Thrombotic thrombocytopenic purpura (TTP) is a disorder of systemic platelet aggregation. Evidence has accumulated that the aggregating agonist in TTP of all types is likely to be von Willebrand factor, especially unusually large von Willebrand factor multimers derived from endothelial cells. Recent evidence indicates that a metalloproteinase involved in von Willebrand factor breakdown is not present in adequate amounts in children with chronic relapsing TTP. Chronic relapsing TTP is, therefore, likely to be a congenital deficiency of von Willebrand factor metalloproteinase. In adults with single episode or intermittent types of TTP, the von Willebrand factor metalloproteinase is inhibited by autoantibodies that are present either transiently or intermittently in patient blood. Single episode and intermittent types of TTP in adults are, therefore, autoimmune processes of a short-term and recurrent nature, respectively.
ABBREVIATIONS: GP = glycoprotein; TP = thrombotic thrombocytopenic purpura; UL = unusually large; vWf = von Willebrand factor.
INDEX TERMS: thrombotic thrombocytopenic purpura; TTP; unusually large vWf; von Willebrand factor; vWf metalloproteinase; vWf.
Clin Lab Sci 1998;11(6);362
Joel L Moake MD is Professor of Medicine at Baylor College of Medicine, Houston TX
Address for correspondence: Joel L Moake MD. The Methodist Hospital and Baylor College of Medicine, 6565 Fannin, MS 902 Main Bldg, Houston TX 77030. (713) 790-2157, (713) 790-0828 (fax). JMoake@TMH. TMC.EDU
Gerald L Davis is the Focus: Platelet Update guest editor.
Focus Continuing Education Credit: see pages 373 to 375 for learning objectives, test questions, and application form.
Thrombotic thrombocytopenic purpura (TTP) was first described by Moschcowitz in 1924.1 The disorder was once considered rare, but is now seen frequently by hematologists in large American medical centers. Platelets reversibly aggregate in the microcirculation in TTP, producing fluctuating ischemia in the brain or other organs,2,3 If sustained, the ischemia can result in tissue infarction. Profound thrombocytopenia, intravascular hemolysis with erythrocyte fragmentation, and extreme elevations in serum lactate dehydrogenase (LDH), are characteristic of TTP Although the majority of patients who develop TTP have no identifiable associated risk factor, some have the disorder in association with pregnancy or exposure to ticlopidine.
It has long been believed that TTP is caused by the inappropriate presence of a platelet aggregating agent in the systemic circulation.4 Harkness and colleagues5 found that early vascular lesions in the brain consist almost exclusively of platelet thrombi, without evidence of overt endothelial cell damage or perivascular inflammation. TTP may, therefore, be a disease of direct platelet aggregation in the microcirculation that is not preceded by endothelial desquamation and platelet adherence to exposed subendothelium.
Immunohistochemical study of early TTP lesions has revealed an abundance of von Willebrand factor (vWf) with little fibrinogen present.' The opposite findings are characteristic of thrombotic lesions in disseminated intravascular coagulation.' vWf multimers within TTP thrombi may function as polymeric bridges promoting direct platelet-platelet cohesion.
von WILLEBRAND FACTOR
vWf monomers (280,000 Daltons) are linked by disulfide bonds into multimers of varying sizes that range into the millions of Daltons.7 vWf multimers are produced within megakaryocytes and endothelial cells and are stored within the cc-granules of platelets and Weibel-Palade bodies of endothelial cells. The predominant sources of plasma vWf multimers are endothelial cells. The entire constellation of vWf multimers found in the normal circulation is produced within both megakaryocytes and endothelial cells.7 Additionally, both cell types construct vWf multimeric forms that are even larger in size than those found in normal plasma.8-10 These unusually large (UL)vWf multimers are presumed to consist of an increased number of mature vWf subunits. ULvWf forms are more effective than the largest plasma vWf forms at binding under the influence of elevated fluid shear stresses to the glycoprotein (GP)Iba component of platelet GPIb-IX-V receptors, and to platelet GPIIbIIIa (GPIIb-p3)complexes resulting in aggregation.9'1
von WILLEBRAND FACTOR BREAKDOWN
A substance in normal platelet-poor plasma and the cryoprecipitate-depleted fraction of normal plasma (cryosupernatant) is capable in vitro of reducing reversibly the size of ULvWf multimeric forms released by cultured human endothelial cells into the somewhat smaller vWf multimers ordinarily in circulation." This activity has characteristics of a limited disulfide bond reductase (Figure 1)pl t2 The ULvWf breakdown process may be made irreversible by the tandem proteolysis of the partially reduced, unfurled vWf multimers by a vWf metalloproteinase. Neither the ULvWf reductase nor the vWf metalloproteinase present in the plasma would be expected to have access to the ULvWf forms secreted in the retrograde direction from endothelial cells into the vascular subendothelium.
