Terry Gernsheimer

Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group

Diagnosis and management of immune thrombocytopenic purpura (ITP) remain largely dependent on clinical expertise and observations more than on evidence derived from clinical trials of high scientific quality. One major obstacle to the implementation of such studies and in producing reliable meta-analyses of existing data is a lack of consensus on standardized critical definitions, outcome criteria, and terminology. Moreover, the demand for comparative clinical trials has dramatically increased since the introduction of new classes of therapeutic agents, such as thrombopoietin receptor agonists, and innovative treatment modalities, such as anti-CD 20 antibodies. To overcome the present heterogeneity, an International Working Group of recognized expert clinicians convened a 2-day structured meeting (the Vicenza Consensus Conference) to define standard terminology and definitions for primary ITP and its different phases and criteria for the grading of severity, and clinically meaningful outcomes and response. These consensus criteria and definitions could be used by investigational clinical trials or cohort studies. Adoption of these recommendations would serve to improve communication among investigators, to enhance comparability among clinical trials, to facilitate meta-analyses and development of therapeutic guidelines, and to provide a standardized framework for regulatory agencies.

International consensus report on the investigation and management of primary immune thrombocytopenia

Previously published guidelines for the diagnosis and management of primary immune thrombocytopenia (ITP) require updating largely due to the introduction of new classes of therapeutic agents, and a greater understanding of the disease pathophysiology. However, treatment-related decisions still remain principally dependent on clinical expertise or patient preference rather than high-quality clinical trial evidence. This consensus document aims to report on new data and provide consensus-based recommendations relating to diagnosis and treatment of ITP in adults, in children, and during pregnancy. The inclusion of summary tables within this document, supported by information tables in the online appendices, is intended to aid in clinical decision making.

Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial

BACKGROUNDnChronic immune thrombocytopenic purpura (ITP) is characterised by accelerated platelet destruction and decreased platelet production. Short-term administration of the thrombopoiesis-stimulating protein, romiplostim, has been shown to increase platelet counts in most patients with chronic ITP. We assessed the long-term administration of romiplostim in splenectomised and non-splenectomised patients with ITP.nnnMETHODSnIn two parallel trials, 63 splenectomised and 62 non-splenectomised patients with ITP and a mean of three platelet counts 30x10(9)/L or less were randomly assigned 2:1 to subcutaneous injections of romiplostim (n=42 in splenectomised study and n=41 in non-splenectomised study) or placebo (n=21 in both studies) every week for 24 weeks. Doses of study drug were adjusted to maintain platelet counts of 50x10(9)/L to 200x10(9)/L. The primary objectives were to assess the efficacy of romiplostim as measured by a durable platelet response (platelet count > or =50x10(9)/L during 6 or more of the last 8 weeks of treatment) and treatment safety. Analysis was per protocol. These studies are registered with ClinicalTrials.gov, numbers NCT00102323 and NCT00102336.nnnFINDINGSnA durable platelet response was achieved by 16 of 42 splenectomised patients given romplostim versus none of 21 given placebo (difference in proportion of patients responding 38% [95% CI 23.4-52.8], p=0.0013), and by 25 of 41 non-splenectomised patients given romplostim versus one of 21 given placebo (56% [38.7-73.7], p<0.0001). The overall platelet response rate (either durable or transient platelet response) was noted in 88% (36/41) of non-splenectomised and 79% (33/42) of splenectomised patients given romiplostim compared with 14% (three of 21) of non-splenectomised and no splenectomised patients given placebo (p<0.0001). Patients given romiplostim achieved platelet counts of 50x10(9)/L or more on a mean of 13.8 (SE 0.9) weeks (mean 12.3 [1.2] weeks in splenectomised group vs 15.2 [1.2] weeks in non-splenectomised group) compared with 0.8 (0.4) weeks for those given placebo (0.2 [0.1] weeks vs 1.3 [0.8] weeks). 87% (20/23) of patients given romiplostim (12/12 splenectomised and eight of 11 non-splenectomised patients) reduced or discontinued concurrent therapy compared with 38% (six of 16) of those given placebo (one of six splenectomised and five of ten non-splenectomised patients). Adverse events were much the same in patients given romiplostim and placebo. No antibodies against romiplostim or thrombopoietin were detected.nnnINTERPRETATIONnRomiplostim was well tolerated, and increased and maintained platelet counts in splenectomised and non-splenectomised patients with ITP. Many patients were able to reduce or discontinue other ITP medications. Stimulation of platelet production by romiplostim may provide a new therapeutic option for patients with ITP.

