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

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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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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Thrombopoietin Receptor Agonist Use, Efficacy and Toxicity in Children with Immune Thrombocytopenia: Data from an Italian Multicenter Survey

Blood ◽

10.1182/blood-2018-99-110652 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4997-4997

Author(s):

Paola Giordano ◽

Giuseppe Lassandro ◽

Marco Spinelli ◽

Momcilo Jancovic ◽

Paola Saracco ◽

...

Keyword(s):

Platelet Count ◽

Immune Thrombocytopenia ◽

Conflicts Of Interest ◽

Immunosuppressive Agents ◽

Real Life ◽

Complete Response ◽

Clinical Use ◽

First Line ◽

Thrombopoietin Receptor ◽

Multicenter Survey

Abstract Background: Immune Thrombocytopenia (ITP) is one of the most common conditions encoutered by the pediatric hematologist. Current first-line therapy includes: observation without drug therapy, corticosteroids and intravenous immune globulin. A minority of patients are refractory to first-line approaches. Second-line treatment options are: immunosuppressive agents and thrombopoietin receptor agonists (TPO-RA). Eltrombopag and Romiplostin are TPO-RA licensed for clinical use. Eltrombopag is, actually, the only TPO-RA approved in Italy (since two years ago) for children, over one year old, with a chronic and/or refractory ITP. Real life data of Eltrombopag are limited. Methods: We performed an Italian multicenter retrospective survey to study the clinical on-label use of TPO-RA, focus on Eltrombopag, in pediatric ITP. Our aims were, primarily, to bring out the prevalence of the use in clinical practice and secondarily to collect data on efficacy and toxicity. Results: We enrolled 69 pediatric ITP subjects from 15 Italian treatment centers (TC). 4 patients received Romiplostin as TPO-RA and were excluded by the analysis. 36/65 patients weer female (55%). Median age at ITP diagnosis: 6 years + 6 months (min 1 y + 2 m; max 16 y + 7 m). Median age at first Eltrombopag assumption: 11 years + 5 months (min 2 y + 0 m; max 17 y + 8 m). Accounting in 344 the total number of chronic ITP subjects treated by TC in the same observation period (July 2016-June 2018), we observed an Eltrombopag clinical use prevalence of 0.19 (95% CI 0.15 to 0.26). We underlined a "no response" to Eltrombopag (platelet count persistently less than 30000 per microliter) in 16/65 (25%); a "partial response" (platelet count between 30000 and 100000 per microliter) in 14/65 (21%) and a "complete response" (platelet count persistently up than 100000 per microliter) in 35/65 (54%). The overall response (partial or complete) was described in 49/65 (75%) children. During the follow up was seen in 16/49 (33%) subjects with initial response a platelet rise that waned to no response. There was no evidence of significant adverse events (clinicians are obliged, to monthly surveillance, by Italian drug agency for hypertransaminasemia and peripheral smear cell abnormalities). Conclusions: Our results demonstrate that Eltrombopag is a therapeutic option quite considered by Italian clinicians. Moreover, according with the percentages of clinical trials, Eltrombopag is safe and effective to rise platelet count. Further studies need to emphasize how factors favor a complete response and to know the incidence of long-term adverse effects. A prospective study designed and driven by Italian Association of Pediatric Hematology Oncology (AIEOP) Coagulation Disorders Working Group is, already, in progress. Disclosures No relevant conflicts of interest to declare.

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Severe Thrombocytopenia Does Not Increase Bleeding Complications in Patients Undergoing Bronchoscopy

Blood ◽

10.1182/blood.v124.21.4293.4293 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4293-4293

Author(s):

Lakshminarayanan Nandagopal ◽

Muthu Veeraputhiran ◽

Tania Jain ◽

Ayman Soubani ◽

Charles A. Schiffer

Keyword(s):

