The Impact of Ethnicity on the Response to Eltrombopag in Patients with Immune Thrombocytopenia (ITP) in Qatar: A Single Institution Experience

Background: Thrombopoietin receptor agonists stimulate platelet production . Eltrombopag olamine (ELT) is alow molecular weight, synthetic nonpeptide agent thathas been studied in multiple phase 3 trials and proved efficacy at a standard dose of 50 mg. ELT exposure has been reported to be different in different ethnic descents. In East Asian ITP patients, the area under the curve (AUC) was reported to be more than 85% those of non-East Asian descent Objectives: The objective of this study is to evaluate the efficacy of ELT in Arab and Asian ITP patients of the subcontinent of India by using a lower starting dose (12.5 mg) and maximum (50 mg) doses of ELT than the standard starting dosing of (50 mg) and maximum of (75 mg) approved in the USA and Europe. Methods A retrospective study was conducted to evaluate the role of ethnicity (Arab and East Asians) in response to ELT among ITP patients by reviewing patients' electronic medical records between Jan 2015 - Jan 2019. A total of 58 patients were identified. We examined retrospectively Arab (n = 41) and non-Arab Asian (n = 17) patients who are 18 years and older in Qatar, with previously treated chronic ITP who had a platelet count of < 30 000 /L and who presented with bleeding manifestations. Patients' responses were evaluated after receiving ELT for 3 months or more, as well as their response to different doses of ELT (100, 75, 50, 25, 12.5 or any alternating doses e.g., 50/25). Results: The response rate (platelet count of ‡ 50 000 /L) after 3 months of ELT treatment was comparable in the Arab (87.5%) and non-Arab (88.2%) patients. 26% of the Arab patients required 12.5 or 25 mg and 41.5 % required 50 mg of ELT to achieve an acceptable response. In the Non-Arab Asian group 17.6% required 25 mg and 52.9% required 50 mg of ELT to achieve acceptable response. 22% of the Arab patients and 35.3% of the Non-Arab Asians patients required 75 mg or more of ELT to achieve acceptable control. Further sub-analysis of this data showed that 70% of the Arab patients who achieved complete response were females (14/20) whereas 33.3% (3/9) were Asian females. Two-third the Arab patients who achieved clinical remission were females whereas more than Two-third were non-Arab Asian males. Conclusion: ELT is generally well tolerated and effectively achieves target platelet counts in adult ITP patients. Low doses (12.5 - 50 mg) of ELT were effective in achieving and maintaining safe platelet counts in most Arab patients. This helps in achieving the maximum benefit for the patient at the lower possible dose to prevent toxicity. Tailoring treatment guidelines to match ethnic variations will help in providing a more cost-effective approach for both the patients and the health care system. Disclosures No relevant conflicts of interest to declare.

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Rituximab Subcutaneous Formulation (SC-R) Is Safe, Effective and Cost-Saving in Patients Suffering from Autoimmune Hemolytic Anemia (AIHA)

Blood ◽

10.1182/blood.v128.22.1269.1269 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1269-1269

Author(s):

Francesco Iuliano ◽

Eleonora Iuliano ◽

Alessia Perricelli ◽

Angelo Pomillo ◽

Maria Luci ◽

...

Keyword(s):

Treatment Time ◽

Conflicts Of Interest ◽

Standard Dose ◽

Subcutaneous Administration ◽

Complete Response ◽

Fixed Dose ◽

First Line ◽

Production Index ◽

The Impact ◽

Reticulocyte Production

Abstract Rituximab, a monoclonal antibody directed against the CD20 antigen expressed on B cells, has been shown to be effective in AIHA, both in idiopathic and secondary including those associated with autoimmune and lymphoproliferative disorders as well as in Evans syndrome. At standard dose of 375 mg/mq weekly for a median of 4 weeks , overall survival (OS), complete response (CR), desease free survival (DFS) were respectively OR 83-87%,CR 54-60% DFS 72% at one and 56% at two years. Moreover rituximab re-treatment is effective and some patients responded to re-treatment more than once. Because is available today a Rituximab solution for subcutaneous injection, we have used this formulation for the treatment of 6 patients (pts) suffering from AIHA. Methods 6 pts (M 2, F 4 ) were enrolled in this study. Median age was 58.3 yr (range, 52-82) 2 out of 6 pts were idiopathic and the remaining 4 were associated with chronic lymphoproliferative syndromes. 2 out of 6 pts had relapsed after a first-line treatment with intravenous rituximab and steroids.For 2 pts mean Hb value and Ht at presentation were 6.2 g/dL ± 1.2, and 26 mL/dL, Median reticulocyte percentage was 10%, and median reticulocyte production index was 2.9 times basal. 24 % of cases had an initial reticulocyte count less than 4%, and 40% had an initial reticulocyte production index less than 2.0 times basal. These reticulocytopenic patients were prevalent in secondary cases. Pts had altered hemolysis markers and direct antiglobulin test (DAT) was positive for both complement and IgG ( IgA 1 pts). All cases had a bone marrow examination during hospitalization Erythroid hypoplasia was seen only in CLL pts.6/6 pts had serial reticulocyte measurements, Rituximab subcutaneous formulation was administered at a fixed dose of 1400 mg weekly for 4 weeks; Before starting MabThera subcutaneous injections, all patients received beforehand, a full dose of Rituximab by intravenous infusion. Premedication consisting of an anti-pyretic and an antihistaminic was given orally in the evening before and the morning of the subcutaneous administration in order to reduce the time to stay in day hospital . All pts received prednisone 1 mg/Kg/day /for 30 days ; for these reason premedication with glucocorticoids was avoided. Results All pts completed treatment. No major infusion related side effects to subcutaneous Rituximab SC-R) were observed. Response criteria were defined as follows: Complete Response (CR): Hb >10 g/dl or Hb increase >1.5 g/dl, resolution of symptoms of anemia, transfusion independent; Partial Response (PR): Hb > 9 g/dl or Hb increase of 1-1.5 g/dl. improvement in symptoms of anemia, transfusion independent; NR (failure to meet CR/PR). 100% were eligible for response.Complete Responses were seen in 6/6 pts .At the end of treatment DAT became negative in 4/6 pts , concentration of lactic dehydrogenase , total bilirubin and indirect bilirubin began to decrease at 12 days after the first dose of rituximab, and decreased to normal range after 22 days. 3 patients required packed red cell transfusions before starting SC-R and all became transfusion-free. A moderate hemolysis still persisted only in one patient. rh-Epo has been administered in three pts initially reticulocytopenic. The reticulocyte production index rapidly increased, indicating a marrow erythropoietic response to rh-Epo Conclusion Our experience demonstrates that SC- Rituximab is an effective and safe alternative to IV formulation both in the first line and in the relapsed pts. SC-Rituximab shortens the treatment time significantly, enabling administration over approximately 5 minutes compared with 3 hours during IV infusion. The ready-to-use SC formulation significantly reduce pharmacy time and the impact on hospital resources as medicine preparation time and hospital staff time per administration are significantly reduced also in our hands. Disclosures No relevant conflicts of interest to declare.

