Risk Of Thrombotic Thrombocytopenic Purpura Research Articles

Abstract 12399: Don’t Burst My Blood: Ticagrelor Induced Thrombotic Thrombocytopenic Purpura

Background: Dual antiplatelet therapy, a fundamental component of the treatment of acute coronary syndromes (ACS), increases bleeding risk. Patients with thrombocytopenia and ACS are difficult to manage as thrombocytopenia increases the risk both of bleeding and ischemic events. Case: A 47 year old male with a medical history most significant for coronary artery disease (requiring multiple stents) and stroke who presented with chest pain and was found to have a NSTEMI. Notably, the patient stopped his ticagrelor six weeks prior to presentation. The initial CBC demonstrated clumped platelets. The patient was loaded with aspirin and ticagrelor, placed on a heparin drip and admitted. Decision Making: Exam on the morning after presentation demonstrated jaundice as well as petechiae on the patient’s extremities. He then exhibited altered mental status concerning for a seizure. Repeat labs demonstrated new severe thrombocytopenia, confirmed on a dedicated platelet count, anemia and indirect hyperbilirubinemia. A peripheral smear did not demonstrate schistocytes; however, the PLASMIC score indicated a high risk of thrombotic thrombocytopenic purpura (TTP) and he was started on plasmapheresis and steroids. His ADAMTS13 activity level returned low, confirming TTP. Common causes of TTP were excluded and Ticagrelor was deemed responsible. With continued plasmapheresis and steroids, his platelets normalized. A diagnostic left heart catheterization demonstrated patent prior stents as well as a 90% mid circumflex lesion. The patient was discharged on aspirin and rivaroxaban per the COMPASS trial, and was advised to avoid further P2Y12 inhibitors. Conclusion: This case demonstrated ticagrelor induced TTP, which has been infrequently reported in the literature. The patient was likely previously sensitized to ticagrelor and then developed TTP when he was loaded on presentation. It also demonstrates the importance of not ignoring clumped platelets and obtaining a true platelet count prior to starting triple therapy. In normal circumstances, his circumflex lesion would likely have been intervened upon; however, the patient’s intolerance of P2Y12 inhibitors limited management options during this presentation and will likely limit future interventions.

A COVID-19 pregnant patient with thrombotic thrombocytopenic purpura: a case report

BackgroundPregnancy seems to increase the risk of thrombotic thrombocytopenic purpura (TTP) relapses and make the TTP more severe in any of the pregnancy trimesters, or even during the postpartum period.Case presentationThis study highlights details of treating a COVID-19 pregnant patient who survived. This 21-year addicted White woman was admitted at her 29th week and delivered a stillbirth. She was transferred to another hospital after showing signs of TTP, which was caused by a viral infection.ConclusionThis viral infection caused fever and dyspnea, and the patient was tested positive for COVID-19 infection. A chest computed tomography scan showed diffuse multiple bilateral consolidations and interlobar septal thickening. She stayed at the Intensive Care Unit for 20 days and treated with plasmapheresis. As far as we know, this is the first report of a TTP pregnant patient with COVID-19 infection.

Validation of the Plasmic Score for Predicting ADAMTS13 Activity < 10% in Patients Admitted to Hospitals in Alberta with Suspected Thrombotic Thrombocytopenic Purpura