Dose of Prophylactic Platelet Transfusions and Prevention of Hemorrhage

BACKGROUNDnWe conducted a trial of prophylactic platelet transfusions to evaluate the effect of platelet dose on bleeding in patients with hypoproliferative thrombocytopenia.nnnMETHODSnWe randomly assigned hospitalized patients undergoing hematopoietic stem-cell transplantation or chemotherapy for hematologic cancers or solid tumors to receive prophylactic platelet transfusions at a low dose, a medium dose, or a high dose (1.1x10(11), 2.2x10(11), or 4.4x10(11) platelets per square meter of body-surface area, respectively), when morning platelet counts were 10,000 per cubic millimeter or lower. Clinical signs of bleeding were assessed daily. The primary end point was bleeding of grade 2 or higher (as defined on the basis of World Health Organization criteria).nnnRESULTSnIn the 1272 patients who received at least one platelet transfusion, the primary end point was observed in 71%, 69%, and 70% of the patients in the low-dose group, the medium-dose group, and the high-dose group, respectively (differences were not significant). The incidences of higher grades of bleeding, and other adverse events, were similar among the three groups. The median number of platelets transfused was significantly lower in the low-dose group (9.25x10(11)) than in the medium-dose group (11.25x10(11)) or the high-dose group (19.63x10(11)) (P=0.002 for low vs. medium, P<0.001 for high vs. low and high vs. medium), but the median number of platelet transfusions given was significantly higher in the low-dose group (five, vs. three in the medium-dose and three in the high-dose group; P<0.001 for low vs. medium and low vs. high). Bleeding occurred on 25% of the study days on which morning platelet counts were 5000 per cubic millimeter or lower, as compared with 17% of study days on which platelet counts were 6000 to 80,000 per cubic millimeter (P<0.001).nnnCONCLUSIONSnLow doses of platelets administered as a prophylactic transfusion led to a decreased number of platelets transfused per patient but an increased number of transfusions given. At doses between 1.1x10(11) and 4.4x10(11) platelets per square meter, the number of platelets in the prophylactic transfusion had no effect on the incidence of bleeding. (ClinicalTrials.gov number, NCT00128713.)

Platelet transfusion: a clinical practice guideline from the AABB.

