Thrombotic Thrombocytopenic Purpura-2005

New discoveries in the last decade have dramatically changed our concept about the etiology and pathogenesis of thrombotic thrombocytopenic purpura (TTP). When we first visited this topic in 1987, in a symposium on thrombotic microangiopathy in Seminars in Hematology,[1] [2] our knowledge of TTP was limited. During the next 10 years, significant advances were made in the pathogenesis of the disease, culminating in the first update of this issue in 1997.[3] At the time, the observation by Moake et al[4] of ultralarge von Willebrand factor (vWF) in congenital TTP patients directed our thinking to this factor as an important pathway in the disease process. Fig. [1] represents our concept at the time. Lian et al[5] reported then that the proposed central pathogenic feature was the formation of platelet aggregates that have abundant vWF antigen with little or no fibrin. Lian is providing an update in this issue. The studies of Moake et al[4] in 1982 initially identified “unusually large” multimers of vWF released from endothelial cells in the plasma of patients with chronic relapsing TTP. Both endothelial cells and platelets produce multimers of vWF that are larger than those in normal plasma. The initial attachment of only a small quantity of unusually large multimers of vWF to glycoprotein (GP)Ib, and subsequently to adenosine diphosphate-activated platelet GPIIb/IIIa complexes, induces platelet aggregation in vitro in the presence of increased fluid shear stress.

Figure 1 Concept of thrombotic thrombocytopenic purpura in 1997. ULvWF, ultralarge von Willebrand factor.

This changing paradigm of TTP since 1997 is discussed by Raife in this issue. This includes the identification of a vWF-cleaving metalloprotease (ADAMTS13) in plasma that normally prevents the entrance into the circulation (or persistence) of unusually large multimers of vWF.[6] [7] This enzyme degrades the multimers by cleaving peptide bonds in monomeric subunits of vWF at position 1605 to 1606 (between tyrosine and methionine).[8] The metalloprotease is referred to as ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type 1 motifs), a member of a family of zinc- and calcium-dependent proteases.[9] [10] The molecular biology and diagnostic utility of ADAMTS13 is updated by Shelat et al in this issue. Unusually large multimers of vWF factor are probably cleaved directly by ADAMTS13 on the surface of endothelial cells. In all instances of familial TTP, plasma ADAMTS13 activity is less than 5% of normal. Porta et al, in this issue, also reports that most cases of acquired TTP are associated with an acquired inhibitor to ADAMTS13 and severely deficient ADAMTS13 activity. Drug-associated TTP is also an important clinical entity to consider; the antiplatelet agents ticlopidine and clopidogrel are the two most commonly reported drugs causing this rare syndrome.[11] [12] In this issue, Zakarija and Bennett note that a similar mechanism is proposed for ticlopidine-associated TTP, whereas other drugs, such as clopidogrel, are reported to have more direct toxic effects. The ADAMTS13 deficiency in plasma from patients with familial, acquired, or drug-induced TTP correlates with deficient ADAMTS13 activity on the surface of endothelial cells. Consequently, unusually large multimers of vWF are not cleaved following secretion from endothelial cells. Passing platelets adhere by means of GPIb receptors to these multimers. Additional platelets subsequently aggregate by means of activated GPIIb/IIIa complexes onto the unusually large multimeric strings. Formation of endothelial-bound vWF-platelet aggregates may be the critical factor in the current version of TTP pathogenesis. In some patients, an additional event (intense stimulation of secretion of unusually large multimers by endothelial cells) may also initiate episodes of TTP.

The end result is that the diagnostic and therapeutic challenges associated with TTP have evolved during the last 10 years, as reported in the first article in this issue. In this article, the current concept of TTP is presented (Fig. [2]). It should be noted that in 1997, the symposium in Seminars in Hematology was entitled “TTP and Hemolytic Uremic Syndrome,” and included an article on transplantation-associated TTP and hemolytic uremic syndrome (HUS). In this issue, Qu and Kiss explain that transplantation and cancer-related thrombotic microangiopathy is distinct from TTP. As a result of the changing paradigm for this syndrome, we do not include HUS in the current title. Our present knowledge allows us to distinguish clearly between TTP and HUS in the pediatric setting, as reported by Lowe and Werner, and also to understand that, as noted by Potti et al, hypercoagulability does not have a major role in explaining the onset or maintenance of the symptoms of TTP.