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic microangiopathy (TMA), characterized by widespread intravascular thrombosis. Diagnosis of TTP is confirmed by a deficiency in ADAMTS13. However, given the urgency of prompt diagnosis and delayed turnaround time of ADAMTS13 assay in most labs, initial diagnosis is based on clinical acumen. Suspected TTP is empirically treated with plasma exchange (PLEX), which, while beneficial in TTP, may delay appropriate treatment for similar disorders. The PLASMIC score was developed by Bendapudi et al. (Lancet Hematology 2017) to utilize clinical signs and investigations to predict which patients had an ADAMTS13 score &lt; 10%, and therefore TTP, who require PLEX. Validation studies have shown a very high sensitivity (90-98%) and high specificity (46-92%), although these studies included an enriched population with available ADAMTS13 assay results (Jajosky et al. Transfusion and Apheresis Science, 2017, Li et al. Journal of Thrombosis and Hemostasis 2018). The purpose of this study is to validate the PLASMIC score using a Canadian population of suspected TTP regardless if ADAMTS13 was ordered, and compare it to clinical gestalt. This is a retrospective cohort study of all adults aged 18 years or older who presented or were transferred to any of the two apheresis centres in Alberta, Canada with a suspected diagnosis of TTP from January 1, 2008 - December 31, 2018. A confirmed diagnosis of TTP was defined as an ADAMTS13 level prior to PLEX &lt; 10%, or ADAMTS13 level between 10-20% if drawn after plasma infusion or PLEX. ADAMTS13 testing was done in accordance with the procedures at these institutions. The PLASMIC score was used to stratify patients into low (0-4), intermediate (5) and high (6-7) risk of TTP (Table 1). Descriptive analyses was performed to examine the proportion of patients with low-, intermediate-, and high-risk PLASMIC score who had ADAMTS13 testing done and who received PLEX. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of PLASMIC score were calculated. Two PLASMIC score cutoffs were used for the analysis, 1) high risk vs low to intermediate risk, and 2) intermediate to high risk vs low risk. Receiver operator curve (ROC) analysis was used to test the association between severe ADAMTS13 deficiency and the PLASMIC score. PLASMIC scores were also compared to clinical gestalt, defined as initiation of PLEX within 48 hours of presentation. The C statistic was calculated from the area under the ROC and compared using the Z-test. As some patients who may have died from TTP did not have ADAMTS13 level sent, sensitivity analysis was performed to assess the ROC curve for the PLASMIC score in detecting both definite and probable TTP. A P-value of &lt;0.05 was considered statistically significant. Of the 162 cases of suspected TTP, 61 (38%) had severe ADAMTS13 &lt;10%. ADAMTS13 was sent prior to plasma exchange in 103 (64%) cases and shortly after PLEX initiation in 15 (9%). Using a high-risk PLASMIC score cut-off (6-7) vs low to intermediate-risk score (0-5), the sensitivity was 83.6%, specificity 67.3%, PPV 60.7% and NPV 87.2%. In contrast, using a cut-off of medium to high-risk PLASMIC score (5-7) vs low-risk score (0-4), the sensitivity improved to 96.7%, whereas the specificity was reduced to 30.7% (PPV 45.7% and NPV 93.9%). The C-statistics were 0.75 (95% CI 0.69-0.82) and 0.64 (95% CI 0.59-0.69) using the high PLASMIC score and medium-high PLASMIC score cut-offs, respectively (Figure 1). In contrast to PLASMIC score-based risk stratification, clinical gestalt has a comparable sensitivity of 83.6%, but a much lower specificity of 38.9%. There was very low correlation between PLASMIC score and clinical gestalt (kappa 0.0883 (95% CI -0.03-0.21). In our cohort, a high-risk PLASMIC score successfully predicted patients with severe ADAMTS13 deficiency in a Canadian TMA population, with similar sensitivity and improved specificity compared to clinical gestalt. Integration of this scoring system into institutional clinical pathways should be considered to supplement clinician judgment and reduce costs. Disclosures No relevant conflicts of interest to declare.