Approximately 2.2 million platelet doses are transfused annually in the United States (1). A high proportion of these platelet units are transfused prophylactically to reduce the risk for spontaneous bleeding in patients who are thrombocytopenic after chemotherapy or hematopoietic progenitor cell transplantation (HPCT) (13). Unlike other blood components, platelets must be stored at room temperature, limiting the shelf life of platelet units to only 5 days because of the risk for bacterial growth during storage. Therefore, maintaining hospital platelet inventories is logistically difficult and highly resource-intensive (4, 5). Platelet transfusion is associated with several risks to the recipient (Table 1), including allergic reactions and febrile nonhemolytic reactions. Sepsis from a bacterially contaminated platelet unit represents the most frequent infectious complication from any blood product today (8). In any situation where platelet transfusion is being considered, these risks must be balanced against the potential clinical benefits. Table 1. Approximate Per-Unit Risks for Platelet Transfusion in the United States Guideline Focus These guidelines were designed to provide pragmatic recommendations, based on the best available published evidence, about when platelet transfusion may be appropriate in adult patients. For several common clinical situations, we attempted to identify a platelet count threshold below which platelet transfusion may improve hemostasis and above which platelet transfusion is unlikely to benefit the patient. We did not attempt to address all clinical situations in which platelets may be transfused, and these guidelines are not intended to serve as standards. Clinical judgment, and not a specific platelet count threshold, is paramount in deciding whether to transfuse platelets. Target Population These guidelines provide advice for adult patients who are candidates for platelet transfusion. Guideline Development Process The AABB commissioned and funded the development of these guidelines. Panel Composition A panel of 21 experts was convened. Fifteen participants were members of the Clinical Transfusion Medicine Committee of the AABB, all of whom were hematologists or pathologists with expertise in transfusion medicine. Five additional panel members included a neurosurgeon, a cardiac surgeon, a critical care specialist, an anesthesiologist, and a hematologist, representing the American Association of Neurological Surgeons, the Society of Thoracic Surgeons, the Society of Critical Care Medicine, the American Society of Anesthesiologists, and the American Society of Hematology, respectively. The final panel member was a Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodologist. Committee members had no substantial conflicts of interest as defined by the AABB conflict of interest policy. Pursuant to the policy, individual members were required to disclose actual and apparent financial, professional, or personal conflicts (Appendix Table 1). Appendix Table 1. Panel Members Conflicts of Interest Systematic Review of the Evidence The guidelines were developed on the basis of a recent systematic review of the literature on platelet transfusions, published separately (11). The search strategy is provided in Appendix Table 2. We searched PubMed from 1946 to the first week of April 2013, and the Cochrane Central Register of Controlled Trials and Web of Science from 1900 to the first week of April 2013 (1024 studies identified). An updated search of these databases was done from the first week of April 2013 to the first week of September 2014. Randomized, controlled trials (RCTs) and observational studies (prospective or retrospective cohort studies, casecontrol studies, and those with no control group) were eligible for inclusion. Outcomes of interest included all-cause mortality, bleeding-related mortality, bleeding, and number of platelet units transfused. Although all observational studies meeting the inclusion criteria were reviewed, data from observational studies were not used when more than 2 RCTs addressed a particular question. There were no language restrictions. After exclusions, 17 RCTs and 53 observational studies were included in the final systematic review. Only 1 relevant observational study (12) from the updated search was identified, and evidence from this study did not change our GRADE judgments of evidence quality or recommendation strength. Appendix Table 2. Search Strategy Used for Systematic Review of the Literature Grading of Evidence The GRADE method was used to assess the quality of the evidence and determine the strength of recommendations (13, 14). The recommendations were developed by consensus at an in-person panel meeting. Panel member judgments on 4 GRADE factors (quality of evidence, balance between the interventions benefits and harms, resource use, and patient values and preferences) and ratings of the strength of recommendations were