GIPTT
Gruppo Italiano
Porpora Trombotica Trombocitopenica

PUBBLICAZIONI RECENTI IN TEMA DI
PORPORA TROMBOTICA TROMBOCITOPENICA

1. Blood  2002 Jun 1;99(11):3971-7
   Ultralarge multimers of von Willebrand factor form spontaneous high-strength bonds with the platelet glycoprotein Ib-IX complex: studies using optical tweezers.
   Arya M, Anvari B, Romo GM, Cruz MA, Dong JF, McIntire LV, Moake JL, Lopez JA. Department of Bioengineering, Rice University; and the Division of Thrombosis Research, Department of Medicine, Baylor College of Medicine, Houston, TX.
   Ultralarge von Willebrand factor (ULVWF) multimers have been implicated in the pathogenesis of the catastrophic microangiopathic disorder, thrombotic thrombocytopenic purpura. Spontaneous ULVWF binding to platelets has been ascribed to increased avidity due to the greatly increased number of binding sites for platelets (the A1 domain) per molecule. To address the mechanism of enhanced ULVWF binding to platelets, we used optical tweezers to study the unbinding forces from the glycoprotein Ib-IX (GP Ib-IX) complex of plasma VWF, ULVWF, and isolated A1 domain. The unbinding force was defined as the minimum force required to pull ligand-coated beads away from their attachment with GP Ib-IX-expressing cells. Beads coated with plasma VWF did not bind to the cells spontaneously, requiring the modulators ristocetin or botrocetin. The force required to break the ristocetin- and botrocetin-induced plasma VWF-GP Ib-IX bonds occurred in integer multiples of 6.5 pN and 8.8 pN, respectively, depending on the number of bonds formed. In contrast, beads coated with either ULVWF or A1 domain bound the cells in the absence of modulators, with bond strengths in integer multiples of approximately 11.4 pN for both. Thus, in the absence of shear stress, ULVWF multimers form spontaneous high-strength bonds with GP Ib-IX, while plasma VWF requires exogenous modulators. The strength of individual bonds formed with GP Ib-IX was similar for both ULVWF and the isolated A1 domain and greater than those of plasma VWF induced by either modulator. Therefore, we suggest that the conformational state of ULVWF multimers is more critical than their size for interaction with platelets.    
2. Semin Thromb Hemost  2002 Apr;28(2):167-72
   Assays of von Willebrand factor- cleaving protease: a test for diagnosis of familial and acquired thrombotic thrombocytopenic purpura. Furlan M, Lammle B. Central Hematology Laboratory, University Hospital, Inselspital, Bern, Switzerland.  
   Endothelial cells secrete von Willebrand factor (vWF) multimers that are larger than those found in the circulating plasma. These very large multimeric forms of vWF, capable of spontaneously binding to and agglutinating the blood platelets under conditions of high fluid shear rate, are degraded by a specific metalloprotease cleaving the peptide bond 842Tyr-843Met of the vWF subunit. The vWF-cleaving protease was found to be deficient in patients with familial thrombotic thrombocytopenic purpura (TTP). The acute events in these patients can be successfully treated and prophylactically prevented by repletion of the missing protease using fresh frozen plasma (FFP). In another, apparently more common, form of TTP, the protease deficiency is due to inhibiting circulating antibodies directed against the vWF-cleaving protease. Therapy of these patients should include immunosuppressive treatment in addition to plasma exchange and replacement with FFP. Normal activity of vWF-cleaving protease was established in patients with a clinically similar disorder: hemolytic-uremic syndrome (HUS). The level of vWF-cleaving protease activity is thus a laboratory parameter that provides important information for the differential diagnosis and treatment of patients with TTP/HUS. Several assays of vWF-cleaving protease have been described and are summarized here.    
