Urgent Management of Bleeding in Immune Thrombocytopenia: Towards a Standardized Protocol in the Emergency Department

Abstract Background Severe bleeding is a rare but serious complication of immune thrombocytopenia (ITP). A standard approach to treatment is lacking and the delivery of emergency care is often disjointed. The objective of this study was to describe 1) the treatments and outcomes of ITP patients who present to the emergency department (ED) with severe thrombocytopenia and bleeding; and 2) predictors of worsening bleeding or death among ITP patients presenting to the ED. Methods We did a retrospective cohort study of all patients with ITP who presented to the ED with severe thrombocytopenia (platelet count <20 x109/L) and bleeding in 4 academic hospitals affiliated with McMaster University in Hamilton, Canada between January 2008 and April 2016. Patients were followed from arrival to the ED until 10 days after hospital admission, discharge or death. We extracted demographic data, bleeding symptoms at presentation, all ITP treatments administered, new or worsening bleeding, thrombosis and mortality. Bleeding was graded using the ITP Bleeding Score. We defined major bleeding as intracranial hemorrhage (ICH), pulmonary bleeding, or gross gastrointestinal bleeding (GIB). We summarized the results descriptively by frequencies (percentage), and medians (interquartile range [IQR]). Ethics approval was obtained from the Hamilton Integrated Research Ethics Board. Funding was provided by the Platelet Disorder Support Association. Results We identified 110 patients who presented to the ED (n=139 ED visits) with platelets <20 x109/L and bleeding. Median age was 59 years (IQR: 38-74) and 57% were female. For 63 patients (57%), this was their initial presentation of ITP; for the remaining 47 patients, 36% had previously been treated for ITP and had received a median of 3 (IQR: 2-4) ITP therapies. Twenty-eight patients presented to the ED with major bleeding; the remaining 82 patients had ED visits with minor bleeding only. There were 31 ED visits with major bleeding at presentation including GIB (n=23 visits), ICH (n=4), pulmonary hemorrhage (n=3) and GIB plus ICH (n=1). Median platelet count among patients with major bleeding was 3 x109/L (IQR: 3-8 x109/L). Patients received a median of 3 ITP therapies (IQR: 2-4) after presentation to the ED, including intravenous immune globulin (IVIG; 90% of visits), corticosteroids (77% of visits), platelet transfusions (74% of visits), and romiplostim (3% of visits). Median time from ED presentation to first treatment was 7.6 (4.5-9.5) hours. Treatment for bleeding was initiated by Internal Medicine or Hematology consultants in 19/31 visits (61%) or Emergency Department physicians in 12/31 visits (39%). One patient developed arterial thrombosis and 2 patients died, both from bleeding. There were 6 patients who initially presented to the ED with minor bleeding but who subsequently developed major bleeding after a median of 2 days (range: 1-7). All 6 patients had oral purpura and 4 had frank hematuria before or coincident with the development of major bleeding. Conclusions Management of ITP-associated bleeding in the ED consisted mostly of IVIG, corticosteroids and platelet transfusions. Time to first ITP treatment was greater than 7 hours from ED presentation. Oral purpura and hematuria were associated with the development of new or worsening bleeding. A standardized protocol for the management of ITP bleeding in the ED would help identify patients at risk for new or worsening bleeding, and improve health care delivery by making appropriate treatments available in a timely manner. Disclosures Arnold: Amgen: Consultancy, Research Funding; UCB: Consultancy; UCB: Consultancy; Amgen: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Consultancy, Research Funding.

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Clinical impact of chemotherapy-induced thrombocytopenia in patients with gynecologic cancer.

Journal of Clinical Oncology ◽

10.1200/jco.1994.12.11.2317 ◽

1994 ◽

Vol 12 (11) ◽

pp. 2317-2320 ◽

Cited By ~ 25

Author(s):

G L Goldberg ◽

D G Gibbon ◽

H O Smith ◽

C DeVictoria ◽

C D Runowicz ◽

...