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The Day 1 Postoperative Platelet Count Predicts Splenectomy Response in Patients with Immune Thrombocytopenia (ITP)

Blood ◽

10.1182/blood.v124.21.1448.1448 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1448-1448

Author(s):

Shylaja Mani ◽

Hashim Abbas ◽

Akhil Parashar ◽

Keith R. McCrae

Keyword(s):

Logistic Regression ◽

Platelet Count ◽

Medical Therapy ◽

Immune Thrombocytopenia ◽

Conflicts Of Interest ◽

Cleveland Clinic ◽

Complete Response ◽

Stepwise Logistic Regression ◽

Severe Thrombocytopenia ◽

Platelet Counts

Abstract Background: Immune thrombocytopenia (ITP) in adults is generally a chronic disorder that may lead to severe thrombocytopenia and bleeding. Though several medical modalities such as thrombopoietin receptor agonists have become available for the management of ITP withinin the last decade, splenectomy remains a valuable option for management of refractory ITP, with approximately 2/3 of treated patients remaining in complete remission 10 years afterwards. However, there are no consistent and reliable predictors of splenectomy response for an individual patient with ITP. Since patients with ITP who fail to respond to splenectomy can develop significant bleeding in the postoperative period it is important to identify those individuals early after their surgical procedure so that aggressive medical intervention may be employed. Despite this concern, there is little information available on the value of postoperative platelet counts obtained soon after splenectomy in predicting the ultimate outcome of surgery. Objectives: The goal of this study was to define the value of platelet counts determined soon after splenectomy on the ultimate success of splenectomy in inducing remission of ITP. Methods: We reviewed the medical records of 66 patients who underwent splenectomy for ITP at the Cleveland Clinic from 2000-2013. A complete response was defined as a stable platelet count >100 x109/L two months after splenectomy without medical therapy. Stepwise logistic regression with backward selection was used to identify significant predictors of complete response. Results: The 66 patients had a median age of 41(IQR 21-56) with a male:female ratio of 1:2. The median platelet count at the time of diagnosis was 12 x 109/L and 43% of the patients had severe ITP (defined per IWG guidelines as bleeding that mandates treatment). Ninety percent of patients were steroid dependent, and 39%, 15% and 5% had been treated with rituximab, eltrombopag or romiplostim respectively. The median time to splenectomy from diagnosis of ITP was 22 months (IQR 6-44 months). At a median follow up of 35 months after splenectomy, 39 patients (59%) achieved a complete response. The median platelet count prior to and 24 hours after splenectomy in responders and non-responders is shown in Table 1. Logistic regression analyses identified a post-op day 1 platelet count greater than the median platelet count of 112 x 109/L (OR- 3.72, CI- 1.14-12.16, p<0.03) and post-operative day 3 platelet count greater than median platelet count of 175x 109/L (OR- 4.87, CI- 1.37-17.2, p<0.01) as a significant predictor of splenectomy response. The probability of response based on the post-operative day 1 platelet count is depicted in Figure 1. The difference between the pre-splenectomy and post-operative day 1 platelet count was also a significant predictor of response (OR 1.01 (1.0001-1.02), p=0.04), (figure 2). The log of the time from the diagnosis of ITP to splenectomy (OR- 0.61, CI 0.40-0.94, p<0.02) was also a weak, but significant predictor. Increased numbers of prior treatments for ITP prior to splenectomy correlated with a decreased response, although this relationship was not statistically significant. Conclusion: The platelet count on postoperative day 1 is a significant predictor of long term response to splenectomy, with almost 4-fold increased probability of achieving remission if this value is >112 x 109/L .This is among the first studies to examine the prognostic value of the platelet count obtained this early after splenectomy, and suggests that in patients with severe ITP and a persistently low postoperative platelet count on day 1, medical therapy should be considered to prevent bleeding. Our data also suggests that responses to splenectomy may be less frequent in patients with a longer interval between ITP diagnosis and splenectomy. Disclosures No relevant conflicts of interest to declare.