Platelet Count ◽

Renal Dysfunction ◽

Platelet Transfusion ◽

Conflicts Of Interest ◽

Bleeding Complications ◽

British Thoracic Society ◽

Severe Thrombocytopenia ◽

Platelet Counts ◽

Number Of Patients ◽

Platelet Transfusions

Abstract Introduction Prophylactic platelet transfusions are often performed prior to bronchoscopy or broncho-alveolar lavage (BAL) to prevent bleeding in thrombocytopenic patients. There is a paucity of data to validate this approach, with a platelet transfusion threshold of <50,000/mm3 largely based on expert opinion. We conducted a retrospective study on the incidence of bleeding complications in thrombocytopenic patients undergoing bronchoscopy. Methods We identified 150 consecutive patients with platelet counts <100,000/mm3 who underwent bronchoscopy and/or BAL from January 2009 to May 2014 at our institution. Bronchoscopies performed in patients with frank hemoptysis and trans-bronchial lung biopsy procedures were excluded. Patient characteristics, underlying diagnosis, platelet count prior to bronchoscopy, administration of platelet transfusions and bronchoscopy details were recorded. Factors affecting bleeding risk including presence of renal dysfunction (defined as BUN >30 and/or Cr>2.0) and coagulation studies (PT, PTT, INR) were identified. The British Thoracic Society guidelines1 were used to categorize bleeding as a result of bronchoscopy. Data were analyzed using descriptive statistics. Results The median age was 59 years (range 27-90), with two-thirds of patients (63%) being male. One hundred and seventeen (78%) patients had underlying malignancy and 55 (37%) had thrombocytopenia related to malignancy. Fellows and residents under the supervision of a bronchoscopy certified attending performed all but 4 of the bronchoscopies. Infection (40%) was the primary indication for bronchoscopy with BAL performed in 127 (85%) patients. Fifty-eight of 89 (65%) patients with baseline platelet counts <50,000/mm3 received prophylactic transfusions compared to 8% of those with platelet counts >50,000/mm3. The platelet count did not rise to >50,000//mm3 in many transfused patients. Seventy patients (47%) had counts <50,000/mm3 and eighty patients (53%) had counts >50,000/mm3 at the time of bronchoscopy. 49% were receiving immunosuppressive medications, 45% had renal dysfunction and 8% had INR >1.5. Bloody lavage that resolved spontaneously without continuous suctioning (Grade 0) was observed in 9 (6%) patients. Bleeding that required continuous suctioning but then resolved spontaneously (Grade 1) was noted in 1 patient with a platelet count of 61,000/mm3. Of 10 total bleeding events, 7 occurred in patients who were intubated. Two additional patients with platelet counts of 30,000/mm3 and 53,000/mm3 had diffuse alveolar hemorrhage, which was present before bronchoscopy. “Old” blood and blood clots were observed in 6 patients. Discussion The low incidence of bleeding complications from bronchoscopy +/- BAL even in patients with platelet counts <30,000/mm3 (3 episodes in 31 patients, all grade 0) demonstrates that bronchoscopy can be safely done in severely thrombocytopenic patients. Adopting a lower threshold for prophylactic transfusions could save a considerable number of platelet units and translate into significant cost savings and decreased risk of transfusion-related complications. Table 1 Platelet count, transfusion history and bleeding complications during bronchoscopy Platelet count at the time of bronchoscopy Number (n) and percentage (%) of patients who underwent bronchoscopy Number of patients who received prior platelet transfusion Bleeding during bronchoscopy n % 0-15,000/mm3 9 6% (9/150) 5 Grade 0=1 pt 16-29 22 15% 16 Grade 0=2 pts 30-39 17 11% 9 Grade 0=1 pt 40-49 22 15% 9 Grade 0=3 pts 50-75 44 29% 14 Grade 1=1 pt 76-100 36 24% 10 Grade 0=2 pts Total 150 63 Grade 0=9 pts, Grade 1=1 pt. 1.Du Rand IA, Blaikley J, Booton R, et al. British Thoracic Society guideline for diagnostic flexible bronchoscopy in adults: accredited by NICE. Thorax. 2013:68 Suppl 1:i1-i44 Disclosures No relevant conflicts of interest to declare.

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Immediate Pre-Splenectomy Platelet Count Predicts Splenectomy Response in Adult Immune Thrombocytopenia Patients

Blood ◽

10.1182/blood-2020-135905 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 11-11

Author(s):

O. A. Soboleva ◽

K. I. Ntanisian ◽

E. K. Egorova ◽

A. L. Melikyan ◽

E. G. Gemdzhian ◽

...