Keyword(s):

Platelet Count ◽

Major Bleeding ◽

Gynecologic Cancer ◽

Minor Bleeding ◽

Clinical Effects ◽

Bleeding Events ◽

Transfusion Therapy ◽

Platelet Counts ◽

Major Bleeding Events ◽

Platelet Transfusions

PURPOSE AND METHODS This retrospective analysis of 501 patients with gynecologic cancer treated with chemotherapy evaluates the relationship between platelet count and clinical bleeding, as well as the clinical effects of platelet transfusion therapy. Thrombocytopenic patients were divided into six groups according to platelet counts, and major or minor bleeding manifestations were documented. Thrombocytopenia was defined as a platelet count less than 100,000/microL. RESULTS Thrombocytopenia occurred in 182 (36.3%) patients over 808 of 1,546 chemotherapy cycles (52%). No intracranial or life-threatening bleeding occurred in any patient. The majority of patients (139 [76.4%]) had no clinical bleeding. Minor bleeding, such as purpura, occurred in 34 patients (18.7%) and 44 cycles (5.4%). Major bleeding occurred in nine patients (4.9%) and 10 cycles (1.3%). Five major bleeding events occurred in 49 patients with platelet counts between 0 and 10,000/microL. Forty-three of these patients received platelet transfusions. Thirty-eight of 43 transfused patients (88.3%) had no bleeding. Of the remaining five patients, two were transfused prophylactically with no effect. Three major bleeding events occurred in patients with platelet counts that ranged from 11,000 to 20,000/microL, but these were due to chronic instrumentation or trauma. In patients with platelet counts more than 20,000/microL, major bleeding occurred only from necrotic metastatic lesions. Random-donor platelet transfusions provided inconsistent increments in platelet counts. Overall, 27.5% of patients achieved the expected increase in platelet number based on units of platelet concentrate transfused. The use of single-donor or human leukocyte antigen (HLA)-matched platelets did not provide greater increments in those patients who were refractory to random-donor platelets. CONCLUSION Platelet counts > or = 10,000/microL are not associated with spontaneous major bleeding. Prophylactic platelet transfusions in patients with gynecologic malignancies and chemotherapy-induced thrombocytopenia should be limited to those with platelet counts < or = 10,000/microL, provided they are not bleeding and have no major anatomic or pathophysiologic precursors of bleeding.

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A Multi-Centre Prospective Observational Study of Platelet Transfusion Practice in Neonates with Severe Thrombocytopenia.

Blood ◽

10.1182/blood.v108.11.961.961 ◽

2006 ◽

Vol 108 (11) ◽

pp. 961-961 ◽

Cited By ~ 4

Author(s):

Neil Murray ◽

Sally Ballard ◽

Angela Casbard ◽

Mike Murphy ◽

Irene Roberts ◽

...

Keyword(s):

Observational Study ◽

Major Bleeding ◽

Platelet Transfusion ◽

Transfusion Practice ◽

Major Haemorrhage ◽

Study Entry ◽

Severe Thrombocytopenia ◽

Minor Bleeding ◽

Grade 3 ◽

Platelet Transfusions

Abstract Background: Platelet transfusion practice in neonates is not evidence-based and there is a lack of data relating transfusion to clinical outcome. To inform the design of clinical trials, we conducted a prospective multicentre observational study of platelet transfusion in thombocytopenic neonates to describe: transfusion practice, including reason for transfusion; clinically-related outcomes, including minor and major bleeding and mortality. Methods: Neonates with platelets <60x109/l were studied at 7 UK neonatal intensive care units Mar 05-Jun 06. With parental consent, daily data were collected on minor bleeding (blood staining of oral/nasogastric/endotracheal secretions and stool; microscopic haematuria; petechial rash; oozing from puncture sites - scored 0–7), and major bleeding (intraventricular (IVH), intra-abdominal, pulmonary or renal). Surviving neonates were studied for 7 days or until platelets were ≥60x109/l. Blood counts and all transfusions were directed by the attending neonatologist, with reason for transfusion and its effect on bleeding prospectively documented. Results: 145 of 167 (87%) eligible neonates were enrolled; 123 (85%) were < 37 weeks gestational age (GA), 89 (61%) were male. The study documented 186 episodes of thrombocytopenia (1606 study days) and 309 platelet transfusions given to 91 (63%) neonates. GA, birth weight and age at thrombocytopenic episode were: 27 (24–32) weeks; 825 (675–1370) grams; 5 (2–16) days, respectively [all data median (IQR)]. 21/145 babies (14%) had major IVH (Grade 3/4) at study entry. Platelets (x 109/l) at study entry, and at platelet nadir, and duration of count <60x109/l were: 44 (33–54); 31 (19–42); 2 (1–5) days respectively. In transfused neonates, platelets (x109/l) pre- and post-transfusion, and number of transfusions were: 27 (19–36); 84 (46–138); 2 (1–4) respectively. The principal indications for transfusion were:- platelet count below threshold of unit guideline: 265/309 (86%); deteriorating clinical condition: 17/309 (6%); and significant bleeding: 7/309 (2%). At least 1 episode of minor bleeding was recorded on 622/1606 (39%) of study days. Minor bleeding scores recorded for 12 hours pre- and post each transfusion were [median (IQR)]: 1 (0–2) and 0 (0–1) respectively. New or extension of IVH bleeding to Grade 3/4 occurred in 7 neonates and other major haemorrhage in 9 neonates (4 pulmonary, 3 GI). A total of 20/145 (14%) neonates died, 13 with major IVH bleeding (of which 10 had Grade 3/4 IVH at study entry); all received platelet transfusions [total 87; median 3 (2 to 7). Conclusion: This study confirms that most neonates with severe thrombocytopenia are preterm, most episodes develop after 72 hours of life (median 5 days) and are of short duration (median 2 days). Minor haemorrhage is common and may be reduced by platelet transfusion. Major haemorrhage is uncommon (11%), is associated with mortality (82%) and affected patients receive a large number of platelet transfusions. There is a clear distinction between the majority of thrombocytopenic neonates who receive one or two transfusions as prophylaxis with a good outcome, and the minority who suffer adverse outcomes despite transfusion. Many neonates are transfused with platelets at thresholds below those suggested in guidelines without apparent clinical detriment. These data will be invaluable for planning the randomised trials necessary for rationalising platelet transfusion in these vulnerable patients.

