    CrossrefPubMedSearch in Google Scholar
  • 34 Van der Plas R M, Schiphorst M E, Huizinga E G et al.. von Willebrand factor proteolysis is deficient in classic, but not in bone marrow transplantation-associated thrombotic thrombocytopenic purpura.  Blood. 1999;  93 3798-3802
    PubMedSearch in Google Scholar
  • 35 Arai S, Carol A, Streiff M, Hutchins G M, Vogelsang G B, Tsai H M. Von Willebrand factor-cleaving protease activity and proteolysis of von Willebrand factor in bone marrow transplant-associated thrombotic microangiopathy.  Hematol J. 2001;  2 292-299
    CrossrefPubMedSearch in Google Scholar
  • 36 Fuge R, Bird J M, Fraser A et al.. The clinical features, risk factors and outcome of thrombotic thrombocytopenic purpura occurring after bone marrow transplantation.  Br J Haematol. 2001;  113 58-64
    CrossrefPubMedSearch in Google Scholar
  • 37 Bacigalupo A, Oneto R, Bruno B et al.. Early predictors of transplant-related mortality (TRM) after allogeneic bone marrow transplants (BMT): blood urea nitrogen (BUN) and bilirubin.  Bone Marrow Transplant. 1999;  24 653-659
    CrossrefPubMedSearch in Google Scholar
  • 38 Vantelon J M, Munck J N, Bourhis J H et al.. Thrombotic microangiopathy: a new dose-limiting toxicity of high-dose sequential chemotherapy.  Bone Marrow Transplant. 2001;  27 531-536
    CrossrefPubMedSearch in Google Scholar
  • 39 Zomas A, Saso R, Powles R et al.. Red cell fragmentation (schistocytosis) after bone marrow transplantation.  Bone Marrow Transplant. 1998;  22 777-780
    CrossrefPubMedSearch in Google Scholar
  • 40 Gharpure V S, Devine S M, Holland H K, Geller R B, O'Toole K, Wingard J R. Thrombotic thrombocytopenic purpura associated with FK 506 following bone marrow transplantation.  Bone Marrow Transplant. 1995;  16 715-716
    PubMedSearch in Google Scholar
  • 41 Roy V, Rizvi M A, Vesely S K, George J N. Thrombotic thrombocytopenic purpura-like syndromes following bone marrow transplantation: an analysis of associated conditions and clinical outcomes.  Bone Marrow Transplant. 2001;  27 641-646
    CrossrefPubMedSearch in Google Scholar
  • 42 Tezcan H, Zimmer W, Fenstermaker R, Herzig G P, Schriber J. Severe cerebellar swelling and thrombotic thrombocytopenic purpura associated with FK506.  Bone Marrow Transplant. 1998;  21 105-109
    CrossrefPubMedSearch in Google Scholar
  • 43 Deschênes G, Veyradier A, Cloarec S et al.. Plasma therapy in von Willebrand factor protease deficiency.  Pediatr Nephrol. 2002;  17 867-870
    CrossrefPubMedSearch in Google Scholar
  • 44 Furlan M, Robles R, Morselli B, Sandoz P, Lämmle B. Recovery and half-life of von Willebrand factor-cleaving protease after plasma therapy in patients with thrombotic thrombocytopenic purpura.  Thromb Haemost. 1999;  81 8-13
    Thieme ConnectPubMedSearch in Google Scholar
  • 45 Llamas P, Romero R, Cabrera R, Sanjuán I, Forés R, Fernández M N. Management of thrombotic microangiopathy following allogeneic transplantation: what is the role of plasma exchange?.  Bone Marrow Transplant. 1997;  20 305-306
    CrossrefPubMedSearch in Google Scholar
  • 46 Milone J, Napal J, Bordone J, Etchegoyen O, Morales V. Complete response in severe thrombotic microangiopathy post bone marrow transplantation (BMT-TM) after multiple plasmaphereses.  Bone Marrow Transplant. 1998;  22 1019-1021
    CrossrefPubMedSearch in Google Scholar
  • 47 Plews D E, Turner M L, Wallace W HB. Plasma exchange as successful treatment of thrombotic thrombocytopenic purpura post autologous bone marrow transplant in a child.  Bone Marrow Transplant. 2000;  25 679-680
    CrossrefPubMedSearch in Google Scholar
  • 48 Sivakumaran M, Roland J. Prophylactic treatment with fresh frozen plasma in chronic thrombocytopenic purpura.  Br J Haematol. 2002;  117 480-483
    PubMedSearch in Google Scholar
  • 49 Hulstein J JJ, de Groot P G, Silence K, Veyradier A, Fijnheer R, Lenting P J. A novel nanobody that detects the gain-of-function phenotype of von Willebrand factor in ADAMTS13 deficiency and vonWillebrand disease type 2B.  Blood. 2005;  106 3035-3042
    CrossrefPubMedSearch in Google Scholar
  • 50 Rick M E, Moll S, Taylor M A, Krizek D M, White II G C, Aronson D L. Clinical use of a rapid CBA for von Willebrand factor-CP in patients with thrombotic thrombocytopenic purpura.  Thromb Haemost. 2002;  88 598-604
    PubMedSearch in Google Scholar

Karim KentoucheM.D. 

Department of Hematology, Children's Hospital, Friedrich-Schiller-University Jena

Kochstr. 2, 07745 Jena, Germany

Email: Karim.Kentouche@med.uni-jena.de