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Long Term Discontinuation of Eltrombopag after Remission in Primary Immune Thrombocytopenia: 8-Year Follow-up Data from 15 Spanish Centers

Blood ◽

10.1182/blood-2019-129274 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2352-2352

Author(s):

Tomas Jose Gonzalez-Lopez ◽

Fernando Fernandez-Fuertes ◽

Maria Cristina Pascual Izquierdo ◽

Isabel Caparros ◽

Silvia Bernat ◽

...

Keyword(s):

Platelet Count ◽

Median Time ◽

Research Funding ◽

Immune Thrombocytopenia ◽

Previous Treatment ◽

Complete Response ◽

Platelet Response ◽

Platelet Counts

Background: Successful discontinuation of eltrombopag in certain immune thrombocytopenia (ITP) patients after complete response has already been demonstrated. However, the frequency of this phenomenon and type of candidate patients are still matter of discussion. Moreover, possibility of long term discontinuation responses is not clearly established. Methods: Here we retrospectively evaluated our whole cohort of 508 adult patients (aged 18 years or more) with primary ITP treated with eltrombopag included in the Spanish Eltrombopag Registry with a focus on the patients who achieved a durable (at least six months) platelet response after stopping eltrombopag. Successful discontinuation of eltrombopag (SDOE) was defined as those patients who reached remission and maintained platelet counts ≥ 50x109/l for at least 6 months in absence of eltrombopag or any rescue therapies administered. Long term discontinuation of eltrombopag (LTDOE) was defined as those patients who reached remission and maintained platelet counts ≥ 50x109/l for at least 36 months in the absence of eltrombopag or any rescue therapies administered. The study was approved by the Hospital Universitario de Burgos Ethics Committee and fulfilled Helsinki declaration standards. Results: While 37.4% of our patients relapsed of ITP with subsequent platelet count drop sometime during first six months of discontinuation of eltrombopag, a total of 74 patients (14.6%) were able to achieve SDOE. The median age of SDOE patients was 62 [range, 47-79] years. There were 47 women and 27 men. According to the standard definition, patients were allocated to newly diagnosed (n=17), persistent (n=15) and chronic (n=42) ITP groups. The median time from diagnosis to eltrombopag initiation was 31 [range, 4-104] months. The median number of previous therapies was 2 [range, 1-2], including splenectomy (14%), rituximab (18%) and romiplostim (12%). As expected, all patients but 1 achieved a complete response (platelet count ≥100 x 109/L) prior to eltrombopag discontinuation The median duration of eltrombopag treatment was 7 [range, 2-19] months. Reasons for eltrombopag discontinuation were: persistent response despite a reduction in dose over time (n=43), platelet count >400x109/L (n=16), aspartate aminotransferase elevation (n=5), diarrhea (n=4), thrombosis (n=3), patient's request (n=2) and other reasons (n=1). Analysis of these SDOE discontinued patients show that with a median follow-up of 55 [range, 29-79] months, 38 patients (51.3%) maintained treatment-free response 36 months after stopping eltrombopag with no need of additional ITP therapies (median time of eltrombopag discontinuation was 70 [range, 50-77] months).This condition is what we define now as LTDOE. Nevertheless, 36 patients relapsed beyond 6 months but before 36 months of eltrombopag discontinuation (median time of eltrombopag discontinuation was 10 [range,7 -22] months). Characteristics of LTDOE population were a median time since ITP diagnosis of 32 [range, 5-88] months with 15/38 patients having ITP <1 year. 9 patients (24%) were male and their median age was 50 [range, 37-64] years. They had received a median of only two previous treatment lines [range: 1-2 lines]. The median platelet count before starting eltrombopag was 19 x 109/L [range, 8-40]. Meanwhile, platelet count before eltrombopag stop was 218 x 109/L [range, 123-356]. The main characteristics (age, gender, duration of ITP, prior ITP lines, platelet count before starting eltrombopag, duration of eltrombopag treatment, and platelet count before eltrombopag withdrawal) of the 38 patients with LTDOE were compared with those of the SDOE cohort who did not achieve a LTDOE. Unfortunately, no predictive factors of LTDOE could be identified. Conclusion: Durable platelet response following eltrombopag cessation may be observed in only 15% of primary ITP patients treated with this drug. On the contrary, half of patients who achieve a sustained response after eltrombopag withdrawal will get a long term discontinuation. However, we are lacking predictor factors for successful and long-term discontinuation of eltrombopag in primary ITP. Disclosures Gonzalez-Lopez: Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Pascual Izquierdo:Novartis: Consultancy; Sanofi: Consultancy. Sánchez-González:Amgen: Consultancy, Speakers Bureau; Gilead: Speakers Bureau; Navartis: Consultancy, Speakers Bureau; Shire: Speakers Bureau; Takeda: Consultancy, Speakers Bureau. Jarque:Takeda: Consultancy, Speakers Bureau; Shire: Consultancy, Speakers Bureau; Shionogi: Consultancy, Speakers Bureau; Servier: Speakers Bureau; Roche: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Grifols: Consultancy; Gilead: Consultancy, Speakers Bureau; CellTrion: Consultancy; Celgene: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Abbie: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau.