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Clinical and Economic Outcomes Associated with Emergency Department Visits in Patients with Immune Thrombocytopenia,

Blood ◽

10.1182/blood.v118.21.4209.4209 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4209-4209

Author(s):

Z John Lu ◽

Mark D. Danese ◽

Marc Halperin ◽

Melissa Eisen ◽

Robert Deuson

Keyword(s):

Emergency Department ◽

Research Funding ◽

Immune Thrombocytopenia ◽

Primary Diagnosis ◽

Secondary Diagnosis ◽

Employment Equity ◽

Ed Visits ◽

Equity Ownership ◽

The Mean ◽

Total Charges

Abstract Abstract 4209 Introduction: Immune thrombocytopenia (ITP) is characterized by low platelet counts, spontaneous bruising, mucosal bleeding, and, more seriously, intracranial hemorrhage. The disease is associated with a high risk of complications, often requiring visits to emergency departments (ED), with possible subsequent hospitalization. To date, information about ED visits in ITP patients, including frequency, cost, hospitalization risk, and mortality risk, has not been well documented, although such data are critical to the understanding of the clinical and financial implications of poorly-controlled, chronic ITP. We used the 2007 Nationwide Emergency Department Sample (NEDS) to examine resource utilization, ED visits, and hospitalization charges in the US. Methods: The 2007 NEDS contains about 27 million ED records from over 970 hospitals in 27 Healthcare Cost and Utilization Project (HCUP) Partner States, representing a 20% stratified sample of US hospital-based ED visits. The database includes hospital and patient characteristics, diagnoses and procedures, disposition from ED including hospitalization and mortality, discharge diagnosis-related group (DRG) for subsequent hospitalizations, and total charges. Its large sample size enables analyses of relatively rare conditions such as ITP. All ED visits in the database were separated into two groups: visits with ITP as one of the diagnoses (ICD-9-CM diagnosis code of 287.31), and those without a diagnosis of ITP. Outcomes and resource use were separately evaluated in these two groups, as well as in several subgroups within the ITP group defined by age and whether the ITP diagnosis was the primary or a secondary diagnosis. Results: Approximately 8,348 (∼0.03%) of all ED visits in the 2007 NEDS database were in patients with ITP (28% as the primary diagnosis), of which nearly 60% were by female patients and 88% by adult patients (≥18 years old). Medicare or Medicaid was listed as the primary payer in 58% of the visits. Seventy-five percent of the ED visits in ITP patients led to hospitalizations, compared with less than 16% of ED visits in non-ITP patients (p < 0.0001). In ITP patients, 3% of the ED visits ended in death, compared with 0.6% in non-ITP patients (p < 0.0001). The mean total charges for ED visits in ITP patients were $1,650 compared with $1,495 for all others (p<0.0001). The average length of stay (LOS) during hospitalizations subsequent to ED visits was >1.5 days longer (6.5 vs. 5.0 days; p < 0.0001) for ITP patients. The mean total combined charges during the ED visit and resulting hospitalization were >60% higher ($47,000 vs. $29,000; p < 0.0001) for ITP patients. Subgroup analyses of ED visits in ITP patients by age showed that in the majority of visits by pediatric patients (<18 years old), ITP was identified as the primary diagnosis (61%) compared with only 24% among visits by adult patients. Furthermore, visits by adult ITP patients were less likely to result in routine discharge (18% vs. 50%), more likely to result in hospitalization (80% vs. 43%), and were associated with higher mortality compared with pediatric ITP patients (4% vs. 0.1%; p < 0.0001 for all comparisons). ED visits identified with ITP as the primary diagnosis were associated with a higher rate of subsequent hospitalizations (81% vs. 73%), but lower total charges and mortality ($1,490 vs. $1,710, and 2% vs. 4%) respectively, compared with those identified with ITP as a secondary diagnosis (p < 0.0001 for all comparisons). Conclusion: ED visits in ITP patients were associated with significantly worse outcomes, higher resource utilization, and greater total charges. For patients with ITP, younger age and a primary diagnosis of ITP were generally associated with better outcomes following ED visits. More robust and rigorous analyses controlling for patient and hospital heterogeneities will be conducted to confirm these findings. Disclosures: Lu: Amgen: Consultancy, Equity Ownership, Research Funding. Danese:Amgen: Consultancy, Research Funding. Halperin:Amgen: Consultancy, Research Funding. Eisen:Amgen: Employment, Equity Ownership. Deuson:Amgen: Employment, Equity Ownership.