Figure 2 Present day concept of thrombotic thrombocytopenic purpura. ULvWF, ultralarge von Willebrand factor.

As noted by Kwaan and Boggio, the clinical spectrum of TTP continues to be similar to that originally reported by Moschowitz in 1924.[13] More reliable and reproducible assays will allow laboratory data to be used in a clinical management strategy. Although the sine qua non of treatment remains plasmapheresis, our 1997 update reported on the use of specific regimens used in plasma exchange, cryosupernatant plasma, corticosteroids, splenectomy, and antiplatelet drugs. Rock advances our understanding of TTP therapy, outlining the role of these therapies as well as the potential of exciting new immunomodulatory treatments such as rituximab. Finally, Willis and Banderanko note that because of the high rates of relapses with TTP, it is essential that concise definitions of this clinical syndrome be outlined and the clinical and therapeutic implications of relapsing TTP be addressed.

For the last 80 years, TTP has been a rewarding endeavor for many research scientists. We hope that this third update of our understanding of TTP, developed in response to the dramatic discoveries related to findings in the last 10 years, will serve our readers well. With the exponential growth in biomedical data, one would anticipate that in another decade, more breakthroughs in diagnosis as well as in therapy would be forthcoming.

REFERENCES

• 1 [No authors listed]. Thrombotic microangiopathy I.  Semin Hematol. 1987;  24 69-139
• 2 [No authors listed]. Thrombotic microangiopathy II.  Semin Hematol. 1987;  24 141-199
• 3 Kwaan (Guest Editor) H C. Thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome.  Semin Hematol. 1997;  34 81-166
• 4 Moake J L, Rudy C K, Troll J H et al.. Unusually large plasma factor VIII: von Willebrand factor mutations in chronic relapsing thrombotic thrombocytopenic purpura.  N Engl J Med. 1982;  307 1432-1435
• 5 Lian E C-Y, Harkness D R, Byrnes J J, Wallach H, Nunez R. The presence of a platelet aggregating factor in the plasma of patients with thrombotic thrombocytopenic purpura and its inhibition by normal plasma.  Blood. 1979;  53 333-338
• 6 Furlan M, Robles R, Solenthaler M et al.. Deficient activity of von Willebrand factor cleaving protease in chronic relapsing thrombotic thrombocytopenic purpura.  Blood. 1997;  89 3097-3103
• 7 Furlan M, Robles R, Galbusera M et al.. Von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and hemolytic uremic syndrome.  N Engl J Med. 1998;  339 1578-1584
• 8 Tsai H M, Lian E C. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura.  N Engl J Med. 1998;  339 1585-1594
• 9 Levy G G, Nichols W C, Lian E C et al.. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura.  Nature. 2001;  413 488-494
• 10 Zheng X, Chung C, Takayama T K, Majerus E M, Sadler J E, Fujikawa K. Structure of von Willebrand factor-cleaving protease (ADAMTS13), a metalloprotease involved in thrombotic thrombocytopenic purpura.  J Biol Chem. 2001;  276 41059-41063
• 11 Bennett C L, Connors J M, Carwile J M et al.. Thrombotic thrombocytopenic purpura associated with clopidogrel.  N Engl J Med. 2000;  342 1773-1777
• 12 Bennett C L, Weinberg P D, Rozenberg-Ben-Dor K, Yarnold P R, Kwaan H C, Green D. Thrombotic thrombocytopenic purpura associated with ticlopidine: a review of 60 cases.  Ann Intern Med. 1998;  128 541-544
• 13 Moschcowitz E. Hyaline thrombosis of the terminal arterioles and capillaries: a hitherto undescribed disease.  Proc NY Pathol Soc. 1924;  24 21-24