The splenic autoimmune response to ADAMTS13 in thrombotic thrombocytopenic purpura contains recurrent antigen-binding CDR3 motifs.

Acquired thrombotic thrombocytopenic purpura (TTP) is the consequence of a severe ADAMTS13 deficiency resulting from autoantibodies inhibiting ADAMTS13 or accelerating its clearance. Despite the success of plasma exchange the risk of relapse is high. From 2 patients (A and B), splenectomized for recurrent episodes of acquired TTP, the splenic B-cell response against ADAMTS13 was characterized through generation of human monoclonal anti-ADAMTS13 autoantibodies (mAbs) by cloning an immunoglobulin G (IgG)4κ- and IgG4λ-Fab library using phage display technology and by Epstein-Barr virus transformation of switched memory B cells (CD19+/CD27+/IgG+). Sequence analysis of the anti-ADAMTS13 IgGs of both patients revealed that the VH gene use was limited in our patients to VH1-3 (55%), VH1-69 (17%), VH3-30 (7%), and VH4-28 (21%) and contained 8 unique and thus far not reported heavy-chain complementarity determining region 3 motifs, of which 4 were shared by the 2 patients. The discovery of several highly similar anti-ADAMTS13 autoantibodies in 2 unrelated TTP patients suggests that the autoimmune response is antigen driven, because the probability that such similar immunoglobulin rearrangements happen by chance is very low (< 10(-9)).

Is expertise in pediatric surgery necessary to perform laparoscopic splenectomy in children? An experience from a department of general surgery.

Splenectomy is frequently required in children for various hematologic pathologic findings. Because of progress in minimally invasive techniques, laparoscopic splenectomy (LS) has become feasible. The objective of this report is to present a monocentric experience and to evaluate the efficacy of and complications observed after laparoscopic splenic procedures in a department of general surgery. 57 consecutive LSs have been performed in a pediatric population between January 2000 and October 2010. There were 33 females and 24 males with a median age of 12 years (range 4-17). Indications were: hereditary spherocytosis 38 cases, idiopathic thrombocytopenic purpura 10, sickle cell disease (SCD) 6, thrombocytopenic thrombotic purpura 2 and non-hodgkin lymphoma 1 case. Patients were operated on using right semilateral position, employing Atlas Ligasure vessel sealing system in 49 cases (86%) and Harmonic Scalpel + EndoGIA in 8. In 24 patients (42.1%), a cholecystectomy was associated. Two patients required conversion to open splenectomy (3.5%). In three cases, a minilaparotomy was performed for spleen removal (5.2%). Accessory spleens were identified in three patients (5.2%). Complications (8.8%) included bleeding (two), abdominal collection (one) and pleural effusion (two). There was no mortality. Average operative time was 128 min (range 80-220). Average length of stay was 3 days (range 2-7). Mean blood loss was 80 ml (range 30-500) with a transfusion rate of 1.7% (one patient). Laparoscopic spleen surgery is safe, reliable and effective in the pediatric population with hematologic disorders and is associated with minimal morbidity, zero mortality, and a short length of stay. Ligasure vessel sealing system shortened operative time and blood loss. On the basis of the results, we consider laparoscopic approach the gold standard for the treatment of these patients even in a department of general surgery.

[Comparison of laparoscopic splenectomy in supine position with hanging-spleen technique in idiopathic thrombocytopenic purpura]. / Vergleich der laparoskopischen Splenektomie in Steinschnittlage mit der Hanging-Spleen-Technik bei idiopathischer thrombozytopenischer Purpura.

BACKGROUND: Laparoscopic splenectomy has become the gold standard intervention for elective splenectomy. Several techniques have been described, which differ in trocar localisations and patient positions. The hanging-spleen technique was examined in comparison to the conventional laparoscopic splenectomy in the supine position among the patient population in our institution over a period of 8 years. PATIENTS AND METHODS: On the basis of a retrospective analysis, data were collected on all patients who underwent elective laparoscopic splenectomy for idiopathic thrombocytopenic purpura between May 1994 and April 2002 and were examined for operation time, blood loss and peri-operative complications. Two types of operation were compared, the conventional laparoscopic splenectomy in the supine position (group A) and the hanging-spleen technique (group B). Finally, the costs of materials of the two operation techniques were compared. RESULTS: For 51 patients (43.1 % men, 56.9 % women) (mean age: 45.5 ± 17.5 years) the mean operation times were 134.2 ± 47.3 min (group A) and 9.8 ± 39.9 min (group B). The mean blood losses were 691.3 ± 544.4 mL in group A and 638.3 ± 1050.6 mL in group B. The perioperative complications were 38.8 % in group A and 21.2 % in group B. There was no significant difference found for operation time, blood loss and perioperative complications in a multivariate analysis. The cost of materials was reduced in group B (use of Endo-GIA 42.4 % in group B, 100 % in group A). In group A 4 incisions, in group B 3 incisions were necessary. CONCLUSIONS: Regarding operation time, blood loss and perioperative complications the 2 laparoscopic techniques for splenectomy do not differ significantly. Merely reduced material costs and a reduction of incisions were found in patients -operated with the hanging-spleen technique. Whether the hanging-spleen technique is the method of choice will have to be shown by further prospective studies.

