Deirdra R. Terrell

Survival and relapse in patients with thrombotic thrombocytopenic purpura.

Survival of patients with thrombotic thrombocytopenic purpura (TTP) improved dramatically with plasma exchange treatment, revealing risk for relapse. The Oklahoma TTP Registry is a population-based inception cohort of all 376 consecutive patients with an initial episode of clinically diagnosed TTP (defined as microangiopathic hemolytic anemia and thrombocytopenia with or without signs and symptoms of ischemic organ dysfunctions) for whom plasma exchange was requested, 1989 to 2008. Survival was not different between the first and second 10-year periods for all patients (68% and 69%, P = .83) and for patients with idiopathic TTP (83% and 77%, P = .33). ADAMTS13 activity was measured in 261 (93%) of 282 patients since 1995. Survival was not different between patients with ADAMTS13 activity < 10% (47 of 60, 78%) and patients with 10% or more (136 of 201, 68%, P = .11). Among patients with ADAMTS13 activity < 10%, an inhibitor titer of 2 or more Bethesda units/mL was associated with lower survival (P = .05). Relapse rate was greater among survivors with ADAMTS13 activity < 10% (16 of 47, 34%; estimated risk for relapse at 7.5 years, 41%) than among survivors with ADAMTS13 activity of 10% or more (5 of 136, 4%; P < .001). In 41 (93%) of 44 survivors, ADAMTS13 deficiency during remission was not clearly related to subsequent relapse.

The incidence of thrombotic thrombocytopenic purpura‐hemolytic uremic syndrome: all patients, idiopathic patients, and patients with severe ADAMTS‐13 deficiency

Summary.  Background: Accurate estimates of the incidence of thrombotic thrombocytopenic purpura (TTP) are important to assess the resources required for current treatments as well as to anticipate the need to develop new treatments. Previous estimates have been indirect and have not reported data on patients with ADAMTS‐13 deficiency. Objective: To determine the incidence of patients with TTP‐hemolytic uremic syndrome (HUS) in three categories: all patients with clinically suspected TTP‐HUS, patients with idiopathic TTP‐HUS, and patients with severe ADAMTS‐13 deficiency. Methods: Incidence rates were estimated from the Oklahoma TTP‐HUS Registry, analyzing all 206 consecutive patients from January 1, 1996 to June 30, 2004 who were treated with plasma exchange for their initial episode of clinically suspected TTP‐HUS. ADAMTS‐13 activity was measured in 186 (90%) of the 206 patients. Results: The age–sex–race standardized annual incidence rates were 11.29 × 106 (95% CI: 9.70–12.88) for all patients with clinically suspected TTP‐HUS; 4.46 × 106 (95% CI: 3.43–5.50) for patients with idiopathic TTP‐HUS; and 1.74 × 106 (95% CI: 1.06–2.41) for patients with severe ADAMTS‐13 deficiency (<5% activity). In all three categories, the incidence rates were greater for women and for blacks. For patients with severe ADAMTS‐13 deficiency, the age–sex standardized incidence rate ratio of blacks to non‐blacks was 9.29 (95% CI: 4.33–19.93). Conclusions: Accurate incidence rate estimates for all patients with clinically suspected TTP‐HUS, idiopathic TTP‐HUS, and TTP associated with severe ADAMTS‐13 deficiency have been determined. The greater incidence among women and blacks is comparable with their increased risk for other autoimmune disorders.

Complications of plasma exchange in 71 consecutive patients treated for clinically suspected thrombotic thrombocytopenic purpura-hemolytic-uremic syndrome

BACKGROUND With the increased frequency of diagnosis and improved survival of thrombotic thrombocytopenic purpura-hemolytic-uremic syndrome (TTP-HUS), the morbidity of plasma exchange (PE) treatment has become more important. STUDY DESIGN AND METHODS Data were prospectively collected on 71 consecutive patients referred to the Oklahoma Blood Institute (OBI) for PE treatment for clinically suspected TTP-HUS from mid-1996 to mid-1999. Complications were defined as major or minor, and distinguished between those related to central venous catheter access or to the plasma. RESULTS Twenty-one patients (30%) had 27 major complications, which caused two deaths. The major complications included 2 episodes of hemorrhage after subclavian line insertion (1 death), 1 pneumothorax requiring a chest tube, 12 systemic infections (1 death), 7 episodes of catheter thrombosis requiring removal of the central venous catheter, 2 episodes of venous thrombosis requiring anticoagulant treatment, 2 episodes of hypoxemia and hypotension, and 1 episode of serum sickness. Minor complications occurred in 22 additional patients (31%). Twenty-eight patients (39%) had no complications. CONCLUSIONS The morbidity and mortality of catheter placement and PE are important considerations when PE treatment for clinically suspected TTP-HUS is anticipated.

Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome following allogeneic HPC transplantation: A diagnostic dilemma

BACKGROUND: Thrombotic thrombocytopenic purpura‐hemolytic uremic syndrome (TTP‐HUS) has been described as a specific sequela of allogeneic HPC transplantation (HPCT). Nevertheless, because multiple transplant‐related sequela can cause the characteristic clinical features of TTP‐HUS, the diagnosis is difficult.

The incidence of immune thrombocytopenic purpura in children and adults: A critical review of published reports

Reports of the incidence of ITP are few and their methodology is variable. Accurate estimates of the incidence of immune thrombocytopenic purpura (ITP) are important to understand the medical and public health impact of the disease. To critically review all published reports on the incidence of ITP in children and adults, all articles identified on the Medline database (searched January 1, 1966‐August 7, 2009) that reported data on the incidence of ITP were retrieved. Articles which directly estimated the incidence of ITP were selected for review. Eight articles reported the incidence of acute ITP in children. After review, four were determined to have the strongest estimates, based on the method of patient identification and study design. The lowest incidence estimate in these four studies was 2.2 per 105 children/year (95% confidence interval 1.9, 2.4) and the highest incidence estimate was 5.3 per 105 children/year (95% confidence interval 4.3, 6.4). Three studies reported the incidence of ITP in adults. The estimate from the article with the strongest methodology reported an incidence estimate of 3.3 per 105 adults/year. The current strongest estimate of the incidence of acute ITP in children is between 1.9 and 6.4 per 105 children/year; for adults the current strongest estimate of the incidence of ITP is 3.3 per 105 adults/year. An important limitation of these studies is that they are primarily from Europe and may not be generalizable to all regions. Am. J. Hematol. 2010.

Management of Adult Patients with Persistent Idiopathic Thrombocytopenic Purpura Following Splenectomy: A Systematic Review