validated using an online survey tool 1 week after the meeting. Definitions In this guideline, a platelet unit refers to 1 apheresis platelet unit or a pool of 4 to 6 whole bloodderived platelet concentrates, typically containing 3 to 41011 platelets. Thrombocytopenia refers to a platelet count below the lower limit of the normal range used by the laboratory performing the count. Seven platelet trials included in the systematic review (1521) used a variation of the World Health Organization scale (22) to assess patient bleeding outcomes (23). A summary of the modified World Health Organization scale is provided in Table 2 . Table 2. Summary of the Modified WHO Bleeding Scale Clinical Recommendations Clinical Setting 1: Hospitalized Adult Patients With Therapy-Induced Hypoproliferative Thrombocytopenia Recommendations Recommendation 1: The AABB recommends that platelets should be transfused prophylactically to reduce the risk for spontaneous bleeding in adult patients with therapy-induced hypoproliferative thrombocytopenia. The AABB recommends transfusing hospitalized adult patients with a platelet count of 10109 cells/L or less to reduce the risk for spontaneous bleeding. The AABB recommends transfusing up to a single apheresis unit or equivalent. Greater doses are not more effective, and lower doses equal to one half of a standard apheresis unit are equally effective. Quality of evidence: moderate; strength of recommendation: strong. Evidence Summary Three RCTs (n=1047) compared bleeding outcomes in hospitalized patients with radiation and/or chemotherapy-induced hypoproliferative thrombocytopenia assigned to receive or not receive prophylactic platelet transfusions (Appendix Table 3) (19, 21, 24, 25). All patients had hematologic malignancy treated with chemotherapy or HPCT. Prophylactic platelet transfusions were found to significantly reduce the risk for spontaneous grade 2 or greater bleeding (odds ratio [OR], 0.53 [95% CI, 0.32 to 0.87]). Most bleeding events were classified as grade 2. In the 2 largest trials (19, 21), grade 2 or greater bleeding in patients assigned to the group that did not receive prophylaxis occurred more frequently among patients receiving chemotherapy for acute leukemia compared with autologous HPCT recipients (58% vs. 47% [19, 25]; 51% vs. 28% [21]). Appendix Table 3. Prophylactic Platelet Transfusion Versus No Prophylactic Platelet Transfusion in Therapy-Induced Hypoproliferative Thrombocytopenia The threshold platelet count at which platelets should be transfused prophylactically to reduce the bleeding risk in hospitalized patients with therapy-induced hypoproliferative thrombocytopenia was examined in 4 RCTs (n=658) (Appendix Table 4). Patients were assigned to receive prophylactic platelet transfusion for a morning platelet count less than 10109 versus 20109 cells/L (2628) or 30109 cells/L (15). A greater platelet count threshold (20109 or 30109 cells/L) was not associated with a significantly lower incidence of grade 2 or greater bleeding (OR, 0.74 [CI, 0.41 to 1.35]) or bleeding-related mortality (OR, 0.37 [CI, 0.02 to 9.22]). The total number of days with bleeding was greater in the 10109cells/L threshold group. The 10109cells/L threshold was associated with lower platelet usage and fewer transfusion reactions. Appendix Table 4. Higher Versus Lower Platelet Count Thresholds for Prophylactic Platelet Transfusions in Therapy-Induced Hypoproliferative Thrombocytopenia Four RCTs (n=1132) (Appendix Table 5) examined whether prophylactic transfusion of low-dose platelets (defined as approximately one half of the standard dose of 3 to 41011 platelets) would provide hemostasis equal to that of standard-dose platelets in patients with therapy-induced hypoproliferative thrombocytopenia (16, 18, 20, 29). There was no difference in grade 2 or greater bleeding in recipients of standard-dose versus low-dose platelets (OR, 0.91 [CI, 0.70 to 1.19]). High-dose platelets (approximately double the standard dose) were compared with standard-dose platelets in 2 RCTs (n=951) (Appendix Table 6) (17, 18). Prophylactic transfusion of high-dose platelets did not reduce the risk for bleeding compared with standard-dose platelets (OR, 1.05 [CI, 0.79 to 1.40]). Appendix Table 5. Standard-Dose Versus Low-Dose Prophylactic Platelet Transfusions in Therapy-Induced Hypoproliferative Thrombocytopenia Appendix Table 6. High-Dose Versus Standard-Dose Prophylactic Platelet Transfusions in Therapy-Induced Hypoproliferative Thrombocytopenia Rationale for Recommendations Before routine platelet prophylaxis was introduced, severe hemorrhage was a common cause of death among patients receiving high-dose chemotherapy (30, 31). Today, severe hemorrhage is rarely encountered in this setting. The original studies of platelet prophylaxis were done decades ago, and both chemotherapy and supportive care for patients with cancer have changed dramatically over time. Therefore, the randomized trials reported by