3. 3: Clin Immunol  2002 Apr;103(1):43-53
   A complement-dependent model of thrombotic thrombocytopenic purpura induced by antibodies reactive with endothelial cells. Ren G, Hack BK, Minto AW, Cunningham PN, Alexander JJ, Haas M, Quigg RJ. Section of Nephrology, The University of Chicago, Chicago, Illinois, 60637  
   Thrombotic thrombocytopenic purpura (TTP) is an immunologically mediated disease characterized by thrombocytopenia, hemolytic anemia, and pathologic changes in various organs, including the kidney, which are secondary to widespread thromboses. Central to TTP is platelet activation, which may occur from a variety of mechanisms, including endothelial cell activation or injury. In this study, injection of K6/1, a monoclonal antibody with widespread reactivity toward endothelia, led to dose-dependent thrombocytopenia in rats. This was magnified if animals were preimmunized with mouse IgG, thereby resulting in an accelerated autologous phase of injury. In this setting, significant anemia also resulted. Rats injected with K6/1 developed renal injury, consisting of tubular damage and glomerular thrombi. Thrombocytopenia and renal morphological abnormalities were eliminated if animals were complement depleted with cobra venom factor prior to K6/1 injection and worsened when the activity of the ubiquitous complement regulator Crry was inhibited with function-neutralizing antibodies. Therefore, we have developed a complement-dependent model of TTP in rats by injecting monoclonal antibodies reactive with endothelial cells. Antibody-directed complement activation leads to stimulation of platelets, through direct interactions with complement fragments and/or indirectly through endothelial cell activation or injury, with the subsequent development of TTP.      
4. 4: Ther Apher  2002 Apr;6(2):159-62
   Reactive hemophagocytic syndrome associated with thrombotic thrombocytopenic purpura during therapeutic plasma exchange. Baz EM, Mikati AR, Kanj NA. Department of Pathology and Laboratory Medicine and Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon.  
   Hemophagocytic lymphohistiocytosis (HLH) is characterized by fever, cytopenia, splenomegaly, and lymphohistiocytic proliferation with hemophagocytosis. Sporadic, familial, and reactive HLH varieties exist. The latter, also termed the reactive hemophagocytic syndrome (RHS), has been associated with a variety of infectious and noninfectious etiologies. Activation of monocytes in RHS is due to stimulation by high levels of activating cytokines. RHS has not been associated previously with thrombotic thrombocytopenic purpura (TTP). TTP is a multisystem disorder characterized by consumptive thrombocytopenia, microangiopathic hemolytic anemia, neurologic symptoms, renal impairment, and fever. We report on a 33 year old male patient with a classic picture of TTP who initially responded to therapeutic plasma exchange but then became refractory to treatment and developed RHS. It is likely that a specific pathophysiology involving the activation of neutrophils during TPE is present for the development of cytokine-induced hemophagocytosis during TTP treatment. The consequent development of RHS possibly caused early TTP relapse.    
5. 5: Ann Hematol  2002 Apr;81(4):210-4
   Thrombotic thrombocytopenic purpura and pregnancy: a case report and a review of the literature. Proia A, Paesano R, Torcia F, Annino L, Capria S, Ferrari A, Ferrazza G, Pacifici E, Pantalissi A, Meloni G. Ematologia, Dipartimento di Biotecnologie Cellulari ed Ematologia, University "La Sapienza", Rome, Italy.  
   Thrombotic thrombocytopenic purpura (TTP) is a severe disorder affecting the microcirculation of multiple organ systems. Plasma therapy has significantly reduced the mortality rate. Infections, pregnancy, cancers, drugs, and surgery were frequently associated with the initial episodes and relapses. Women who are either pregnant or in the postpartum period make up 10-25% of TTP patients, suggesting the interrelationship between TTP and pregnancy. The introduction of aggressive treatment with plasma transfusion or plasmapheresis improved maternal and fetal survival rates. We describe a case of a first successful pregnancy concomitant to a late relapse of TTP, in which the identification of important risk factors for both TTP and pregnancy allowed us easier hematological and obstetrical management. Proposed guidelines for pregnancy-related TTP management and a brief review of current treatment options for this rare condition are also included.    
6. Br J Haematol  2002 May;117(2):480-3
   Prophylactic treatment with fresh-frozen plasma in chronic thrombotic thrombocytopenic purpura. Sivakumaran M, Roland J. Departments of Haematology and General Medicine, Peterborough District Hospital, Peterborough PE3 6LA, UK    
7. Bone Marrow Transplant  2002 Mar;29(6):542-3
   Defibrotide as a promising treatment for thrombotic thrombocytopenic purpura in patients undergoing bone marrow transplantation. Corti P, Uderzo C, Tagliabue A, Della Volpe A, Annaloro C, Tagliaferri E, Balduzzi A. Bone Marrow Transplantation Center, Paediatric Dept of Universita di Milano-Bicocca, San Gerardo Hospital, Monza, Italy.    