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Treatment of Idiopathic (autoimmune) Thrombocytopenic Purpura (ITP): A Single Mexican Institution Experience

Blood ◽

10.1182/blood.v112.11.4559.4559 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4559-4559

Author(s):

Gregorio Campos-Cabrera ◽

Virgina Campos-Cabrera ◽

Augusto Gomez-Leal ◽

Fernando Gomez-Garcia ◽

Jose-Luis Campos-Villagomez

Keyword(s):

Platelet Count ◽

Chronic Disease ◽

Major Bleeding ◽

Initial Treatment ◽

Complete Response ◽

Minor Bleeding ◽

Special Cases ◽

Chronic Course ◽

Immunological Alterations ◽

Platelet Transfusions

Abstract Background: ITP is an autoimmune disorder in wich an IgG autoantibody is formed that binds to platelets. The platelet autoantibody may bind complement, but platelets are not destroyed by direct lysis, rather, destruction takes place in the spleen, where splenic macrophages with Fc receptors bind to antibody coated platelets. It has an incidence from 50 to 100 cases per million persons per year and half of these occur in children. The infantile form affects both sexes the same, with greater incidence between the 2 and 4 years, major bleeding is common, the response to the treatment is good and mortality is low. In the adult form, women are effected more the men in relation 3 to 1, specially between 15 and 40 years, with minor bleeding, it may requires long treatment and it has greater mortality. The diagnosis is based in medical history and physical examination, valuing the type of bleeding and data of systemic diseases that can cause thrombocytopenia; by laboratory the CBC is necessary, coagulation tests, immunological panel and study of bone marrow, antiplatelet autoantibodies are not necessary; in special cases the imaging studies will be indicated. The treatment is established by guides from the American Society of Hematology. Material and methods: consecutive patients with newly diagnosed ITP were enrolled between October 2004 and April 2008 to study the treatment, response, evolution, fatality and current status. Ambulatory patients received prednisone (PDN), and hospitalized patients received methylprednisolone (MPD). In these second groups platelets transfusions were given as necessary. Results: 88 patients were eligible: 24 were 15 years or younger and 64 were older. Among infantile patients relation female/male was of 1 to the 1 (12/12), major bleeding in 29% (7/24), platelet count less than 20,000 per cubic millimeter in 83% (20/24), chronic course 12% (3/24), no death by any cause, the lab studies without immunological alterations. In the adult patients relation female/male was of 3 to 1 (48/16), major bleeding 23% (15/64), platelet count less than 20,000 per cubic millimeter in 43% (28/64), chronic course 23% (15/64), death by hemorrhage 3% (2/64), nonrelated deaths 8% (5/64), only one patient had positive autoimmune panel without systemic autoimmune disease. Initial treatment with MPD in 45 patients, 8 evolved to chronic disease (18%) and was 7 deaths; 43 patients received PDN as initial treatment, 6 evolved to chronic disease (14%) and had not fatalities in this group. Refractory to steroids patients from both groups received other treatments: 12 (2 children) splenectomy with 8 in complete response, 2 (one child) with chronic disease in complete remission with azathioprine; and 2 deaths without any response; 2 patients did not accept splenectomy and are receiving azathioprine with complete response. Thirteen patients received platelet transfusions, 6 evolved to chronic disease and 7 deaths: 2 by hemorrhage and 5 by non related causes, mainly sepsis. Conclusions: similar epidemiology that is reported in the world; minor frequency of immunological alterations; the majority of patients had remissions with initial treatment and in the evolution to chronic disease it does not concern the initial treatment, but platelet transfusions do; greater mortality of the MPD arm due to a more aggressive disease.