Clinical practice guidelines from the AABB: Red blood cell transfusion thresholds and storage

ImportancenMore than 100 million units of blood are collected worldwide each year, yet the indication for red blood cell (RBC) transfusion and the optimal length of RBC storage prior to transfusion are uncertain.nnnObjectivenTo provide recommendations for the target hemoglobin level for RBC transfusion among hospitalized adult patients who are hemodynamically stable and the length of time RBCs should be stored prior to transfusion.nnnEvidence ReviewnReference librarians conducted a literature search for randomized clinical trials (RCTs) evaluating hemoglobin thresholds for RBC transfusion (1950-May 2016) and RBC storage duration (1948-May 2016) without language restrictions. The results were summarized using the Grading of Recommendations Assessment, Development and Evaluation method. For RBC transfusion thresholds, 31 RCTs included 12u202f587 participants and compared restrictive thresholds (transfusion not indicated until the hemoglobin level is 7-8 g/dL) with liberal thresholds (transfusion not indicated until the hemoglobin level is 9-10 g/dL). The summary estimates across trials demonstrated that restrictive RBC transfusion thresholds were not associated with higher rates of adverse clinical outcomes, including 30-day mortality, myocardial infarction, cerebrovascular accident, rebleeding, pneumonia, or thromboembolism. For RBC storage duration, 13 RCTs included 5515 participants randomly allocated to receive fresher blood or standard-issue blood. These RCTs demonstrated that fresher blood did not improve clinical outcomes.nnnFindingsnIt is good practice to consider the hemoglobin level, the overall clinical context, patient preferences, and alternative therapies when making transfusion decisions regarding an individual patient. Recommendation 1: a restrictive RBC transfusion threshold in which the transfusion is not indicated until the hemoglobin level is 7 g/dL is recommended for hospitalized adult patients who are hemodynamically stable, including critically ill patients, rather than when the hemoglobin level is 10 g/dL (strong recommendation, moderate quality evidence). A restrictive RBC transfusion threshold of 8 g/dL is recommended for patients undergoing orthopedic surgery, cardiac surgery, and those with preexisting cardiovascular disease (strong recommendation, moderate quality evidence). The restrictive transfusion threshold of 7 g/dL is likely comparable with 8 g/dL, but RCT evidence is not available for all patient categories. These recommendations do not apply to patients with acute coronary syndrome, severe thrombocytopenia (patients treated for hematological or oncological reasons who are at risk of bleeding), and chronic transfusion-dependent anemia (not recommended due to insufficient evidence). Recommendation 2: patients, including neonates, should receive RBC units selected at any point within their licensed dating period (standard issue) rather than limiting patients to transfusion of only fresh (storage length: <10 days) RBC units (strong recommendation, moderate quality evidence).nnnConclusions and RelevancenResearch in RBC transfusion medicine has significantly advanced the science in recent years and provides high-quality evidence to inform guidelines. A restrictive transfusion threshold is safe in most clinical settings and the current blood banking practices of using standard-issue blood should be continued.

Mechanisms of response to treatment in autoimmune thrombocytopenic purpura

To determine the mechanisms of an increase in the platelet count after therapy for autoimmune thrombocytopenic purpura, we determined the survival time and localization of radiolabeled autologous platelets and measured platelet-associated immunoglobulin levels before and after prednisone therapy or splenectomy in 19 patients with the disease. Eleven of 12 patients (92 percent) responded to prednisone with a mean threefold increase in the platelet count, resulting from increased platelet production (P less than 0.005); platelet survival was unchanged. Treatment with steroids failed in only one patient, whose pretreatment platelet production was already above normal. After splenectomy, 6 of 10 patients had a mean fourfold rise in the platelet count that correlated with increased platelet survival (P less than 0.005), together with improved platelet recovery (the percentage of platelets circulating in the blood immediately after the injection). Platelet production was unchanged. Base-line 111In-labeled platelet localization in the liver was normal in five patients in whom splenectomy was effective and increased to above normal in two of three in whom it was ineffective. Total platelet localization in the liver and spleen decreased by more than half after successful splenectomy (P less than 0.001), whereas it decreased by less than 25 percent after unsuccessful splenectomy. Platelet-associated immunoglobulin levels neither predicted nor correlated with treatment responses to prednisone or splenectomy. We conclude that prednisone improves platelet counts primarily by increasing platelet production, whereas the effect of splenectomy is to prolong platelet survival. Baseline measurements of platelet turnover and of platelet localization in the liver may be helpful in predicting the response to prednisone or splenectomy, respectively.