Keyword(s):

Risk Factors ◽

Platelet Count ◽

Immune Thrombocytopenia ◽

Conflicts Of Interest ◽

Univariate Analysis ◽

Multivariate Logistic Regression Analysis ◽

Complete Response ◽

Preoperative Treatment ◽

Female Ratio ◽

Factors Associated

Background: Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by isolated thrombocytopenia. Splenectomy remains an effective and safe treatment for ITP. Objective: Identify and estimate risk factors associated with no response (platelet count < 30 x 109/L) to splenectomy for adult ITP patients. Patients and Methods: The study conducted at National Research Center for Hematology (Moscow) from 03/2015 to 11/2019 included all patients (in total, 111) with ITP, who underwent laparoscopic splenectomy. Median (Med) platelet count at admission was 12 x 109/L (range from 1 to 239 x 109/L). The time from diagnosis of ITP to splenectomy varied from 3 months to 51 years. All patients had received from 1 to 3 lines of treatment prior to splenectomy. Pre-splenectomy treatment was carried out at platelet count < 20 x 109/L and/or in the presence of bleeding. Results: Of the 111 patients 31 were male (Med age 43 years [IQR 27-55]) and 80 were female (Med age 37 [IQR 29-49]). The male/female ratio was 1:2.6. Complete response to splenectomy (platelet count > 100 x 109/L) was achieved in 79/111 (71.2%) cases, 11/111 (9.9%) patients had partial response (platelet count: 30-100 x 109/L) and 21/111 (18.9%) failed to respond (platelet count < 30 x 109/L). Patients who achieved complete response to splenectomy had a significantly higher immediate pre-splenectomy platelet count than non-responders: Med platelet count (95% CI): 47 (35-58) vs 16 (9-20) (x 109/L), Mann-Whitney U test, P < 0.001 (CI, confidence interval) (Figure 1). Multivariate logistic regression analysis was carried out to identify factors associated with splenectomy outcome (response/no response). Multivariate analysis included patient's gender and age, duration of ITP, grade of bleeding at admission, platelet count at admission, preoperative platelet count and number of prior lines of therapy. Continuous variables were dichotomized using ROC analysis, in particular, cut-off point for preoperative platelet count was 23 x 109/L. As a result, following statistically significant (Wald test) factors were selected: • an unfavorable predictor: immediate pre-splenectomy platelet count < 23 x 109/L, RR (95% CI): 2.5 (1.1-8.6), P = 0.001 (RR, relative risk) (Figure 1) and • combined unfavorable risk factor: male gender in the age over 60 (compared to men in the age ≤60 and women in general), RR (95% CI): 2.0 (0.9-7.1), P = 0.05 (Figure 2). Response rate was negatively correlated (in univariate analysis) with the number of treatment lines prior to splenectomy (negative Spearman's rank correlation coefficient, −0.30; P = 0.01). When preoperative platelet count ≥ 23 x 109/L was achieved, probability of complete response to splenectomy was 80% (Figure 3). The rate of postoperative complications was 12.6%. According to our follow-up data (up to 5 years) 66/79 (83.5%) patients maintained complete response. Conclusions: High-risk groups were identified: patients with immediate pre-splenectomy platelet count < 23 x 109/L (i.e. with no effect of preoperative treatment) and men over the age of 60. Identified risk factors could be taken into account in decision-making process. Disclosures No relevant conflicts of interest to declare.

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Megakaryocyte Abnormalities Occur In The Absence Of Cell-Mediated Immunity In a Murine Model Of Passive Immune Thrombocytopenia (ITP)

Blood ◽

10.1182/blood.v122.21.3537.3537 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3537-3537

Author(s):

John W. Semple ◽

Kristin Hunt ◽

Yu Hou ◽

Rukhsana Aslam ◽

Edwin R. Speck ◽

...

Keyword(s):

Bone Marrow ◽

Immune Thrombocytopenia ◽

Conflicts Of Interest ◽

In Vivo Model ◽

Cell Mediated Immunity ◽

Severe Thrombocytopenia ◽

Platelet Destruction ◽

Platelet Counts ◽

Antiplatelet Antibodies ◽

Platelet Antibodies

Abstract Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by increased peripheral immune platelet destruction and megakaryocyte defects in the bone marrow. Although ITP was originally thought to be primarily due to humoral mediated autoimmunity it is now evident that T cells can also play a contributing role to the thrombocytopenia. In fact, the exact interplay between platelet destruction, megakaryocyte dysfunction, and the elements of both the humoral and cell mediated immune systems still remain incompletely defined. In murine passive models of ITP, the direct administration of anti-platelet antibodies can result in severe thrombocytopenia which is evident within 24 hours of injection. While most studies have focused on immune platelet destruction in the spleen, an additional possibility is that the anti-platelet antibody also has an effect on megakaryocytes. To unequivocally determine if antiplatelet antibodies have an effect on megakaryocytes in an in vivo model, BALB/c mice were intravenously administered 2 ug of an anti-GPIIbIIIa antibody (MReg30) or 50 uL of a high tittered anti-GPIIIa (anti-β3) serum from BALB/c GPIIIa (CD61) knockout mice immunized with wild type platelets. Platelet counts were assessed over time and the bone marrow and spleens were harvested for histological examination of megakaryocytes. Both preparations of antiplatelet antibodies significantly reduced platelet numbers within 1 day of antibody or serum administration. This thrombocytopenia could be rescued by administration of 2 g/kg of IVIg ip. Compared with naïve control mice, histological (H&E staining) examination of the bone marrow and spleens revealed that megakaryocytes were significantly increased in number and all exhibited abnormalities consistent with apoptosis e.g. pyknotic nuclei. IVIg administration completely prevented these megakaryocyte abnormalities. These results show that passively administered anti-platelet antibodies not only affect platelet counts but also significantly affect megakaryocyte physiology in the absence of cell mediated immunity. Disclosures: No relevant conflicts of interest to declare.