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Impact of Platelet Count on Bleeding in the Setting of Anti-Platelet Therapy

Blood ◽

10.1182/blood-2020-142893 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 18-18

Author(s):

Robert Hugh Lee ◽

Wolfgang Bergmeier

Keyword(s):

Real Time ◽

Conflicts Of Interest ◽

Thrombotic Event ◽

Platelet Inhibition ◽

Intravital Imaging ◽

Severe Thrombocytopenia ◽

Platelet Counts ◽

Anti Platelet Therapy ◽

The Impact

Anti-platelet therapy (APT) is used for secondary prevention of thrombosis. The most commonly prescribed anti-platelet drugs are aspirin and P2Y12 inhibitors, including clopidogrel, prasugrel and ticagrelor. Dual anti-platelet therapy (DAPT) consisting of aspirin and a P2Y12 inhibitor is often used in the first 1-12 months after an initial thrombotic event and has a greater anti-thrombotic effect than single agents, but is also associated with a higher risk of bleeding. Due to this risk of hemorrhage, the appropriate use of DAPT in patients requiring percutaneous coronary intervention (PCI) with baseline or periprocedural thrombocytopenia remains unclear. To study the impact of thrombocytopenia on bleeding with APT, we used intravital imaging in a murine hemostasis model and adoptive platelet transfer to generate mice with specific platelet counts with or without platelet inhibition. To generate experimental mice, we used transgenic mice in which platelets express a chimeric GPIb receptor with the extracellular domain replaced with a domain of the human IL-4R (hIL-4R/GPIb-Tg). Endogenous platelets were depleted by injection of anti-hIL-4R antibody, and the recipient mice were then transfused with wild-type (WT) platelets from donor mice treated, or not, with single or dual APT (aspirin 20 mg/kg; clopidogrel 25 mg/kg) to achieve specific platelet counts ranging from 50,000 to 400,000 platelets/μL. We also compared these mice with WT mice (with normal platelet counts, ~1,200,000 platelets/μL) treated with APT. Platelet inhibition was confirmed prior to performing in vivo experiments. Hemostasis was determined by intravital imaging in our saphenous vein laser injury model, in which a 50 μm injury was induced by laser ablation. Real-time top-down epifluorescence imaging was used to determine time to initial hemostasis, rebleeding events, and platelet and fibrin accumulation. In each mouse, 3-5 injuries were induced at different sites and each injury was visualized for 10 minutes. Following real-time imaging, spinning disk confocal Z-stacks of platelet plugs were obtained for 3D reconstruction to compare platelet plug volume. In untreated WT mice, hemostasis was achieved in ~20 seconds. In WT mice treated with DAPT, initial hemostasis was often rapidly achieved but this was followed by significant rebleeding events. Paradoxically, platelet accumulation was increased in WT + DAPT mice due to extravascular accumulation of platelets which occurred during bleeding. However, in plugs that stabilized, plug volume was reduced in WT + DAPT mice. In hIL-4R/GPIb-Tg mice with reduced platelet counts, untreated platelets were able to form a stable hemostatic plug even at 50,000/μL, although time to hemostasis was slightly prolonged. However, as platelet counts decreased in mice with DAPT-treated platelets, initial hemostasis became more prolonged and many injuries never achieved initial hemostasis. These results suggest that DAPT may not be safe in the setting of severe thrombocytopenia. Disclosures No relevant conflicts of interest to declare.

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Autoimmune Thrombocytopenic Purpura Complicating Chronic Lymphocytic Leukemia: Analysis of 60 Patients.

Blood ◽

10.1182/blood.v108.11.4932.4932 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4932-4932

Author(s):

Carlo Visco ◽

Roberto Stasi ◽

Marco Ruggeri ◽

Achille Ambrosetti ◽

Stefania Fortuna ◽

...

Keyword(s):