Key Summary Points This review analyzed all reports from 1966 through September 2003 on the treatment of adult patients with idiopathic thrombocytopenic purpura who had persistent thrombocytopenia after splenectomy. Current evidence supporting effectiveness and safety of any therapy is minimal. In this patient group, there are no randomized, controlled trials comparing 1 treatment with another or comparing treatment with observation alone. Most reports describe only platelet count responses; bleeding symptoms are rarely described. Agents that may be most promising for further study are cyclophosphamide, azathioprine, and rituximab; they must be evaluated for effectiveness and safety in randomized, controlled trials with assessment of clinical outcomes and platelet count responses. Adult patients with idiopathic (immune) thrombocytopenic purpura who have severe thrombocytopenia are initially treated with glucocorticoids (1-3). Splenectomy has been a standard treatment for more than 50 years for patients who do not respond to initial glucocorticoid treatment, providing durable, complete remissions in about two thirds of patients (1-3). However, there is no consensus on appropriate management for patients with persistent severe thrombocytopenia after splenectomy (1-4). Management of these patients remains a dilemma. Persistent severe thrombocytopenia implies a risk for serious bleeding, yet many patients have minimal symptoms and may do well with no treatment (1-4). Recommended treatments often have adverse effects that may be serious and unacceptable. Many different treatments have been described with frequent reports of success, but the experience of many physicians suggests that responses are uncommon (2). To understand and interpret the evidence for the many different reported treatments, we systematically reviewed (5) all articles describing treatment of adult patients with idiopathic thrombocytopenic purpura who had persistent thrombocytopenia after splenectomy. This review assesses the efficacy of the different treatments for achieving a durable complete response. Treatments used to achieve temporary platelet count responses or to manage acute bleeding episodes were not assessed. Methods Our research strategy was to obtain individual-level patient outcome data from case series. We first identified studies that met our inclusion criteria. We then used 5 inclusion criteria to select specific patients from tables that contained patient-level data. If patient-level data were not available in the article but all patients in the article met the 5 inclusion criteria, we used the group-level data. We grouped the findings according to the treatment and recorded the platelet count response as well as the outcomes of bleeding and death. Finally, we aggregated the data into group-level findings for each treatment. Literature Search We used Ovid software to search the MEDLINE database from 1 January 1966 to 30 September 2003. Case series published before 1966 were excluded because they often included patients treated before current supportive care measures were available. Key words searched were idiopathic thrombocytopenic purpura, immune thrombocytopenic purpura, idiopathic thrombocytopenia, and immune thrombocytopenia. The MeSH subheading search was idiopathic thrombocytopenic purpura. These terms were combined with the 40 identified treatment methods that are listed in the text and Table 1 (using both generic and brand names when appropriate) and with the phrases treatment outcomes or treatment. The search was limited to English-language reports. For publications from 1989 to 2003, alternative literature search software (Reference Update, Thomson ISI, Philadelphia, Pennsylvania) was also used. The bibliographies of all retrieved articles were searched for additional relevant articles. Table 1. Treatments for Chronic Refractory Idiopathic Thrombocytopenic Purpura Criteria for Article Selection We determined selection criteria a priori to limit articles to reports describing treatment of adults. Our goal was to assess the effectiveness of treatments to establish a durable complete response. Articles published in pediatric journals were not retrieved. Articles describing treatment with glucocorticoids (except for regimens of intermittent high-dose dexamethasone) were excluded because glucocorticoids were used principally as adjunctive treatment with other therapies. Articles describing treatment with intravenous immunoglobulin and anti-Rh(D) were excluded because these agents were typically used to achieve a temporary platelet count response rather than a durable response. However, articles describing treatment with anti-(Rh)D-opsonized D+erythrocytes were included because the authors stated that the goal of treatment was to establish a durable complete response. Supportive treatments, such as those with platelet transfusions and antifibrinolytic agents, were excluded. Articles reporting fewer than 5 total patients were excluded to avoid reports of exceptional patients. Articles reporting 5 or more total patients were reviewed to determine whether they described any eligible patients. Criteria for Patient Selection We selected patients by using 5 a priori criteria to define chronic refractory idiopathic thrombocytopenic purpura: 1. The diagnosis was idiopathic thrombocytopenic purpura (1). 2. The patients were adults, since spontaneous remissions occur in many children with persistent thrombocytopenia (6). Adults were defined as patients older than 16 years of age; when we reviewed the data, 16 years of age was the predominant age distinction for children and adults described in the reviewed articles. 3. The patients had undergone a splenectomy, because splenectomy is effective in most patients (1-3) and the goal of this review was to address management options for patients who had not responded to splenectomy. 4. The duration of idiopathic thrombocytopenic purpura was more than 3 months, a criterion established to exclude most patients who have a spontaneous remission (1) or in whom another cause of thrombocytopenia becomes apparent (7, 8). 5. The platelet count was less than 50 109 cells/L, since patients with platelet counts greater than 50 109 cells/L are not at risk for spontaneous major bleeding (1-3, 8). Articles describing only group data were included if it was clear that all reported patients met the eligibility criteria. Patients were excluded if they were also reported in another publication or if the data were insufficient to assess the eligibility or response criteria. For example, in some articles, children could not be distinguished from adults or the course of different treatments could not be determined. Article Assessment Two of the authors independently reviewed each article to determine patient eligibility. Each article that reported at least 1 eligible patient was further reviewed by 2 of the authors using a standard form and a priori criteria for outcome assessments of the individual patients or of group data. Disagreements were resolved by consensus among all of the authors. The level of evidence for each article with at least 1 eligible patient was defined as a randomized, controlled clinical trial; a nonrandomized clinical trial with contemporary or historical controls; a prospective cohort study of consecutive patients; a prospective study with enrollment of selected patients; a retrospective analysis of consecutive patients; or a retrospective analysis of selected patients. In some articles, the method of the study was not clearly described and the level of evidence was determined by consensus among the authors. To assess outcomes in patients who have greater risk for bleeding and therefore greater need for treatment, eligible patients were further separated into 3 groups according to their baseline platelet count before the treatment of interest: less than 50 109 cells/L, less than 30 109 cells/L, and less than 10 109 cells/L. Patients with a platelet count less than 10 109 cells/L were therefore included in the analysis of all 3 groups; patients with a platelet count less than 30 109 cells/L were included in 2 of the groups. Many patients were described only as having platelet counts less than 50 109 cells/L; therefore, analysis of separate patient groups defined by platelet counts of 30 to 50 109 cells/L, 10 to 30 109 cells/L, and less than 10 109 cells/L was not possible. Articles describing treatment with vincristine and vinblastine administered by intravenous bolus or infusion or by vinca-loaded erythrocytes are reported together as vinca alkaloids. Articles describing intravenous and oral cyclophosphamide were also combined; the article describing high-dose cyclophosphamide with stem-cell support is described separately. Assessment of Platelet Count Response We defined responses as complete, partial, or none. For a complete response, a normal platelet count (150 109 cells/L or as defined in the original report) had to be achieved and maintained while the patient received no treatment for at least 3 months and for the duration of observation. For a partial response, a platelet count more than 50 109 cells/L, more than 30 109 cells/L, or more than 10 109 cells/L, according to the patients group, for any duration, with or without additional treatment, had to be achieved. Patients who qualified for complete remission were excluded. Therefore, some patients with partial responses may have had only trivial platelet count increments for brief durations while continuing to receive treatment. For no response, the platelet count did not increase to more than 50 109 cells/L, more than 30 109 cells/L, or more than 10 109 cells/L, according to the patients group. Concurrent therapy, the duration of treatment, and the total duration of observation were recorded. Assessment of Bleeding and Death Definitions of bleeding were established as we reviewed the data. Bleeding was defined as major if it

Pregnancy outcomes after recovery from thrombotic thrombocytopenic purpura–hemolytic uremic syndrome

BACKGROUND:  Recurrent thrombotic thrombocytopenic purpura–hemolytic uremic syndrome (TTP‐HUS) during a subsequent pregnancy is an important concern because pregnancy may increase the risk for relapse.