Description of the First Cases with ADAMTS13 Mutations in Hungary

INTRODUCTIONLow ADAMTS13 activity is associated with an increased risk of thrombotic thrombocytopenic purpura (TTP). This may be caused by the presence of inhibitory autoantibody (immune-mediated TTP) or genetic deficiency of the enzyme. The latter condition is also known as Upshaw-Schulman syndrome (USS), the extremely rare congenital form of TTP. The clinical picture typically presents during infancy or early childhood but an increasing number of late-onset cases are detected. OBJECTIVEClinical and laboratory characterization of the first 5 Hungarian cases with ADAMTS13 mutations. PATIENTSDuring the last 4 years, 5 cases with ADAMTS13 gene mutations were recognized in Hungary. All were adults, 4 females and 1 male. Two patients (Pts) showed an immune-mediated TTP like clinical picture, while 3 Pts were examined in conjunction with their pregnancies. The first Pt was an 18 years old girl, initially presenting with stroke and isolated cerebral vasculitis. She responded promptly to plasma exchange (PE) combined with immunosuppressive treatment (ISU) and acetylsalicylate (AS). However, severe headache with progressively decreasing platelet (PLT) count into the low normal range and repeatedly deficient ADAMTS13 activity returned after one week of PE cessation necessitating further treatment. ISU was stopped when cerebral vasculitis was excluded. There were several, plasma (PE/infusion) responsive severe headache+bradycardia episodes without hematologic manifestation in the follow-up period. The first TTP episode of the only male Pt occurred at age of 25 and the later clinical course highly resembled autoimmune relapsing (intermittent type) TTP. The Pt received several series of PEs, ISU, even splenectomy, before having the correct diagnosis. Interestingly, this Pt had unclassified HUS in the childhood. The 3rd case was a 40 years old woman with HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count) needing an immediate cesarean section (CS) in the 25th week of gestation. She achieved a spontaneous remission and remained symptom-free. The fourth Pt a 29 years old female had typical HUS at 3 years of age. Her kidney function slowly declined without HUS flares to end-stage kidney failure necessitating kidney transplantation. She had deep venous thrombosis (DVT) and intrauterine fetal death at 20 weeks of gestation. The workup showed decreased but not severely deficient ADAMTS13 activity. She received AS + low molecular weight heparin (LMWH) and increasing dose of plasma treatment starting at the 10th week of gestation of her next pregnancy. CS was done due to progressive hypertension and worsening placental circulation at the 30th week of gestation. The last Pt was a 41-year-old pregnant woman with recurrent abortions in her history. She received AS and LMWH only. The pregnancy was terminated by CS due to severe vaginal bleeding at the 30th week of gestation. RESULTSPts 1 and 2 with TTP clinical phenotype and Pt 3 with HELLP syndrome had deficient ADAMTS13 activity (0-0-8%, respectively). The activity was decreased but not deficient in Pts 4 and 5 (13-35%). All deficient Pts were compound heterozygous for ADAMTS13 mutations: c.3178C>T and c.4143-4144dupA (Pt1), c.1016_1017delCA and c.3199T>A (Pt2), c.1261C>T and c.3283C>T (Pt3). Three of these mutations were described in patients with USS, 1 in Pts with DVT, whereas 2 mutations are novel. By family study, we could demonstrate the association of c.1261C>T mutation described in DVT and one USS Pts with reduced ADAMTS13 activity. The two non-deficient cases were heterozygous for one of the following mutations: c.3178C>T and c.2839C>T. The previous was identified in late-onset USS, the latter has not yet been described, its association with reduced ADAMTS13 activity was also proven by family study. CONCLUSIONSClinical and molecular characterization of the first 5 Hungarian cases with ADAMTS13 mutations was presented. Compound heterozygous, damaging ADAMTS13 mutations with deficient plasma ADAMTS13 activity were associated with serious clinical consequences. In case of thrombotic microangiopathy in young patients with stroke, or HELLP syndrome, complete workup for ADAMTS13 activity and inhibitors is necessary, and genetic analysis should be considered. Three new ADAMTS13 mutations (c.1016_1017delCA, c.3199T>A , c.2839C>T) were identified and shown to be associated with decreased plasma ADAMTS13 activity. DisclosuresKremer Hovinga:Ablynx: Other: Member of Advisory Board; Shire: Other: Member of Advisory Board, Research Funding. Masszi:AbbVie: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Janssen-Cilag: Consultancy; BMS: Consultancy; Pfizer: Consultancy.

Plasmic Score in Thrombotic Microangiopathy May Not be Discriminatory in Many Instances