Platelet Count ◽

Chronic Lymphocytic Leukemia ◽

Complete Response ◽

Lymphocytic Leukemia ◽

Severe Thrombocytopenia ◽

Short Term ◽

Thrombocytopenic Purpura ◽

Autoimmune Thrombocytopenic Purpura ◽

Cytotoxic Treatment ◽

The Impact

Abstract Autoimmune thrombocytopenic purpura (AITP) represents the autoimmune condition most frequently associated with chronic lymphocytic leukemia (CLL) after autoimmune haemolytic anemia. However, the main characteristics and outcome of AITP in the course of CLL, as well as the impact of this complication in the natural history of the tumor remain unknown. We identified 60 consecutive patients with CLL who developed AITP, representing 3,5% of CLL patients diagnosed in the three participating centers between 1995 and 2004. To be included in this study patients had to experience at least one episode of AITP, which was defined as the occurrence of acute and severe thrombocytopenia in the presence of normal or augmented number of megakariocytes in the bone marrow, without extensive lymphoid marrow infiltration, splenomegaly or recent cytotoxic treatment. A complete response (CR) to AITP treatment was defined by a platelet count > or = 150×10(9)/L, and a partial response (PR) by a platelet count > 50×10(9)/L or by an increase of at least twofold the initial level. Remaining patients were considered as no responders (NR). Median age of our 60 patients was 65 years (range 48–83) and 40 were males. At CLL presentation RAI stage was 0 to 2 in 88%, time to CLL treatment was 13,8 months (range 0–120), while first line treatment for CLL consisted of Chlorambucile alone (Chl) in 73% of patients with 18% of patients that received no treatment for their malignancy. Median overall survival was 57 months. AITP occurred concomitantly to CLL diagnosis in 13 patients (22%), while median time to AITP for remaining 47 patients was 30 months (range 2–147). The median platelet count at AITP diagnosis was 23 × 10(9)/L(range, 1–81). Twenty-five patients (42%) presented with moderate bleeding signs at AITP diagnosis, while 4 patients (7%) experienced severe hemorrhagic episodes, requiring hospitalization and blood transfusions. Fifty-two of the 60 patients (87%) received at least one treatment for AITP: 32 patients received i.v.Ig alone or in combination with steroids, leading to a short-term NR in 66% (CR 19%, PR 15%); nine patients underwent splenectomy and 7 (78%) experienced a durable CR; patients who were treated with chemotherapy (Chl, COP, CVP) +/− steroids had at least a PR in 73% of cases. With a median follow-up from AITP onset of 35 months, 17 of the 52 treated patients are still NR (33%) and 13 of them are on treatment. In our series of patients with CLL and AITP we observed an unexpectedly short survival regardless of a large prevalence of low RAI stages at diagnosis. Treatment of AITP with i.v. Ig +/− steroids leaded to a low rate of short-term responses, while splenectomy and chemotherapy seemed sufficiently adequate therapeutic approaches.

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A Case of Clopidogrel Induced TTP Recurring After Four Years

Blood ◽

10.1182/blood.v116.21.4678.4678 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4678-4678

Author(s):

Nanda K. Methuku ◽

Abhinav B. Chandra ◽

Anuradha Belur ◽

Lech Dabrowski

Keyword(s):

Platelet Count ◽

Renal Insufficiency ◽

Peripheral Blood ◽

Blood Smear ◽

Reticulocyte Count ◽

Conflicts Of Interest ◽

Peripheral Blood Smear ◽

Severe Thrombocytopenia ◽

Platelet Counts ◽

Multiple Organs

Abstract Abstract 4678 Case description - A 61 year old woman was started on clopidogrel after having PTCA with stent placement in February 2006. Four weeks after starting clopidogrel she developed thrombocytopenia with platelet nadir of 17,000. Her LDH was 700 IU/L and she was anemic with hemoglobin of 7.4 gm/dl with elevated reticulocyte count. Peripheral blood smear showed schistocytes and diagnosis of TTP secondary to clopidogrel was made. She did not have renal insufficiency. Clopidogrel was discontinued and patient was started on plasmapheresis with recovery of platelet counts. Early attempts in weaning plasmapheresis resulted in drop in platelet count and Rituximab was given to the patient weekly for four weeks. Subsequently, patient was weaned off plasmapheresis. For four years patient was followed periodically with CBC showing platelet counts greater than 250,000. In May 2010, four years after initial event patient was admitted to hospital for abdominal pain and found to have splenic infarcts. Subsequently, she also developed bilateral cerebral infarcts. Platelet count had decreased to less than 100,000. Her LDH was elevated at 419 IU/L. Reticulocyte count was 2.3%. Peripheral blood smear revealed significant number of schistocytes. There was no renal insufficiency or fever. Trans-esophageal echocardiogram (TEE) was done that did not reveal any vegetations. Patient was diagnosed as having recurrence of TTP and started on plasmapheresis with recovery in platelet counts. Pt was also treated with Rituximab. Discussion- We describe a case of TTP initially occurring within weeks of starting clopidogrel. Patient was treated with plasmapheresis and Rituximab and clopidogrel was discontinued. Patient had recurrence after four years as manifested by infarcts in multiple organs, with mild thrombocytopenia, elevated LDH and significant number of schistocytes on peripheral blood smear. It is very uncommon for clopidogrel associated TTP to recur after such a prolonged period of 4 years. Most cases of clopidogrel associated TTP have mild thrombocytopenia. This patient had severe thrombocytopenia on first presentation of TTP but had mild thrombocytopenia on recurrence. This case illustrates the importance of extended follow up and high index of suspicion for TTP as delays in initiation of plasmapheresis has a poor clinical outcome. Disclosures: No relevant conflicts of interest to declare.

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Release of Procoagulant and Proinflammatory Cell-Derived Microparticles (MP) During Blood Storage: Effects of Storage Time, Leukoreduction, and Residual Platelets,

Blood ◽

10.1182/blood.v118.21.3373.3373 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3373-3373

Author(s):

Wenche Jy ◽

Sherry Shariatmadar ◽

Marco Ricci ◽

Orlando Gomez-Marin ◽

Carlos Bidot ◽

...