8. Clin Rheumatol  2002 Feb;21(1):57-9
   Thrombotic thrombocytopenic purpura as an initial presentation of primary Sjogren's syndrome. Schattner A, Friedman J, Klepfish A. Kaplan Medical Center, Hebrew University-Hadassah Medical School, Jerusalem, Israel.  
   A healthy woman presented with ecchymoses due to thrombocytopenia, with numerous bone marrow megakaryocytes, microangiopathic haemolytic anaemia, disorientation, irritability, and normal renal function. Thrombotic thrombocytopenic purpura (TTP) was diagnosed and treated successfully by plasma exchange therapy, both on presentation and during a further three relapses. The TTP was considered idiopathic until, 4 months later, definite primary Sjogren's syndrome (1 degree SS) was diagnosed following the appearance of sicca symptoms. Only four similar cases have been cited in the literature. TTP should be added to the varied haematological manifestations that may occur in patients with 1 degree SS. The possible presentation of 1 degree SS not with classic sicca symptoms but rather with haematological abnormalities, including TTP, should be recognised.    
9. Br J Haematol  2002 Apr;117(1):251-2
   Chronic relapsing thrombotic thrombocytopenic purpura due to a deficiency of von Willebrand factor-cleaving protease activity. Stark GL, Wallis JP, Allford SL, Hanley J.    
10. Am J Hematol  2002 Mar;69(3):228-31
    Management of a patient with HIV infection-induced anemia and thrombocytopenia who presented with thrombotic thrombocytopenic purpura. Gruszecki AC, Wehrli G, Ragland BD, Reddy VV, Nabell L, Garcia-Hernandez A, Marques MB. Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35233, USA. agruszec@path.uab.edu  
    A 32-year-old male presented with fever, mental status changes, renal dysfunction, cytopenias and hemolysis. His platelet count was 14,000/microL, hemoglobin 5.7 g/dL and LDH 2,636 U/L. He was diagnosed with thrombotic thrombocytopenic purpura (TTP) and also found to be HIV positive on admission. TTP was confirmed by a low von Willebrand factor-cleaving protease level, the gold standard test for TTP, which was 10-15%. No protease-specific antibody was detected. Treatment of this patient consisted of 23 plasmapheresis procedures and trials of vincristine and dextran-70. Despite therapy, the patient remained anemic and thrombocytopenic, though his mental status and renal abnormalities improved. Highly active anti-retroviral therapy (HAART) consisting of efavirenz, 3TC, and d4T was started. Only after plasma exchanges were discontinued and HAART was instituted did the cytopenias resolve. He continued to improve following discharge, and platelet count was 206,000/microL and hemoglobin, 12.5 g/dL one month after the initiation of HAART.    
11. J Intern Med  2002 Mar;251(3):280-1
    Simple plasma exchange reduced autoantibody to von Willebrand factor-cleaving protease in a Japanese man with ticlopidine-associated thrombotic thrombocytopenic purpura. Orimo S, Ozawa E, Yagi H, Ishizashi H, Matsumoto M, Fujimura Y.    
12. Br J Haematol  2002 Mar;116(4):909-11
    von Willebrand factor-cleaving protease inhibitor in a patient with human immunodeficiency syndrome-associated thrombotic thrombocytopenic purpura. Sahud MA, Claster S, Liu L, Ero M, Harris K, Furlan M. Department of Hematology, San Francisco General Hospital, San Francisco, CA, USA. bloodres@pacbell.net  
    Antibodies that inhibit von Willebrand Factor (VWF)-cleaving protease activity occur in patients with acute thrombotic thrombocytopenic purpura (TTP) and often persist in the chronic phase. A deficiency of this protease is likely to be responsible for the generation of ultrahigh VWF multimers and influence the formation of intra-arterial platelet aggregates that result in microangiopathic haemolytic anaemia, thrombocytopenia and end in organ failure. This report demonstrates complete deficiency of VWF-cleaving protease and the presence of a concentration-dependent IgG1 inhibitor in the plasma of a patient with acquired immunodeficiency syndrome (AIDS). These data may contribute to understanding the pathophysiology of human immunodeficiency syndrome (HIV)-related TTP.    