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Methylprednisolone Versus Intravenous Immunoglobulin As Initial Therapy In Adult Immune Thrombocytopenia

Blood ◽

10.1182/blood.v122.21.3557.3557 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3557-3557

Author(s):

Ik-Chan Song ◽

Deog-Yeon Jo ◽

Yoon Seok Choi ◽

Hyo-Jin Lee ◽

Hwan-Jung Yun ◽

...

Keyword(s):

Intravenous Immunoglobulin ◽

Immune Thrombocytopenia ◽

Conflicts Of Interest ◽

Complete Response ◽

Early Response ◽

Adult Patients ◽

Term Outcome ◽

Long Term Outcome ◽

Platelet Counts

Abstract Background Both intravenous methylprednisolone (methyl-Pd) and intravenous immunoglobulin (IVIg) have been used as standard initial therapies in adult patients with immune thrombocytopenia (ITP). Nonetheless, few studies have addressed whether there are differences in clinical efficacy between these two treatments. In this study, we compared platelet responses, toxicities, and bleeding-related mortality associated with these two treatments in adult ITP. Patients and Methods Adult patients newly diagnosed with ITP, with platelet counts of less than 20,000/mL, were prospectively enrolled. Patients with comorbidities such as diabetes and uncontrolled cardiovascular disorders and who were pregnant were excluded. Patients who entered the study between 1993 and 2002 received intravenous methyl-Pd therapy (10 mg/kg/day for 3 days) followed by oral Pd (1 mg/kg/day). Patients who entered the study between 2003 and 2008 received IVIg (400 mg/kg/day for 5 days) together with oral Pd (1 mg/kg/day). After 6 weeks, the prednisolone began to be tapered in both arms. Early response and maintenance of response were assessed at 7 days and 6 months after treatment, respectively, based on the outcome criteria proposed by an international working group (Blood 2009). Results Of 87 patients enrolled, 77 (88.5%) were eligible for analysis. Initial platelet counts did not differ between the two groups. Early responses occurred in 30 of 39 patients (76.9%) receiving methyl-Pd versus 33 of 38 patients (86.6%) receiving IVIg (p = 0.187). Maintenance of response was observed in 28 patients (71.8%) in the methyl-Pd arm and 23 patients (60.5%) in the IVIg arm (p = 0.187). The time to a complete response in the IVIg arm (6 days; range, 1–35 days) was shorter than that in the methyl-Pd arm (13.5 days; range, 2–29 days) (p = 0.002). Side effects were mild and tolerable in both arms. Five years after treatment initiation, 5 patients (12.8%) and 7 patients (18.4%) were still under salvage treatment in the methyl-Pd and IVIg arms, respectively. During a median follow-up of 98 months (range, 33-228 months) in the methyl-Pd arm and 71 months (range, 52-180 months) in the IVIg arm, 19 patients (48.7%) and 18 patients (47.4%) patients required one or more salvage treatments, respectively (p = 0.906). No bleeding-related death was observed in either group during the follow-up period. Conclusion These results indicate that neither the early response rate nor the long-term outcome differs between methyl-Pd and IVIg treatments. IVIg, however, more rapidly induces a complete response than methyl-Pd. Disclosures: No relevant conflicts of interest to declare.

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Mpl Expression on AML Blasts Predicts Cytopenia

Blood ◽

10.1182/blood.v126.23.1387.1387 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1387-1387

Author(s):

Philipp J Rauch ◽

Corinne Widmer ◽

Kristin Fritsch ◽

Jana M Ellegast ◽

Jeroen S Goede ◽

...