von WILLEBRAND FACTOR IN TTP
Serial studies of plasma samples from patients during single episodes of TTP have often shown either the presence of ULvWf multimers or, alternatively, absence of the largest plasma vWf forms.8'3 The presence of ULvWf multimers in TTP patient plasma may reflect the failure of TTP plasma to process adequately the ULvWf multimers released from endothelial cells. The disappearance of large vWf forms in some TTP patient plasma samples during acute TTP episodes may be predominantly because these ULvWf forms, along with the largest plasma vWf multimers, bind to platelets and cause aggregation.
Recently conducted serial flow cytometry studies of EDTA-whole blood samples from patients with initial episode, intermittent, or chronic relapsing TTP confirm that vWf multimers are the likely aggregating agents in TTP The amount of vWf bound to single platelets has been found to be significantly increased during TTP relapses relative to remission periods in patients with all types of TTP.'4 No concordance has been detected between vWf and Pselectin expression on most samples of TTP patient platelets.'4 This latter finding suggests that the vWf bound to platelets in TTP is likely to be from plasma, rather than from platelet a-granules'4 (platelet a-granules contain both vWf and P-selectin).
von WIT VI F.RRAND FACTOR METALLOPROTEINASE IN TTP
Four patients with chronic relapsing TTP reported in 1997 by Furlan had decreased or absent vWf metalloproteinase activity (Figure 1). 5 This deficiency was not associated with an inhibitor and was, therefore, considered to be congenital. In late 1997, Tsai as well as Krause, independently reported preliminary data obtained on adult initial episode and intermittent TTP patients. 17 The two investigators found that 40 out of a total of 42 TTP patient samples evaluated had deficient vWf metalloproteinase activity during, but not after, TTP episodes (Figure 1 ). An inhibitor of the vWf metalloproteinase activity was responsible for this deficiency in 28 of the 32 patients studied further. Tsai and Lian characterized the inhibitor as an IgG antibody (presumably an autoantibody) in eight of the nine patient samples analyzed for inhibitor type.'16
The plasma vWf multimeric patterns, platelet-bound vWf data, and studies of the vWf metalloproteinase imply that adult TTP may often be an autoimmune disorder associated with the defective breakdown of a potent platelet aggregating agent, i.e., ULvWf multimeric forms, after their release from systemic endothelial cells. The cause of this putative transient or intermittent defect of immune regulation is presently unknown, as is the reason why the vWf metalloproteinase is selectively targeted for autoantibody attack. The vWf metalloproteinase autoantibodies may appear for only a brief period (single-episode TTP) or may recur at unpredictable intervals (intermittent TTP).
If a TTP patient survives an initial episode and suffers no subsequent relapse, vWf multimeric forms in recovery samples are almost always normal.'3 In contrast, ULvWf multimers found in multiple adult patient plasma samples after recovery may indicate persistent autoantibody-mediated interference with the vWf metalloproteinase.'17
In chronic relapsing TTP, which usually begins in childhood and recurs about every three to four weeks, there may be a congenital defect in the production, survival, or activity of the vWf metalloproteinases (as in the four patients reported by Furlan).15 It has been suggested that in chronic relapsing TTP, the accumulation of ULvWf forms in the blood stream may periodically exceed the threshold level required for attachment to platelets (and induction of aggregation) under the high shear conditions of the microcirculation.14,18
ACKNOWLEDGEMENT
Some of the work described in this review was supported by NIH grants HL 18584 and HL 54169.