Treatment of refractory thrombotic thrombocytopenic purpura using multimodality therapy including splenectomy and cyclosporine.

ADAMTS13 mediated thrombotic thrombocytopenic purpura (TTP) is an immunological disease that is very difficult to treat. Plasma exchange, with plasma replacement and steroids have been the first line of treatment for this condition. Ten to 20% of the patients either have no response or a partial response to the treatment. Refractory TTP has been treated in few case reports with anti-CD20 agents, intravenous gamma globulin, vincristine and splenectomy. We report two cases of refractory TTP that responded to multimodality immunosuppressive therapy that included splenectomy, intravenous gamma globulin, and cyclosporine after numerous plasma exchange treatments, steroids, rituximab and vincristine had failed to induce remission. Combining drugs that target T and B lymphocytes is a standard in organ transplantation and deserves more consideration in the treatment of severe and refractory autoimmune diseases such as TTP.

Intraoperative death due to thrombotic thrombocytopenic purpura (TTP)-related acute myocardial failure in a patient undergoing laparoscopic splenectomy.

Thrombotic thrombocytopenic purpura (TTP) is an uncommon disorder characterized by a pentad of microangiopathic hemolytic anemia, thrombocytopenia, renal dysfunction, fever, and a fluctuating neurologic syndrome. Splenectomy is performed for patients who are refractory to plasma therapy and for relapsing TTP. We describe a case of a patient who died due to intramyocardial hemorrhage after undergoing laparoscopic splenectomy for TTP resistant to treatment with plasmapheresis. A 52-year-old woman was admitted with ecchymoses, low platelet count, weakness of left face and upper extremity, and a presumptive diagnosis of TTP. Vital signs were stable. White blood count was 7800/microL, hemoglobin 7.9 g/dL, and platelet count of 13,000/microL. Her basic metabolic panel and liver function tests were normal. Further laboratory workup confirmed the diagnosis of TTP. The patient was initially treated with plasmapheresis and high dose steroid therapy but underwent an emergent laparoscopic splenectomy due to refractory TTP. At the end of the uneventful procedure, the patient suffered a cardiac arrest and died. Autopsy concluded that the death was from myocardial failure due to extensive myocardial hemorrhage secondary to TTP. There are several published case reports of sudden death due to cardiac involvement in TTP. However, intraoperative mortality is not reported. We conclude that TTP-related acute heart failure may represent an extremely important clinical risk in these patients who are undergoing surgery.

Splenectomy for the treatment of thrombotic thrombocytopenic purpura.

Plasma exchange is the treatment of choice for patients with thrombotic thrombocytopenic purpura (TTP) and results in remission in >80% of the cases. Treatment of patients who are refractory to plasma therapy or have relapsing disease is difficult. Splenectomy has been a therapeutic option in these conditions but its value remains controversial. We report on a series of 33 patients with TTP who were splenectomised because they were plasma refractory (n = 9) or for relapsed disease (n = 24). Splenectomy generated prompt and unmaintained remissions in all except five patients, in whom remission was delayed (n = 4) or who died with progressive disease (n = 1). Four postoperative complications occurred: one pulmonary embolism and three surgical complications. Median follow-up after splenectomy was 109 months (range 28-230 months). The overall postsplenectomy relapse rate was 0.09 relapses/patient-year and the 10-year relapse-free survival (RFS) was 70% (95% CI 50-83%). In the patients with relapsing TTP, relapse rate fell from 0.74 relapses/patient-year before splenectomy to 0.10 after splenectomy (P < 0.00001). Two patients died from first postsplenectomy relapse. Although these results are based on retrospective data and that the relapse rate may spontaneously decrease with time, we conclude that splenectomy, when performed during stable disease, has an acceptable safety profile and should be considered in cases of plasma refractoriness or relapsing TTP to reach durable remissions and to reduce or prevent future relapses.