Background: Bendapudi et al. (Lancet Hematol. 2017) have recently developed and validated a clinical scoring system, the “PLASMIC score,” to aid in assessing the risk of thrombotic thrombocytopenic purpura (TTP) in the absence of ADAMTS13 activity (Table 1). Although a few external validations describe good to excellent discriminatory value (Table 2), our experience using the PLASMIC score has not been helpful overall. We sought to perform our own validation of the PLASMIC score for clinical prediction of severe ADAMTS13 deficiency.Methods: We evaluated 323 patients who had ADAMTS13 testing performed between January 1, 2006 and June 20, 2018. We excluded patients who did not meet criteria for thrombotic microangiopathy (TMA), defined as schistocytes noted on peripheral blood smear within 2 days prior to ADAMTS13 testing and platelet count ≤ 100 x 109/L on the day of ADAMTS13 testing. We also excluded patients who were seen as outpatients, had PLEX elsewhere prior to admission, presented with a known TTP history, had possible interferences with the ADAMTS13 assay, or had irretrievable records. A total of 186 patients were excluded, including 9 “missing data” patients for whom all 7 components of the PLASMIC score were not available to calculate a score. 137 patients were included in the final analysis, 90 with an initial ADAMTS13 activity >10% and 47 with a severe deficiency (≤10% activity). We calculated a PLASMIC score for each patient, using the earliest admission laboratory values if initial ADAMTS13 testing was within Day 3 of admission. If initial ADAMTS13 testing occurred on or after Day 4 of admission, we used the closest laboratory values within 5 days prior to ADAMTS13 testing. This methodology was used in previous external validations of the PLASMIC score. We also experimented with two modifications on the original methodology. Our first modified PLASMIC score (“Mod 1”) was designed to maximize the PLASMIC score, in order to err on the side of caution and help avoid missing potential TTP. Rather than just the earliest or closest laboratory value, any eligible laboratory value within 5 days prior to ADAMTS13 testing could be used to assign 1 point for a given category. Our second modified score (“Mod 2”) assigns 1 point for serum creatinine <2.5 mg/dL rather than <2.0 mg/dL. With <7% of patients with missing data, we were able to use complete-case analysis for logistic regression.Results: The original PLASMIC score model predicted severe ADAMTS13 deficiency with a concordance “c” statistic of 0.88, where a value of 1 would indicate perfect prediction. The Mod 1 and Mod 2 models had a c statistic of 0.87 and 0.88, respectively. Sensitivity, specificity, and positive and negative predictive value for each of these 3 models, when PLASMIC score was dichotomized at high (score 6-7) versus low-intermediate risk (score ≤ 5), are summarized in Table 3. Almost 20% of patients with ADAMTS13 activity >10% had high scores, and the majority had a score of intermediate (score = 5) or higher (Table 4). We performed chi-square testing for each original PLASMIC score parameter; there was no statistically significant relationship between presence of severe ADAMTS13 deficiency and mean corpuscular volume <90 fL (z-score, p = 0.236). Among those patients with a high risk PLASMIC score by original methodology, we found a significant improvement in overall survival for those patients who received PLEX versus those who did not (log rank, p =0.0003), while no such difference was found among those with a low-intermediate risk score (log rank, p =0.3085).Conclusion: Our study uses a sample size similar to previously published external validations and shows a lower predictive value (c = 0.88) of the PLASMIC score for identifying a severe ADAMTS13 deficiency. Across all 3 of our models the specificity is also lower than previously published (81%, vs. 92%). Our first modification increased sensitivity while decreasing specificity compared to the original model, while the second modification had results similar to the original model. Overall our results suggest that the PLASMIC score may not show the same diagnostic performance across all populations and may cause an increase in unnecessary PLEX. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

HIV Infection Increases the Risk of Thrombotic Thrombocytopenic Purpura

An association between HIV infection and Thrombotic Thrombocytopenic Purpura (TTP) remains controversial.We conducted a cross-sectional analysis of 39 consecutive, non-referral cases of TTP encountered over 9 years ata single institution. Thirteen cases had HIV infection. The patients were treated with daily plasma exchange untilremission. The mean (standard deviation) duration of follow-up was 48 (37) months. Seven patients died. TTPcaused 3 of the 4 deaths in the HIV- group but none of the 3 deaths in the HIV+ groups. The age and sex adjustedincidence rate of TTP was 14.5 cases per 106 person-years. The relative risk of TTP was 38.5 (95% confidenceinterval, 19.7-75.0) for HIV infection, 2.7 (1.3-5.7) for female gender and was not increased for the black race.Neither HIV infection nor gender affect the overall and relapse free survivals. While relapse continued to occurthroughout the follow-up period in the HIV- group, it did not occur in the HIV+ group after the first year. We concludethat HIV infection is a major risk factor of TTP. The risk of late TTP relapse is low in HIV infected patients treatedwith anti-retroviral therapies.

Proteolytic inactivation of ADAMTS13 by plasmin in human plasma: risk of thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is caused by inactivation of a von Willebrand factor (VWF)-cleaving enzyme, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), which leads to platelet-rich thrombi comprising unusually large VWF multimers. We have found that ADAMTS13 can bind to the inactivated form of plasmin. In addition, plasmin cleaves purified ADAMTS13 into several fragments and inactivates it. Hence, we hypothesized that activation of plasminogen to plasmin becomes a new-onset factor for TTP due to ADAMTS13 inactivation. Plasmin was added exogenously or activated from plasminogen by streprokinase addition in human plasma (HP). ADAMTS13 digestion and effects of the digestion on ADAMTS13 activity were evaluated. Exogenous plasmin cleaved ADAMTS13 into several fragments, but a portion of ADAMTS13 remained in full-length form. Digestion profile of ADAMTS13 with streprokinase added exogenously in HP was similar to that of ADAMTS13 with exogenous plasmin. ADAMTS13 activity measured using FRETS-VWF73 decreased to ∼40% compared with that for normal plasma. Endogenous VWF multimer-cleaving activity was attenuated more severely (∼10%). These data suggest that endogenous plasmin cleaves ADAMTS13 into fragments and reduces its activity to ∼10%. We suggest that endogenous plasmin activation alone is not sufficient to cause TTP, but plasmin activation with ADAMTS13 deficiency might increase the risk of TTP onset.