REFERENCES
1. Moschcowitz E. Hyaline thrombosis of the terminal arterioles and capillaries: A hitherto undescribed disease. Proc NY Pathol Soc 1924;24:21-14. 2. Rock GA, Sumak KH, Buskard NA, and others. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. N Engl J Med 1991;325:393-7. 3. Bell WR, Braine HG, Ness PM, Kickler TS. Improved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome-clinical experience in 108 patients. N Engl J Med 1991;325:398-402. 4. Baer G, Klemperer patients PI Schrifrin A: An acute febrile anemia with thrombocytopenic purpura with diffuse platelet thrombosis of capillaries and arterioles. Trans Assoc Am Phy 1936;65:43-58. 5. Harkness DR, Byrnes JJ, Lian EC-Y, and others. Hazard of platelet transfusion in thrombotic thrombocytopenic purpura. JAMA 1981;246:1931-3.
6. Asada Y, Sumiyoshi A, Hayashi T, and others. Immunohistochemistry of vascular lesions in thrombotic thrombocytopenic purpura, with special reference to factor VIII related antigen. Thromb Res 1985;38:469-79. 7. Wagner DD, Ginsburg D. Structure, biology, and genetics ofvon Willebrand factor. In: Hoffman R, and others, editors. Hematology - basic principles and practice, New York: Churchill Livingstone; 1995. p 1717-25. 8. Moake JL, Rudy CK, Troll JH, and others. Unusually large plasma factor VIII: von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. N Engl J Med 1982; 307:1432-5.
9. Moake JL, Turner NA, Stathopoulos NA, and others. Involvement of large plasma von Willebrand factor (vWf) multimers and unusually large vWf forms derived from endothelial cells in shear stress-induced platelet aggregation. J Clin Invest 1986;78:1456-61. 10. Moake JL, Turner NA, Stathopoulos NA, and others. Shear-induced platelet aggregation can be mediated by vWf released from platelets, as well as by exogenous large or unusually large multimers, requires adenosine diphosphate, and is resistant to aspirin. Blood 1988;71:1366-74. 11. Frangos JA, Moake JL, Nolasco L, and others. Cryosupernatant regulates accumulation of unusually large vWf multimers from endothelial cells. Am J Physiol 1989;256:H1635-44.
12. Phillips MD, Moake JL, Nolasco L, Garcia R: Plasma von Willebrand factor processing activity functions like a disulfide bond reductase: reversible decrease of multimer size. Thomb Haemost 1993;69:2342 (abst). 13. Moake JL, McPherson PD: Abnormalities of von Willebrand factor in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. Am Med 19897:3-9N.
14. Chow TW, Turner NA, Chintagumpala M, and others. Increased von Willebrand factor binding to platelets in single episode and recurrent types of thrombotic thrombocytopenic purpura. Am J Hematol (In press). 15. Furlan M, Robles R, Solenthaler M, and others. Deficient activity of von Willebrand factor-cleaving protease in chronic relapsing thrombotic thrombocytopenic purpura. Blood 1997;89:3097-103. 16. Tsai HM, Lian EGY: Inhibitors to vWf-deaving metalloproteinase in thrombotic thrombocytopenic purpura. Blood 1997;90 (suppl 1):2620 (abst). 17. Krause M, Furlan M, Ehrenforth S: Relevance of the von Willebrand factor cleaving protease in the diagnosis and clinical course in patients with thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS). Blood 1997; 90 (suppl 1):404 (abst). 18. Moake J, Chintagumpala M, Turner N, and others. Solvent/detergent-treated plasma suppresses shear-induced platelet aggregation and prevents episodes of thrombotic thrombocytopenic purpura. Blood 1994;84:490-7.
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