Keyword(s):

Inflammatory Markers ◽

Storage Time ◽

Time Course ◽

Conflicts Of Interest ◽

Annexin V ◽

Bioactive Substances ◽

Platelet Counts ◽

The Impact ◽

Stored Blood ◽

Over Time

Abstract Abstract 3373 Introduction Several studies have indicated that transfusion with older blood carries more risk of adverse reactions than transfusion with younger blood, but this remains controversial. It is not clear why older blood may carry increased risks, or what the “safe age” of stored blood is. It is known that multiple bioactive substances are generated from blood during storage, and one or more of these substances may be involved in transfusion-related complications. Among them, MP are a recognized marker of the storage lesion, and their involvement in transfusion-related complications has been postulated. However, questions such as MP species, quantity, biological activity, and factors affecting their release are not well elucidated. The purpose of this study was to quantify MP species and their activity in stored RBC as a function of storage time, and to evaluate the impact of leukoreduction and residual platelets on MP release. Methods (I) MP generation and functional activity Thirty-four bags of packed RBC (16 non-leukoreduced, 18 leukoreduced) of known blood types (A+, B+, AB+, O+) were obtained from the blood bank within 2–4 days of drawing, and then stored at 4°C. Time of receipt was defined as day 0. At days 0, 10, 20, 30, and 40, 40 mL samples were centrifuged at 1000xg for 20 min to remove cells. The supernatants were then assayed for: (1) subtypes of MP by flow cytometry comprising (a) red cell MP (RMP) assessed by CD235a, (b) leukocyte MP (LMP) by CD45, (c) platelet MP (PMP) by CD41, (d) endothelial MP (EMP) by CD144, and (e) generic MP by Ulex Europaeus (Ulex) or Annexin V (AnV); (2) MP-mediated thrombin generation assay (TGA); (3) MP-mediated inflammatory activity by CD 11b expression in neutrophils following incubation with MP. (II) Reconstitution of increasing platelet counts in leukoreduced RBC. To investigate the effect of residual platelets on RMP generation, we mixed a constant amount of RBC with increasing amounts of type-matched platelets (0 to 250,000/μL f.c.) in standard storage bags and measured time-dependent MP release. Results (A) Time-course of MP generation (i) Non-leukoreduced. RMP, PMP and LMP all increased with time, but with different patterns. RMP increased little to day 10 but then rose exponentially, and by day 40 they were 4–6 fold higher than at day 0. PMP counts rose steadily from day 0 and peaked at day 20, being 2–3 fold higher than at day 0. LMP showed no significant change until day 20 when they started to increase, and then increased sharply after day 30, and by day 40 were 1.5–2 fold higher than at day 0. Levels of PMP (days 0 to 20) and RMP (days 20 to 40) correlated with increasing MP-mediated procoagulant and inflammatory markers. (ii) Leukoreduced. Pre-storage leukoreduction decreased RMP generation by 20–40%, completely suppressed PMP and LMP generation, and reduced total MP-mediated procoagulant and inflammatory markers by 40–60%. CBC showed that leukoreduction not only removed >99% WBC but also reduced residual platelets by >95% (from 90 ±30 ×103/μL to 3.5 ±1.3 ×103/μL). This suggests that residual leukocytes and platelets potentiate RMP generation. (B) Effects of residual platelets on RMP generation. To further study the effects of platelets on RMP generation, we mixed known counts of platelets with leukoreduced RBC, and then evaluated RMP generation over time. We found that RMP levels released were proportional to the platelet counts, as were the procoagulant and inflammatory markers. These results show that platelets in stored RBC play a key role in RMP generation. Conclusion Multiple MP types (PMP, LMP, RMP) are released during storage, and their levels increase over time but their patterns of change are different. Procoagulant and inflammatory markers increase in parallel with PMP and RMP. Our data support the hypothesis that age of stored blood could be important in transfusion-related complications, via MP production. Leukoreduction sharply reduces MP generation and procoagulant and inflammatory markers, suggesting that known benefits of leukoreduction may be attributable to reduced MP production. The finding that residual platelets in stored RBC can potentiate RMP generation suggests that minimizing platelets in non-leukoreduced packed cells could reduce the risk of transfusion-related complications. (Supported by NIH grant 1R01HL098031). Disclosures: No relevant conflicts of interest to declare.

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The Independent Effect of Platelet Count On Mortality in a Large Inner City Elderly Outpatient Population

Blood ◽

10.1182/blood.v120.21.4645.4645 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4645-4645

Author(s):

Pavlos Msaouel ◽

Anthony P. Lam ◽

Krishna Gundabolu ◽

Grigorios Chrysofakis ◽

Yiting Yu ◽

...

Keyword(s):