Weight loss reduces anti-ADAMTS13 autoantibodies and improves inflammatory and coagulative parameters in obese patients.

Obese patients have been described at increased risk of thrombotic thrombocytopenic purpura, a disease caused by anti-ADAMTS13 autoantibodies. ADAMTS13 has a structure homology with the adipokine thrombospondin-1. We previously demonstrated an increased presence of anti-ADAMTS13 antibodies in obese patients. We aimed to study the changes induced by weight loss after bariatric surgery on some inflammatory and coagulative parameters and their link with anti-ADAMTS13 autoantibodies. We studied 100 obese patients before and after weight loss induced by bariatric surgery and 79 lean volunteers as controls. We measured anthropometric, metabolic and inflammatory parameters, thrombospondin-1, ADAMTS13 activity, anti-ADAMTS13 autoantibodies, Von Willebrand factor. At baseline, 13 % of patients was positive for anti-ADAMTS13 autoantibodies, while all controls were negative. Thrombospondin-1 levels were higher in obese subjects with than without antibodies, with a positive correlation between the two parameters. In multiple logistic regression analysis only thrombospondin-1 levels predicted positivity for anti-ADAMTS13 antibodies. After weight loss both anti-ADAMTS13 antibodies and thrombospondin-1 reduced significantly. Weight loss in obesity improves the inflammatory and coagulative profile, and in particular anti-ADAMTS13 autoantibodies, ADAMTS13 activity and thrombospondin-1.

Thrombotic Thrombocytopenic Purpura in Black People: Impact of Ethnicity on Survival and Genetic Risk Factors.

Black people are at increased risk of thrombotic thrombocytopenic purpura (TTP). Whether clinical presentation of TTP in Black patients has specific features is unknown. We assessed here differences in TTP presentation and outcome between Black and White patients. Clinical presentation was comparable between both ethnic groups. However, prognosis differed with a lower death rate in Black patients than in White patients (2.7% versus 11.6%, respectively, P = .04). Ethnicity, increasing age and neurologic involvement were retained as risk factors for death in a multivariable model (P < .05 all). Sixty-day overall survival estimated by the Kaplan-Meier curves and compared with the Log-Rank test confirmed that Black patients had a better survival than White patients (P = .03). Salvage therapies were similarly performed between both groups, suggesting that disease severity was comparable. The comparison of HLA-DRB1*11, -DRB1*04 and -DQB1*03 allele frequencies between Black patients and healthy Black individuals revealed no significant difference. However, the protective allele against TTP, HLA-DRB1*04, was dramatically decreased in Black individuals in comparison with White individuals. Black people with TTP may have a better survival than White patients despite a comparable disease severity. A low natural frequency of HLA-DRB1*04 in Black ethnicity may account for the greater risk of TTP in this population.

Thrombotic microangiopathy associated with gemcitabine: rare but real

Gemcitabine-associated thrombotic thrombocytopenic purpura is a rare complication of gemcitabine treatment with an incidence ranging from 0.015 to 1.4%. Clinically, this disease manifests as haemolytic anaemia, thrombocytopenia and renal insufficiency; hypertension and neurological and pulmonary symptoms are also known complications. The risk of thrombotic thrombocytopenic purpura increases as the cumulative dose of gemci-tabine approaches 20,000 mg/m2. The pathophysiology of this disease entity is unknown although several theories, involving both immune and non-immune mechanisms, have been proposed. The most effective treatment is discontinuation of gemcitabine, the provision of antihypertensive medications as needed, and consideration of plasmapheresis or use of immunoadsorption column in severe cases.