How I treat thrombocytopenia in pregnancy.

A mild thrombocytopenia is relatively frequent during pregnancy and has generally no consequences for either the mother or the fetus. Although representing no threat in the majority of patients, thrombocytopenia may result from a range of pathologic conditions requiring closer monitoring and possible therapy. Two clinical scenarios are particularly relevant for their prevalence and the issues relating to their management. The first is the presence of isolated thrombocytopenia and the differential diagnosis between primary immune thrombocytopenia and gestational thrombocytopenia. The second is thrombocytopenia associated with preeclampsia and its look-alikes and their distinction from thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome. In this review, we describe a systematic approach to the diagnosis and treatment of these disease entities using a case presentation format. Our discussion includes the antenatal and perinatal management of both the mother and fetus.

The effects of leukoreduced blood transfusion on infection risk following injury: a randomized controlled trial.

ABSTRACT Allogeneic blood transfusions in surgical patients have been associated with an increased risk of infectious complications and organ dysfunction. Residual leukocytes contaminating units of packed red blood cells have been incriminated through the induction of anergy and/or a potentiated inflammatory response, leading to the possibility that leukoreduced red blood cell transfusion might mitigate these effects. We set out to evaluate the effect of leukoreduced red cell transfusion on the risk of infections complications in patients requiring transfusion following injury. We conducted a single-center, double-blinded randomized controlled trial of leukoreduced versus standard, nonleukoreduced red blood cell transfusions in injured patients receiving transfusion within 24 hrs of injury. The primary endpoint was infectious complications within 28 days of randomization. Secondary end points were multiple organ failure, length of stay, febrile episodes, and mortality. Two hundred sixty eight subjects were eligible for analysis. Rates of infectious complications were similar in subjects receiving leukoreduced transfusions (30%) or standard transfusions (36%) ([RR], 0.84 [0.55-1.3]) and there was no statistically significant effect of leukoreduced blood transfusion on mortality [RR, 1.20 (0.74-1.9)], febrile episodes [RR, 1.01 (0.89-1.2)], or organ dysfunction scores (5.9 vs. 6.6; P = 0.29). Thus, pre-storage leukoreduction of allogeneic red blood cells had a small, but non-significant effect on the rate of infectious complication in this high-risk population requiring transfusion. There was no effect on the rates of febrile episodes, mortality, length of stay, or severity of organ dysfunction.

Platelet production and platelet destruction: assessing mechanisms of treatment effect in immune thrombocytopenia

This study investigated the immature platelet fraction (IPF) in assessing treatment effects in immune thrombocytopenia (ITP). IPF was measured on the Sysmex XE2100 autoanalyzer. The mean absolute-IPF (A-IPF) was lower for ITP patients than for healthy controls (3.2 vs 7.8 × 10⁹/L, P < .01), whereas IPF percentage was greater (29.2% vs 3.2%, P < .01). All 5 patients with a platelet response to Eltrombopag, a thrombopoietic agent, but none responding to an anti-FcγRIII antibody, had corresponding A-IPF responses. Seven of 7 patients responding to RhoD immuneglobulin (anti-D) and 6 of 8 responding to intravenous immunoglobulin (IVIG) did not have corresponding increases in A-IPF, but 2 with IVIG and 1 with IVIG anti-D did. This supports inhibition of platelet destruction as the primary mechanism of intravenous anti-D and IVIG, although IVIG may also enhance thrombopoiesis. Plasma glycocalicin, released during platelet destruction, normalized as glycocalicin index, was higher in ITP patients than controls (31.36 vs 1.75, P = .001). There was an inverse correlation between glycocalicin index and A-IPF in ITP patients (r² = -0.578, P = .015), demonstrating the relationship between platelet production and destruction. Nonresponders to thrombopoietic agents had increased megakaryocytes but not increased A-IPF, suggesting that antibodies blocked platelet release. In conclusion, A-IPF measures real-time thrombopoiesis, providing insight into mechanisms of treatment effect.