Overall Survival ◽

Platelet Count ◽

Inner City ◽

Complete Blood Count ◽

Conflicts Of Interest ◽

Reference Group ◽

Critical Role ◽

Independent Effect ◽

Platelet Counts ◽

Independent Association

Abstract Abstract 4645 Introduction: Platelets play a critical role in hemostasis and are also important in the development of pathologic processes including atherosclerosis and arterial thrombosis. Both thrombocytopenia and thrombophilia are common findings in several illnesses including liver diseases, infections, autoimmune disorders and malignancies. However, to date no study has directly investigated the effect of thrombocytopenia and thrombocytosis on the overall survival of the general population. The present study was thus undertaken to elucidate the independent association of abnormal platelet counts with subsequent mortality among a large inner city outpatient elderly cohort comprised of different ethnicities and comorbid conditions. Methods: All 36,262 non-acutely ill individuals >65 years of age who were seen at an outpatient clinic within the Montefiore medical system from January 1st 1997 to May 1st 2008 and who underwent a complete blood count within 3 months of the visit were included in our cohort. Thrombocytopenia and thrombocytosis were defined as a platelet count of <150,000 per microliter or >450,000/microliter respectively. Data on 19 co-morbidities that could affect mortality and confound the analysis were extracted from the electronic medical records of each patient. These included the presence of anemia, neutropenia, congestive of heart failure, baseline anemia and/or neutropenia, prior myocardial infarction, peripheral vascular disorders, cerebrovascular disease, dementia, chronic pulmonary disease, rheumatologic disease, peptic ulcer disease, liver disease, diabetes, renal disease, malignancy, neurologic deficits and HIV infection. A Cox proportional hazard model was constructed to assess the independent association of abnormal platelet counts with subsequent mortality after controlling for all extracted co-morbidities, age, gender and race. Results: As shown in table 1, caucasians had higher thrombocytopenia rates compared to blacks, Hispanics and other ethnicities (p<0.001 for all comparisons). Ethnicities other than Caucasians, Blacks or Hispanics had significantly lower rates of thrombocytosis compared to Caucasians or Blacks (p values <0.01). The median platelet count was 237,000/microliter. The median follow-up period was 3.3 years with a total of 134,132 person-years of observation. Fully adjusted hazard ratios (HR) using normal platelet counts (≥150,000 and ≤450,000) as the reference group showed a significant association of thrombocytopenia (HR=1.43, 95% CI 1.34–1.53; p<0.001) and thrombocytosis (HR=1.73, 95% CI 1.54–1.94; p<0.001) with shorter overall survival. A statistically significant interaction term was also identified between race and thrombocytopenia (Table 1). More specifically, we found that Hispanics with thrombocytopenia are at a higher risk compared to Caucasians with thrombocytopenia (HR=1.34, 95% CI 1.13–1.59; p=0.001). Conclusions: Thrombocytopenia and thrombocytosis are independently associated with increased mortality in our study population. The effect of thrombocytopenia on overall survival is more prominent on Hispanics. These findings suggest that abnormal platelet count may be a mediator of increased mortality risk in older patients and this effect may differ by ethnicity. Disclosures: No relevant conflicts of interest to declare.

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Impact Of Dose-Density Delays In Diffuse Large B-Cell Lymphoma (DLBCL) Treated With R-CHOP21 Or R-CHOP14

Blood ◽

10.1182/blood.v122.21.4374.4374 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4374-4374

Author(s):

Antonio Gutierrez ◽

Antonia M Bautista-Gili ◽

Leyre Bento ◽

Ines Herraez ◽

Lucia Garcia ◽

...

Keyword(s):

Conflicts Of Interest ◽

B Cell Lymphoma ◽

Complete Response ◽

University Hospital ◽

Aggressive Lymphoma ◽

High Dose ◽

Prognostic Impact ◽

Non Hodgkin Lymphoma ◽

Ann Arbor ◽

The Impact

Abstract Background DLBCL is the more common non Hodgkin lymphoma. This is an aggressive lymphoma that is treated with a standard chemotherapy regimen: R-CHOP. In the last years attempts have been done to improve the outcome both increasing dose-density (DD) (CHOP14) or intensity (CHOEP, ACVBP, frontline high dose therapy followed by autologous stem cell transplantation). Although phase 2 studies of these interventions suggested promising results, when randomized phase 3 trials have been conducted, there is no demonstrated benefit of these higher toxicity approaches when compared with R-CHOP alone. Only addition of rituximab to CHOP has proved a survival advantage. This has allowed setting R-CHOP administered every 21 days (R-CHOP21) as the standard treatment for DLBCL patients. The purpose of this study is further analyzing the prognostic impact of DD delays in two cohorts of DLBCL patients treated with R-CHOP21 or R-CHOP14. Methods All patients diagnosed between 1999 and 2013 of DLBCL in University Hospital Son Espases were identified from Pathology Department registry. Only patients treated with R-CHOP21 or R-CHOP14 +/- radiotherapy were included. Patients receiving other chemotherapy regimens or consolidations were excluded. DD delay was calculated as follows: DD delay = real number of days from first to last cycle of chemotherapy / expected number of days from first to last cycle in every regimen. Results A total of 166 cases were identified: considering inclusion and exclusion criteria finally 111 cases were selected (71 in the R-CHOP21 cohort and 40 in the R-CHOP14 cohort). Respectively for R-CHOP21 and R-CHOP14, 61% and 37% were older than 60 years (p=0.02), 26% and 35% had an ECOG PS higher than 1 (p=0.3), 49% and 62% had an Ann Arbor stage III-IV (p=0.09), 44% and 51% an a-IPI higher than 1 (p=0.47). Median DD delay was 2% versus 14% for R-CHOP21 and R-CHOP14 groups (p<0.001). Clinically significant DD delay was considered those patients with DD delay higher than the median of the R-CHOP14 group. Complete response (CR) rate in patients with or without DD delay higher than 14% was 50% versus 85% in the R-CHOP21 group (p=0.004) and 80% versus 78% for R-CHOP14 group (p=0.87). Median follow-up was 60 months (4-169). OS and PFS were not significantly different in patients treated with R-CHOP21 or R-CHOP14: respectively 5y-OS of 73% vs 82% (p=0.97) and 5y-PFS 78% vs 70% (p=0.46). However, DD delay higher than 14% influenced OS and PFS only in the R-CHOP21 group (5y-OS of 39% vs 82% with or without DD delay; p=0.002 and 5y-PFS of 61% versus 81%; p=0.024) but not in the R-CHOP14 group (5y-OS of 78% vs 84% with or without DD delay; p=0.24 and 5y-PFS of 57% versus 72%; p=0.56). Conclusions Overall in our series there were no differences in terms of response or survival between patients treated with R-CHOP21 or R-CHOP14. Significantly higher rates of DD delay were observed in the R-CHOP14 group. However, the impact of DD delays on response and survival was only observed in the R-CHOP21 group but not in patients treated with R-CHOP14. We can conclude that R-CHOP21 and R-CHOP14 are equivalent regimens in terms of response and survival only if DD delays are avoided. For patients receiving R-CHOP21 we recommend using clinical and support measures in order to avoid DD delays. Disclosures: No relevant conflicts of interest to declare.