13. Trends Mol Med  2002 Jan;8(1):1-3
    Thrombotic thrombocytopenic purpura (TTP)--an enigmatic disease finally resolved? Aster RH.   Thrombocytopenic thrombocytopenic purpura (TTP), characterized by hemolytic anemia, thrombocytopenia and fluctuating neurological abnormalities, was almost universally fatal until in the 1970s, when it was discovered that remissions could usually be achieved by exchanging plasma from patients with that of donors. For the following 25 years, this therapy was routinely used without any real understanding of why it was effective. Three recent papers published almost simultaneously offer insights into the molecular basis of TTP, a rationale for why plasma exchange is helpful, and avenues for development of new and highly specific therapeutic agents.    
14. Arch Intern Med  2002 Jan 28;162(2):221-2 Pulmonary renal syndrome and thrombotic thrombocytopenic purpura in a patient with giant cavernous hemangioma of the leg. Au WY, Tang SC, Chan KW, Wong KK, Ooi CG.    
15. Pediatrics  2002 Feb;109(2):322-5 Thrombotic thrombocytopenic purpura attributable to von Willebrand factor-cleaving protease inhibitor in an 8-year-old boy. Robson WL, Tsai HM. University of Oklahoma, Health Sciences Center, Oklahoma City, OK 73104, USA. lanerobson@msn.com    
16. Annu Rev Med  2002;53:75-88 Thrombotic thrombocytopenic purpura: the systemic clumping "plague". Moake JL. Hematology/Oncology Section, Department of Medicine, Baylor College of Medicine and Bioengineering Laboratory, Rice University, Houston, Texas 77030, USA. jmoake@rice.edu   In thrombotic thrombocytopenic purpura (TTP), a multimeric form of von Willebrand factor (vWf) that is larger than ordinarily found in the plasma causes systemic platelet aggregation under the high-shear conditions of the microcirculation. A divalent cation-activated, vWf-cleaving metalloprotease that metabolizes large vWf multimers to smaller forms in normal plasma is severely reduced or absent in most patients with TTP. The vWf-cleaving metalloprotease either is not produced or is defective in children with chronic relapsing TTP. When the enzyme is provided by the infusion of normal plasma, these patients remain free of TTP symptoms for about three weeks. An IgG autoantibody to the vWf-cleaving metalloprotease is found transiently in many adult patients with acute idiopathic, recurrent, and ticlopidine/clopidogrel-associated TTP. These patients require plasma exchange, i.e., concurrent replacement of the inhibited vWf-cleaving metalloprotease by plasma infusion and plasmapheresis. The vWf-cleaving metalloprotease is present in fresh-frozen plasma, in cryoprecipitate-depleted plasma (cryosupernatant), and in plasma that has been treated with solvent and detergent. The pathophysiology of platelet aggregation in bone marrow transplantation/chemotherapy-associated thrombotic microangiopathy, and in the hemolytic-uremic syndrome, is not established. In neither condition is there a severe decrease in plasma vWf-cleaving metalloprotease activity.    
17. Ann Hematol  2002 Jan;81(1):7-10 Vincristine as treatment for recurrent episodes of thrombotic thrombocytopenic purpura. Ferrara F, Annunziata M, Pollio F, Palmieri S, Copia C, Mele G, Pocali B, Schiavone EM. Division of Hematology, Cardarelli Hospital, Via Niccolo Piccinni 6, 80128 Naples, Italy. felicettoferrara@katamail.com   The clinical course of thrombotic thrombocytopenic purpura has dramatically improved after the introduction of plasma-based therapy, including plasma exchange and plasma infusion. However, a considerable number of patients still experience relapse after initial successful treatment. In this study, vincristine (VCR) was given as salvage treatment in 12 episodes of recurrent thrombotic thrombocytopenic purpura in seven patients, concomitantly with short-term plasma infusion. Complete remission (CR) was defined by normal platelet, hemoglobin, and serum lactic dehydrogenase (LDH) values as well as by absence of clinical signs. Of 12 patients, 12 achieved CR following therapy with VCR. The median duration of CR was 15 months (range: 2-16). Toxicity was mild consisting of paresthesias in three cases, leukopenia in one case, and autonomic neuropathy leading to paralytic ileus in one case. We conclude that VCR is remarkably effective for recurrent thrombotic thrombocytopenic purpura with acceptable toxicity.    
18. Haematologica  2002 Jan;87(1):ECR01 Thrombotic thrombocytopenic purpura and bone marrow necrosis as a complication of gastric neoplasm. Gonzalez N, Rios E, Martin-Noya A, Rodriguez JM. Servicio de Hematologia y Hemoterapia, Hospital Universitario Virgen del Rocio, Avda. Manuel Siurot, s/no. 41013 Seville, Spain.