Drug-induced thrombotic microangiopathy: a systematic review of published reports

Many patients with syndromes of thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome, have been reported to have a drug-induced etiology, and many different drugs have been suspected as a cause of TMA. We established criteria to assess the strength of evidence for a causal association of a drug with TMA and systematically searched for all published reports of drug-induced TMA. We identified 1569 articles: 604 were retrieved for review, 344 reported evaluable data for 586 individual patients, 43 reported evaluable data on 46 patient groups. Seventy-eight drugs were described; 22 had evidence supporting a definite causal association with TMA. Three drugs accounted for 61 of the 104 patient reports with definite evidence (quinine, 34; cyclosporine, 15; tacrolimus, 12). Twenty additional drugs had evidence supporting a probable association with TMA. These criteria and data can provide support for clinicians evaluating patients with suspected TMA.

Clinical outcomes after platelet transfusions in patients with thrombotic thrombocytopenic purpura

BACKGROUND: Reports of deterioration and death after platelet (PLT) transfusions in patients with thrombotic thrombocytopenic purpura (TTP) have led to recommendations that they should not be given except for life‐threatening hemorrhage.

Complications of plasma exchange in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: a study of 78 additional patients

Complications of plasma exchange in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: a study of 78 additional patients The frequency of patients treated with plasma exchange (PE) for thrombotic thrombocytopenic purpurahemolytic uremic syndrome (TTP-HUS) increased sevenfold from 1981 to 1997.1 Therefore, the morbidity and mortality due to PE is an increasingly important consideration in management decisions for patients with clinically suspected TTP-HUS. Some studies have described few complications associated with PE,2 but our previous report on 71 consecutive patients with clinically suspected TTP-HUS treated with PE from 1996 to 1999 demonstrated a major complication rate of 30 percent, including two deaths.3 This report describes our experience during the subsequent 3 years, 1999 to 2002, with 78 consecutive patients. From June 25, 1999, to June 25, 2002, a total of 81 consecutive patients were referred to the Oklahoma Blood Institute for PE treatment of their first episode of clinically suspected TTP-HUS. Three patients were excluded because they died before a central venous catheter for PE was inserted. Twenty-one of 78 patients (27 percent) had 27 major complications (Table 1). One patient died immediately after percutaneous insertion of a subclavian central venous catheter from pneumothorax and hemorrhage. Two patients suffered cardiac arrest with pulseless electrical activity: one from an anaphylactic reaction to plasma and the other from pericardial hemorrhage and tamponade, presumably due to cardiac perforation by an internal jugular catheter insertion guidewire. Other major catheter-related complications included one patient with a retroperitoneal hemorrhage following femoral catheter insertion and seven patients with catheter thrombosis that prevented PE and/or required placement of a new central venous catheter; two of these seven patients had catheter-related venous thrombosis requiring systemic anticoagulation. Ten patients developed systemic infection: eight had blood cultures positive for the presence of bacteria (Staphylococcus aureus [five], Staphylococcus epidermidis [three]); the two patients with negative blood cultures were treated with parenteral antibiotics for presumed sepsis. Other major plasma-related complications included hypotension in two patients requiring dopamine, acute hypoxia in two patients, serum sickness in one patient requiring systemic glucocorticoids, and severe vomiting in one patient that prevented completion of PE. Twenty-seven (35 percent) patients developed minor complications, including 10 patients who also had major complications. The majority of the minor complications were urticaria (22 patients); other minor complications included vomiting, tetany, and hypotension responding to intravenous fluids. These data confirm and extend our previous report.3 In summary, over 6 years we have observed 54 major complications, including 3 deaths, related to PE in 42 of 149 (28 percent) consecutive patients treated for clinically suspected TTP-HUS. These observations are essential to understand the risks of PE when evaluating the management of patients who may have TTP-HUS. J.R. McMinn, Jr., MD Ira A. Thomas, BS Deirdra R. Terrell, MPH Deanna Duvall, BSN Sara K. Vesely, PhD James N. George, MD Hematology-Oncology Section The University of Oklahoma Health Sciences Center PO Box 26901 Oklahoma City, OK 73190 e-mail: Jim-George@OUHSC.edu.