Laparoscopic splenectomy: a selected retrospective review.

Previous investigators have suggested that laparoscopic splenectomy should be the procedure of choice for the treatment of benign hematologic disorders unresponsive to medical therapy. To evaluate the safety and utility of laparoscopic splenectomy for a variety of splenic disorders, we reviewed our collective experience at 2 institutions. We studied our 8-year experience by retrospective chart review. Patient demographic data, splenic pathology, intraoperative events, concomitant procedures, and all adverse perioperative events were recorded. A total of 131 patients had laparoscopic splenectomy, and there were 8 conversions to open surgery. Pathology included 63 with idiopathic thrombocytopenic purpura (ITP), 23 malignancies, 12 thrombotic thrombocytopenic purpura (TTP), 10 autoimmune hemolytic anemia (AIHA), and 23 others. Accessory spleens were noted in 21 patients (16%). Concomitant surgical procedures included 12 hepatic biopsies, 4 distal pancreatectomies, 4 cholecystectomies, and 7 others. Mean operative time was 170 minutes. There were 16 major complications in 16 patients and 2 deaths. Median postoperative length of stay was 3 days. Conversions, due mostly to bleeding, are related to splenic pathology and medical comorbidity and are not temporally related to surgical experience (learning curve). The morbidity, mortality, and conversion rates were low. Laparoscopic splenectomy permits an appropriate abdominal exploration and is associated with a short hospital stay. It is the procedure of choice for most indications for splenectomy.

Results of emergency surgery in patients with Moschowitz's disease refractory to hematological treatment: is splenectomy always advisable?

BACKGROUND: Patients with thrombotic thrombocytopenic purpura (TTP), Moschowitz's disease, run a high risk of perioperative bleeding and need intensive hematologic support. In some patients, TTP is associated with cancer but the surgical role in these patients is still unclear. To illustrate the surgical problems and outcome we present the case histories of three patients with TTP observed in our emergency department. MATERIALS AND METHODS: Two patients had TTP secondary to cancer and one patient with primary TTP (no evidence of neoplasia) had emergency operation for gastric hemorrhage, occlusion and TTP unresponsive to plasmapheresis. RESULTS: The first two patients who had not radical resection of cancer and no splenectomy, died for TTP complications. The third patient who underwent emergency splenectomy, had an uneventful postoperative course and TTP completely regressed. CONCLUSIONS: These case reports suggest that patients with TTP should be screened to rule out cancer. In patients with acute cancer-related complications emergency surgery should aim to resect the cancer. An associated splenectomy may increase the effectiveness of postoperative hematologic therapy.

Automated measurement of schistocytes after bone marrow transplantation.

Bone marrow transplantation-related thrombotic microangiopathy (BMT-TMA) is a severe complication partly suspected on the evidence of a microangiopathic haemolysis. Microscopic schistocyte observation confirms the mechanical origin of the haemolysis, but remains a tedious procedure that lacks standardization. Direct measurement of abnormal red blood cell (RBC) fragments is now available on some automated haematology systems. We compared in 131 patients (69 BMT with five BMT-TMA, 38 thrombotic thrombocytopenic syndromes, 11 macroangiopathies, 13 dyserythropoiesis) percentages of microscopic schistocytes and automated RBC fragments (Bayer ADVIA 120) to evaluate the clinical relevance of the automated measurements for BMT-TMA detection. The analyser correlated well with the microscope (intraclass correlation coefficient: 0.82) and quantified RBC fragments with a moderate overestimation (+0.4%) as compared to microscopic counts. BMT patients had higher RBC fragments when they had TMA (1.1 vs 0.4% without TMA). Automated counting was useful to flag BMT-related TMA, particularly when RBC fragments were above 1%. As RBC fragments were frequently detected in BMT patients even without TMA, a threshold of less 1% that ruled out TMA was determined with a 98% negative predictive value. The new RBC fragment automated parameter proved its clinical value to assess BMT-TMA, which might be useful for day-to-day monitoring of the post BMT period.

Splenectomy in relapsing and plasma-refractory acquired thrombotic thrombocytopenic purpura.