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Autologous 111 Indium-Oxinate-Labelled Platelet Sequestration Study in Patients with Immune Thrombocytopenia Treated By Thrombopoietic Receptor-Agonists

Blood ◽

10.1182/blood.v128.22.2555.2555 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2555-2555

Author(s):

Matthieu Mahevas ◽

Sandrine Van Eeckhoudt ◽

Guillaume Moulis ◽

Christine Dosquet ◽

Marc Michel ◽

...

Keyword(s):

Platelet Count ◽

Life Span ◽

Kinetic Study ◽

Immune Thrombocytopenia ◽

Complete Response ◽

Splenic Sequestration ◽

Platelet Production ◽

Receptor Agonists ◽

Day Range ◽

The Impact

Abstract Introduction In immune thrombocytopenia (ITP), isotopic assessment of the site of platelet destruction using autologous111Indium-oxinate-labelled platelet sequestration study could be an helpful parameter to determine whether or not to perform splenectomy. Two independent studies have suggested that a purely splenic sequestration could be a significant predictive factor of long-term complete response after splenectomy. An increasing number of patients receives thrombopoietic receptor-agonists (TPO-RAs) but such treatments are not curative and therefore do not necessarily prevent from considering splenectomy in the course of ITP. TPO-RAs increase platelet production by inducing proliferation and differentiation of the megakaryocyte lineage. We have only very few data evaluating the impact of TPO-RAs, on mean platelet life span (MPLS), platelet production and platelet site of destruction. The aim of this study was to assess these parameters and clinical outcome of patients treated with TPO-RAs who underwent kinetic study of autologous111Indium-oxinate-labelled platelet. Patients and Methods We carried out a retrospective study in the Ile de France region, between 2008 and 2016. Patients were retrospectively selected from a prospective clinical database at the Cellular Biology Department of Saint Louis Hospital. We selected adult patients with definite ITP according to the international criteria. The isotopic method used to study platelet lifespan was previously described. Analyses were based on the radioactivity accumulation slopes in the hepatic or splenic area. We excluded patients who had received less than 3Mbeq of 111In. Data from patients' medical charts were collected using the standardized form of the Referral Center for Adult ITP. Complete response (CR) and Response (R) were defined according to standardized international criteria: platelet count > 30x 109/L with at least a doubling of the baseline value or >100 x 109/L. Results of platelet kinetic study from patients treated with TPO-RAs were compared with those from patients receiving no treatments. Results Two hundred and fifty three adults ITP patients were included. At the time of platelet kinetic study, 24 patients (10 men/14 women) with a median age of 63 years [range: 22-83] were treated with TPO-RAs (romiplostim n= 10, eltrombopag n = 14) and 229 (81 men/148 women) had no treatment. Among the TPO-RAs treated patients, some also received low dose steroids (n=6), dapsone (n=1) or intravenous immunoglobulins (n=2) at least two weeks before the kinetic study. Three were newly diagnosed, 9 had persistent ITP and 12 chronic ITP. The median platelet count was 62 x109/L [range: 22-175], and 7 patients had a platelet count > 100 x109/L. The median Mean Platelet Life Span (MPLS) was reduced in both groups (1.44 day [range: 0.4-7.5] (normal: 7-10) in patients treated with TPO-RAs), but was significantly higher in untreated patients (2.3 day [0.4-11], p = 0.004). The median turnover platelets ratio was increased in both groups (48% per day [range: 11-173] in patients treated with TPO-RAs), but was significantly lower in untreated patients (30% per day [range: 0.8-247]). Ratio of platelet production was significantly increased in patients treated with TPO-RAs (median: 2, [range: 0.1-5.0]) compared with untreated patients (median: 0.84, [range: 0.1-85.0]). Repartition of the site of platelet sequestration was similar in the two groups, 12 (50%) patients treated with TPO-RAs had a splenic uptake, versus 112 (49.1%) in untreated patients, and 2 (20%) patients treated with TPO-RAs had an hepatic uptake versus 9 (3.9%) in untreated patients. A splenectomy was performed in 9 out of the 12 patients with a purely splenic sequestration. After a median follow-up of 26 months [range 0-53], 8 (88%) had achieved CR and 1 had relapsed 5 months after splenectomy. Conclusion Our study shows that despite an increase production and turnover of platelets due to the stimulation of the megakaryopoiesis by TPO-RAs, the MPLS was clearly reduced and the repartition of platelet sequestration was not modified in patients receiving these drugs. Moreover, it would seem that a purely splenic sequestration is also predictive of CR after splenectomy in this group of patients. More importantly platelet kinetic study can be used in patients treated with TPO-RAs to position the splenectomy in the therapeutic management. Disclosures No relevant conflicts of interest to declare.

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