Keyword(s):

Platelet Count ◽

Negative Correlation ◽

Conflicts Of Interest ◽

Gene List ◽

Receptor Expression ◽

Severe Neutropenia ◽

Severe Thrombocytopenia ◽

Hematopoietic Stem ◽

Platelet Counts ◽

Blast Count

Abstract Acute myeloid leukemia (AML) induces profound impairment of healthy hematopoiesis. The production deficit in the bone marrow (BM) leads to development of peripheral anemia, thrombocytopenia and neutropenia, which is a major cause of AML-associated morbidity and mortality. Despite much progress in understanding of AML biology, the mechanisms by which AML blasts interact with elements of normal hematopoiesis to cause cytopenia are unclear. Conventional wisdom has it that blasts infiltrate the marrow and displace normal hematopoiesis. If this concept were to be true, there should be a strong correlation between BM blast count and peripheral cytopenia. Surprisingly, analysis of 223 patients with newly diagnosed AML at a tertiary referral center revealed lack of correlation between initial BM blast count [% of cellularity] and hemoglobin level (ρ=-0.11, P=0.12), platelet count (ρ=-0.00, P=0.53) and absolute neutrophil count (ρ=0.13, P=0.06). This indicates that mechanisms other than displacement of normal hematopoiesis dictate the severity of cytopenia in AML patients. Hematopoiesis is tightly regulated by cytokines. Among them, thrombopoietin (TPO) acts through its receptor c-Mpl as the master regulator of megakaryopoiesis, but also exerts upstream effects on hematopoietic stem and progenitor cells (HSPC). TPO levels are controlled by receptor-mediated scavenging by cells carrying c-Mpl on the surface, with platelets representing the lion's share in a healthy organism. This negative feedback loop results in strong negative correlation between serum TPO concentration and platelet count in the steady state. When we examined this relationship in our AML cohort, TPO levels did not follow the expected negative correlation with platelet counts (ρ=-0.10, P=0.59). Comparison with historic controls with thrombocytopenia induced by chemotherapy for non-hematopoietic malignancy revealed that the lack of correlation was driven by AML cases with severe thrombocytopenia that had lower than expected levels of TPO in the serum. As HSPC are known to express c-Mpl, we hypothesized that HSPC-derived AML blasts may also express the receptor and cause insufficiency of hematopoiesis by means of receptor-mediated TPO scavenging. To test this hypothesis, we compared c-Mpl expression on blasts in AML cases with severe thrombocytopenia and low TPO concentration (potential scavenger cases) to cases with TPO levels adequate for the degree of cytopenia. Both surface flow cytometry and qPCR demonstrated higher c-Mpl expression in potential scavenger cases (3.1-fold, P=0.02). To determine whether this difference in expression translates into increased serum TPO clearance, we incubated AML blasts with high (c-Mpl+) and low (c-Mpl-) receptor expression in serum containing recombinant human TPO at a concentration of 100 pg/mL. After 2h, TPO clearance reached 45 pg per 106 cells in wells with c-Mpl+ blasts, compared to only 4 pg per 106 cells in wells with c-Mpl- blasts (P=0.02). This confirms the hypothesis that AML blasts can lower TPO levels by virtue of their c-Mpl expression. Validation studies in an independent, multi-center Dutch-Belgian-Swiss cohort of 437 AML cases confirmed lack of correlation between initial BM blast count and cytopenia. Ranked gene list correlation analysis of whole genome microarray data proved significant enrichment of the MPL transcript in patients with severe thrombocytopenia when compared to patients with average platelet counts (rank 27/20'589, FDR<10-6). MPL enrichment could also be observed in patients with severe neutropenia (P<0.01), but there was no correlation between MPL transcript level and degree of anemia. Lastly, we asked if MPL expression was related to cytogenetic or molecular AML subtype: indeed, microarray analysis showed higher MPL expression in cases of AML with t(8;21) than in any other subtype (P<10-4). Concurrently, these patients displayed significantly lower platelet count (40 vs 83 x 109/L, P=0.02) when compared to all other AML cases. In summary, our study demonstrates that cytopenia in AML is independent of BM blast count, but strongly correlated with c-Mpl expression on blasts. We show that c-Mpl+ blasts clear TPO, causing insufficient TPO levels and contributing to development of thrombocytopenia and neutropenia. The work may have important ramifications for treatment of AML-induced cytopenia, especially in the relapsed or refractory setting. Disclosures No relevant conflicts of interest to declare.