BACKGROUND AND OBJECTIVES: Acquired thrombotic thrombocytopenic purpura (TTP) is often due to autoantibodies inhibiting ADAMTS-13 activity resulting in impaired processing of very large von Willebrand factor multimers. TTP usually presents with an acute onset and a fulminant, sometimes fatal course. With appropriate treatment including plasma exchange, and fresh frozen plasma replacement, often supplemented by immuno-suppressive therapy, the acute episode generally resolves within days to weeks. DESIGN AND METHODS: We describe the clinical course of 3 patients with acquired TTP. One was refractory to PE, the other 2 relapsed after this treatment. All three were treated with splenectomy. ADAMTS-13 activity and inhibitor levels were monitored. RESULTS: ADAMTS-13 activity was initially < 5% in all 3 patients. After splenectomy the inhibitor against ADAMTS-13 disappeared rapidly in 2 patients and there was full recovery of ADAMTS-13 activity in all 3 patients. INTERPRETATION AND CONCLUSIONS: Splenectomy, by eliminating a source of pathogenic autoantibody production, can be a successful treatment for patients with relapsing or plasma-refractory acquired TTP due to autoantibody-mediated ADAMTS-13 deficiency.

Role of splenectomy in patients with refractory or relapsed thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) was once uniformly fatal. Therapeutic plasma exchange in combination with immunosuppressive and anti-platelet agents, however, have resulted in improved survival rates of greater than 80% for patients with TTP. In spite of aggressive plasma exchange and adjuvant therapy, a number of TTP patients are refractory to treatment. In addition, up to 40% of TTP patients who initially respond to therapy eventually relapse. Alternative therapies such as splenectomy have been used with varying degrees of success in refractory and relapsing TTP patients. The usefulness of splenectomy in preventing relapse of TTP or treating those patients who are refractory to plasma exchange remains controversial. We present a single institution's experience with 14 patients who underwent splenectomy for refractory (six patients) or relapsed (eight patients) TTP since 1984. In both patient groups, splenectomy induced stable long-term remissions. Six of six (100%) patients who were refractory to plasma exchange, survived to be discharged from the hospital, apparently free of disease. Four of eight patients (50%) who had a splenectomy for relapsing TTP went into a complete remission and had no further relapses of their disease. Moreover, in relapsing patients who failed to experience long-term remission, the relapse rate after splenectomy was 0.3 events per patient year compared to 1.0 events per patient year prior to splenectomy. We conclude that splenectomy is a reasonable treatment option for TTP patients refractory to standard plasma exchange therapy or who have experienced multiple and/or complicated relapses. We believe this is the first series that demonstrates efficacy of splenectomy in plasma exchange-refractory TTP.

Laparoscopic splenectomy for chronic recurrent thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is a serious hematologic disorder with a high rate of morbidity and mortality when it fails to go into remission. The primary treatment is total plasma exchange. The addition of corticosteroids, chemotherapeutic agents, or antiplatelet agents is of unproven benefit, and splenectomy has been offered as salvage therapy in refractory cases. We performed laparoscopic splenectomy (LS) on two patients with chronic refractory TTP. The early and late postoperative courses, including hematologic data, are presented here. The mean duration of surgery was 113 minutes and the mean estimated blood loss was 35 mL. Mean hospital stay was 1.5 days. The early postoperative platelet count showed an immediate rise in both patients. After 19 months and 16 months of follow-up, respectively, both patients remain in remission without further episodes of TTP. Laparoscopic splenectomy is a safe and effective therapy for patients with chronic relapsing and refractory TTP. The inherent benefits of the minimally invasive approach, its low morbidity, short hospital stay, and faster recovery, are significant advantages for these patients.

Chronic relapsing thrombotic thrombocytopenic purpura in adult onset Still's disease.

We report the first known case of chronic relapsing thrombotic thrombocytopenic purpura associated with adult-onset Still's disease. The patient presented with diffuse arthralgias, sore throat, and a maculopapular rash involving the trunk and extremities; she was hospitalized with fever and confusion. Thrombocytopenia, renal failure, and microangiopathic hemolytic anemia developed within several days. After a diagnosis of thrombotic thrombocytopenic purpura was made, she responded well to a series of plasma exchanges. Evaluation for infection, autoimmune disorders, and malignancy was negative. She was discharged to home in good condition, with normal renal function and normal platelet count. Two more episodes of TTP developed 7 and 9 months after the first hospitalization. The diagnosis of adult-onset Still's disease was then determined on the basis of clinical and laboratory criteria. She was successfully treated with plasma exchange, prednisone, and azathioprine. She later had splenectomy and has subsequently been without recurrence of thrombotic thrombocytopenic purpura for 2 years.