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A Comparison of an Individualized and Weight-Based Opioid Protocols for the Treatment of Vaso-Occlusive Episodes in the Emergency Department

Blood ◽

10.1182/blood.v128.22.3674.3674 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3674-3674

Author(s):

Paula J Tanabe ◽

Regina D. Crawford ◽

Susan Silva ◽

Jeffrey A. Glassberg ◽

Christopher Miller ◽

...

Keyword(s):

Emergency Department ◽

Medical Record ◽

Research Funding ◽

Site Effects ◽

Assisted Ventilation ◽

Research Staff ◽

Pain Scores ◽

Ed Visits ◽

Secondary Outcomes ◽

Standard Weight

Abstract Introduction: Vaso-occlusive episodes are the most common complication experienced by individuals with sickle cell disease (SCD). Treatment in an emergency department (ED) is often required and significant variability in care exists. In 2014, NHLBI published evidence based recommendations suggesting treatment with either an individualized opioid dosing or standard weight-based protocol; however the supporting evidence grade was Consensus - Panel Expertise. As outlined in the results section, the aim of this project was to compare change in pain scores, patient safety and system utilization variables between patients randomized to an individualized or weight based (standard) dosing protocol for treatment of VOC from arrival to discharge in an ED setting. Methods: A randomized controlled trial was conducted in two EDs (OH and NY). Adults with SCD were eligible for inclusion and recruited during a hospitalization, clinic visit or at the end of an ED visit. Patients were randomized to treatment with an individualized opioid dosing protocol (developed by the SCD physician based on patients' prior opioid use) or standard weight based protocol. Both protocols were supported by the NHLBI recommendations for treatment of VOE (2014) to include repeat dosing. Protocols were made available on the electronic medical record for future ED visits (up to five visits/patient), should they occur. ED physicians were informed of the protocol and ordered analgesics. Research staff was notified when ED visits occurred for enrolled patients and obtained assessments of pain (0-100 cm VAS) every 30 minutes from placement in the ED to one of 3 study endpoints: 1) 6 hours; 2) decision to admit to the hospital; 3) discharge home. The unit of analysis was the ED visit rather than patient. The primary outcome was change in pain score from arrival to study endpoint. Research staff reviewed the medical record 30 days after the ED visit to determine secondary outcomes of hospital admission, re-admission and new ED visits within 72 hours, 7 and 30 days post the index ED visit. The medical record was reviewed for administration of narcan, intubation, or assisted ventilation. A hierarchical linear mixed effects model adjusting for nested patient and site effects were used to test for a difference in the mean pain change scores in the treatment arms. Generalized Linear Models adjusting for nested patient and site effects were performed to evaluate differences in the dichotomized secondary outcomes. Results: 106 patients enrolled in the study with 52 patients (sites: 25 OH, 27 NY) contributing a total of 126 ED visits over 12 months. Among the 52 patients with visits, the median number of ED visits/patient was 2.0, 58% were male, and the median age was 27 years (range: 21 to 60). No patients in either treatment arm required narcan, intubation, or assisted ventilation. Pain change: Mixed effect model adjusted mean ± standard deviation, higher positive score = greater pain reduction; *Fisher's Exact Test result due to low cell frequency. Conclusions: An individualized opioid dosing protocol resulted in a larger reduction in pain scores and lower hospital admission rate among patients with SCD treated for VOE in two EDs when compared to treatment with a weight-based opioid protocol. However, there was a tendency for more frequent ED re-visits within 72 hours, 7 and 30 days among patients in the individualized opioid dosing protocol. A pragmatic RCT with a larger and more heterogeneous sample of patients and ED settings is required to provide definitive evidence to guide treatment of VOE. Table 1. Table 1. Disclosures Tanabe: NHLBI: Research Funding. Bosworth:WestMeadVaco: Research Funding; CVS carematix: Consultancy; Improved Patient Outcomes: Research Funding; Johnson & Johnson: Consultancy, Research Funding; Genentech: Consultancy; sanofi: Honoraria, Research Funding; Pharma Foundation: Research Funding.