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Increased FVIII and Anti-Phospholipid Antibodies Do Not Modify the Clinical Course of Chronic Immune Thrombocytopenia

Blood ◽

10.1182/blood.v124.21.5013.5013 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5013-5013

Author(s):

Meet Kumar ◽

Maitryee Bhattyacharyya ◽

Shyamali Datta

Keyword(s):

Platelet Count ◽

Lupus Anticoagulant ◽

Immune Thrombocytopenia ◽

Clinical Course ◽

Conflicts Of Interest ◽

Age Groups ◽

Platelet Counts ◽

Bleeding Score ◽

Chronic Immune Thrombocytopenia

Abstract INTRODUCTION: Immune thrombocytopenia is a heterogenous disease with majority patients having a mild bleeding phenotype and one-fourth being asymptomatic. Bleeding episodes are usually seen in patients with platelet counts typically <30,000/cumm. There is no study till date to identify patients with platelet count <30,000/cumm and at high risk for bleeding. Although patients who harbor anti phospholipid antibodies have a higher risk of arterial and venous thrombosis, it is not known whether presence of acquired thrombophilia modifies the clinical course of bleeding in low platelet count ITP patients. We evaluated the role of FVIII and lupus anticoagulant in modifying the clinical course of such patients. MATERIALS AND METHODS: Patients of all age groups with persistent and chronic immune thrombocytopenia were eligible for study enrolment. Patients with acute ITP and secondary ITP were excluded. Eligible patients were evaluated with baseline parameters, ITP bleeding score (ITP-BAT, version 1.0 by IWG on ITP) at baseline and then at every visit and FVIII and lupus anticoagulant at baseline and repeat at six months.Patients were called for monthly scheduled visits if platelet counts were >30,000/cummand more frequently at lower platelet counts. Patients with any evidence of underlying infection or raised c-reactive protein and procalcitonin were deferred evaluation.All patients were treated as per institutional protocol to avoid treatment bias. Patients were followed up for one year. We finally calculated the average bleeding scores of all patients at different platelet counts (for eg. average of skin, mucosal and organ bleeding scores of all patients that had platelet counts <10,000/cumm, 10-30,000/cumm etc) and analysed it with FVIII and anti-phospholipid antibody levels. RESULTS: A total of 45 patients were enrolled with M:F=1:3.2. Median age of patients is 28years (3-72 years). Two patients were excluded (both progressed to SLE) and another two were lost to follow-up. Median duration from ITP diagnosis to study enrolment was 62.4months (8-590 months). Median follow-up of all patients was 14.2 months (13.2-16.4 months). Nine patients had persistent and 32 patients had chronic ITP. ITP-BAT could differentiate intensity of bleeding at different platelet counts by means of bleeding scores (Table 1). Correlation of bleeding scores with prothrombotic markers could not establish a disease course modifying relationship between the two (Table 2). CONCLUSION: Presence of high FVIII and anti phosphoilipid antibodies donot modify the bleeding risks in patients with ITP and low platelet counts. Table 1Platelet count (x109/cumm)Total episodesAverage bleeding scoreP value<1014S2.4 M1.4 O0 0.00210-3015S1.4 M0.9 O030-6018S0.3 M0.1 O0>600S0 M0 O0 Table 2 Platelet count <10,000/cumm Platelet count 10-30,000/cumm N Av BS P= N Av BS P= FVIII>150 5 S2.5M1.1O0 0.02 6 S1.1M0.8O0 0.1 FVIII<150 9 S2M0.7O0 11 S1.4M0.6O0 LA1:LA2>2 1 S2.2M1.5O0 0.03 S1.1M0.8O0 0.2 LA1:LA2<1 12 S2.6M1.2O0 S1.2M0.6O0 Table 3 Platelet count 30-60,000/cumm Av BS P= FVIII>150 4 S0.9M0.1O0 0.2 FVIII<150 11 S0.3M0.1O0 LA1:LA2>2 Nil LA1:LA2<1 9 S1.1M0.4O0 Disclosures No relevant conflicts of interest to declare.

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

Blood ◽

10.1182/blood-2020-134416 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 7-8

Author(s):

Mohamed A Yassin ◽

Aya Alasmar ◽

Rola Ghasoub ◽

Omer Ismail ◽

Abdulqadir Jeprel Nashwan ◽

...

Keyword(s):

Platelet Count ◽

Treatment Guidelines ◽

Conflicts Of Interest ◽

Standard Dose ◽

East Asian ◽

Area Under The Curve ◽

Cost Effective ◽

Complete Response ◽

Platelet Counts ◽

The Impact

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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