Effect of blood group on idiopathic thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is a condition caused by deficiency of ADAMTS13 resulting in accumulation of ultra large Von Willebrand factor multimers (ULVWF), leading to micro thrombi in multiple organs. The varying susceptibilities of blood group antigens to ADAMTS13 have been demonstrated. A and B antigens are protective of VWF; and VWF purified from blood group O individuals has been shown to be cleaved faster by ADAMTS13 compared to VWF from blood group AB individuals. We proposed that there may be a difference in the incidence of blood groups in TTP patients compared with the general population. We felt this to be important for a life-threatening disease with poorly understood epidemiology. We report a retrospective analysis of 74 patients presenting from 1993 to 2008 with idiopathic TTP. We studied the incidence across various blood groups and also estimated the recurrence and mortality in each group. The incidence of various blood groups were as follows: O 36%, A 36%, B 25%, and AB 2%, compared with expected frequencies in the Detroit area: O 44%, A 33% B 20%, and AB 3%. There was a trend of lower than expected frequency of blood group O. There were 24 recurrences and 14 deaths, uniform across blood groups. We hypothesized that there may be an association between blood groups and the risk of TTP; however the differences in our study were not statistically significant. Recurrence and disease specific mortality did not appear to be impacted by blood group.

A single center review of the experience with mitomycin C (MMC) and the risk of thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS)

15167 Background: MMC related TTP/HUS has been reported between 4 and 15%, with a higher incidence in patients receiving cumulative doses of 60 mg or higher. It tends to occur within 4 months of drug administration independently of patients’ cancer status. The ability of MMC to upregulate enzymes relevant for new cytototoxic agents (topoisomerase I for CPT-11 and thymidine phosphorylase for capecitabine) make phamacobiologically based therapeutic combinations including MMC attractive. Methods: All patients (n=100) that participated in four institutional clinical studies from 2000 through 2004 were included. The studies were OSU 9947 (phase I trial of CPT-11 and MMC in solid tumors, n=31) OSU 0151 (phase II trial of CPT-11 and MMC in advanced esophageal and stomach cancer, n=41) OSU 0155 (phase II trial of CPT-11 and MMC in patients with refractory breast cancer, n=26) OSU 0330 (phase I study of capecitabine and MMC in patients with advanced GI tumors n=2). In each study, the maximum cumulative dose of MMC was 36 mg/m2. All patients were followed for clinical signs or symptoms of TTP/HUS including the presence of anemia, thrombocytopenia and renal insufficiency and had a thorough review of the peripheral smear. Results: The median cumulative dose was 12 mg/m2 (range 3–36 mg/m2). No patients met the clinical diagnosis of TTP/HUS except for one patient had anemia, thrombocytopenia and renal insufficiency but did not manifest any other findings consistent with TTP/HUS such as changes in mental status, azotemia or any other clinical symptom. The laboratory abnormalities resolved without intervention within seven days with subsequent continuation on the clinical trial. Conclusions: In this study we have demonstrated that by capping the cumulative dose of MMC to 36 mg/m2, the incidence of TTP/HUS is minimal. Furthermore, our preliminary analysis of an additional 100 patients treated with MMC at OSU shows no reported cases of TTP/HUS (additional data will be presented at the meeting). Since MMC is effective in a wide variety of solid tumors including breast, lung and GI malignancies and is inexpensive and easy to administer, further exploration of MMC in the treatment of solid malignancies is indicated including rational combination studies. No significant financial relationships to disclose.

Impact of thrombotic thrombocytopenic purpura on leukemic children undergoing bone marrow transplantation.

Thrombotic thrombocytopenic purpura (TTP) has emerged as one of the main transplant-related complications over the last 15 years. The current study defines the incidence and the risk factors for the occurrence of TTP in 131 consecutive leukemic children who were transplanted between January 1994 and December 1997 at four Italian pediatric centers. Patients with ALL (101), AML (21), MDS (9), underwent an HLA-identical sibling BMT (82) or an HLA-identical unrelated BMT (49), receiving a conditioning regimen consisting of high-dose chemotherapy in 24 patients and of F-TBI combined with high-dose chemotherapy in 107 patients. The diagnosis of TTP was retrospectively evaluated on the basis of parallel criteria. TTP treatment varied according to the protocol of each treatment center. Twenty-eight of 131 patients (21.4%) developed TTP at a median of 46 days (range 21-80) after BMT. Multivariate analysis demonstrated that the risk of TTP was higher in patients who underwent unrelated BMT (P value = 0.02). Acute GVHD, stage of disease at BMT, conditioning with TBI, gender, age, did not appear to be associated with the occurrence of TTP. As to the outcome, TTP resolved in 19 patients while in nine it was the principal cause of death (32.1%). In patients with TTP, LDH peak value was the only statistically significant factor (P = 0.001) related to severe TTP. In conclusion, our experience demonstrates that leukemic children undergoing BMT, especially from an unrelated donor, should be carefully assessed for TTP which appears to be a severe and relatively common transplant-related complication when strict diagnostic criteria are applied.