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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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Regulation of thrombopoiesis: effects of the degree of thrombocytopenia on megakaryocyte ploidy and platelet volume

Blood ◽

10.1182/blood.v70.1.177.177 ◽

1987 ◽

Vol 70 (1) ◽

pp. 177-185 ◽

Cited By ~ 89

Author(s):

L Corash ◽

HY Chen ◽

J Levin ◽

G Baker ◽

H Lu ◽

...

Keyword(s):

Bone Marrow ◽

Platelet Count ◽

Immune Thrombocytopenia ◽

Temporal Relationship ◽

Recovery Phase ◽

Severe Thrombocytopenia ◽

Detectable Change ◽

Platelet Volume ◽

Murine Bone Marrow ◽

Ploidy Class

Abstract We have established a murine model and techniques with which to serially study thrombocytopoiesis after induction of experimental immune thrombocytopenia of variable severity and duration. Bone marrow megakaryocyte ploidy distribution was determined by using unfractionated bone marrow, a polyclonal megakaryocyte-specific probe, and two-color, fluorescence-activated flow cytometry. With these techniques, the modal megakaryocyte ploidy class in normal murine bone marrow was 16N. Serial studies of bone marrow megakaryocyte ploidy after the induction of acute, severe thrombocytopenia (platelet count, less than 0.05 X 10(6) microL) demonstrated no detectable change in the ploidy distribution at 12, 24, and 36 hours after the onset of thrombocytopenia. At 48 hours, the modal ploidy class shifted from 16N to 32N, and the 64N class increased significantly (P less than .001). The ploidy distribution returned to normal 120 hours after the onset of thrombocytopenia. A lesser degree of thrombocytopenia (platelet count reduction to 0.100 to 0.200 X 10(6)/microL) delayed the modal ploidy class shift from 16N to 32N until 72 hours after the onset of thrombocytopenia. Chronic, severe thrombocytopenia (platelet count, less than 0.05 X 10(6)/microL for seven days) resulted in a modal ploidy class shift from 16N to 32N during the thrombocytopenic phase and an enhanced increase in the 64N megakaryocyte class during the recovery phase. Mean platelet volume (MPV) was simultaneously measured on isolated total platelet populations after induction of thrombocytopenia. MPV was significantly increased (P less than .001) as early as eight hours after the onset of acute, severe thrombocytopenia, 40 hours before a shift in the ploidy distribution. Mild thrombocytopenia (platelet count reduction to 0.400 X 10(6)/microL) was not associated with a ploidy shift but did result in a significantly increased MPV (P less than .001). These studies demonstrate that the temporal relationship and magnitude of the effects of thrombocytopenia upon megakaryocyte ploidy distribution are dependent upon the degree and the duration of the thrombocytopenic stimulus and that the effects of experimental thrombocytopenia on platelet volume and megakaryocyte ploidy are dissociated.

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A Risk Model for Thrombocytopenia Requiring Platelet Transfusion After Cytotoxic Chemotherapy

Blood ◽

10.1182/blood.v92.2.405 ◽

1998 ◽

Vol 92 (2) ◽

pp. 405-410 ◽

Cited By ~ 93

Author(s):

J.Y. Blay ◽

A. Le Cesne ◽

C. Mermet ◽

C. Maugard ◽

A. Ravaud ◽

...

Keyword(s):

Risk Factors ◽

Platelet Count ◽

High Risk ◽

Risk Model ◽

Univariate Analysis ◽

Cytotoxic Chemotherapy ◽

Phase Iii ◽

Severe Thrombocytopenia ◽

Increased Risk ◽

Platelet Transfusions

Abstract Severe thrombocytopenia is a rare but life-threatening side effect of cytotoxic chemotherapy for which risk factors are not well known. Our objective was to delineate a risk model for chemotherapy-induced thrombocytopenia requiring platelet transfusions in cancer patients. Univariate and multivariate analysis of risk factors for chemotherapy-induced thrombocytopenia requiring platelet transfusions were performed on the cohort of the 1,051 patients (CLB 1996) treated with chemotherapy in the Department of Medicine of the Centre Léon Bérard (CLB) in 1996. In univariate analysis, performance status (PS) greater than 1, platelet count less than 150,000/μL at day 1 (d1) before the initiation of chemotherapy, d1 lymphocyte count ≤700/μL, d1 polymorphonuclear leukocyte count less than 1,500/μL, and the type of chemotherapy (high risk v others) were significantly associated (P < .01) with an increased risk of severe thrombocytopenia requiring platelet transfusions. Using logistic regression, d1 platelet count less than 150,000/μL (odds ratio [OR], 4.3; 95% confidence interval [CI], 1.9 to 9.6), d1 lymphocyte counts ≤700/μL (OR, 3.37; 95% CI, 1.77 to 6.4), the type of chemotherapy (OR, 3.38; 95% CI, 1.77 to 6.4), and PS greater than 1 (OR, 2.23; 95% CI, 1.22 to 4.1) were identified as independent risk factors for platelet transfusions. The observed incidences of platelet transfusions were 45%, 13%, 7%, and 1.5% for patients with ≥3, 2, 1, or 0 risk factors, respectively. This model was then tested in 3 groups of patients treated with chemotherapy used as validation samples: (1) the series of 340 patients treated in the CLB in the first 6 months of 1997, (2) the prospective multicentric cohort of 321 patients of the ELYPSE 1 study, and (3) the series of 149 patients with non-Hodgkin's lymphoma treated in the CLB within prospective phase III trials (1987 to 1995). In these 3 groups, the observed incidences of platelet transfusions in the above-defined risk groups did not differ significantly (P > .1) from those calculated in the model. This risk index could be useful to identify patients at high risk for chemotherapy-induced thrombocytopenia requiring platelet transfusions.

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Association of Interleukin-18 Gene Polymorphism with Severity of Chronic Immune Thrombocytopenia (ITP).

Blood ◽

10.1182/blood.v116.21.3693.3693 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3693-3693

Author(s):

Takayuki Saitoh ◽

Norihiko Moriyama ◽

Tomonori Takani ◽

Takeki Mitsui ◽

Takumi Hoshino ◽

...

Keyword(s):

Platelet Count ◽

Immune Thrombocytopenia ◽

Initial Diagnosis ◽

Severe Thrombocytopenia ◽

Interleukin 18 ◽

Single Nucleotide ◽

Chronic Itp ◽

Significant Difference ◽

Haplotype Frequencies ◽

And Control

Abstract Abstract 3693 Introduction: Immune thrombocytopenia (ITP) is a chronic acquired organ-specific autoimmune disorder characterized by the production of antibodies against antigens on the membranes of platelets. Several cytokine studies have shown Th1 polarization in ITP patients. Interleukin-18 (IL-18) plays an important role in Th1 and Th2 immune response. Recent studies showed that single-nucleotide promoter polymorphisms influence the transcriptions of IL-18 mRNA. IL-18 polymorphism has been implicated in autoimmunity, including Crohn's disease, rheumatoid arthritis, and asthma. We examined the single nucleotide polymorphisms (SNPs) in the promoter regions of the IL-18 genes in patients with ITP, and analyzed the relationship between IL-18 SNPs and clinical features. Patients and Methods: One hundred patients (male/female; 22/78, median age; 54.5) diagnosed as chronic ITP and 151 healthy controls were included. Chronic ITP was defined as thrombocytopenia (platelet count < 100×109/L) persisting greater than 12 months, normal or increased marrow megakaryocytes, and no secondary immune or non-immune abnormality that could account for the thrombocytopenic state. ITP with severe thrombocytopenia was defined as thrombocytopenia (platelet count < 10×109/L) at presentation of ITP. The response criteria of the ITP International Working Group was used. A complete response (CR) is defined as any platelet count of at least 100×109/L, and a response (R) was defined as any platelet count between 30 and 100×109/L and at least doubling of the baseline count. Allparticipants gave written informed consent about the study. Genomic DNA was isolated from peripheral blood using the DNA Kit (QIAGEN, Hilden, Germany). An allele-specific polymerase chain reaction was used to analyze polymorphism in IL-18 –607A/C and -137G/C. Genotype and allele frequencies were compared between the study groups using Χ2-test. The characteristics and laboratory features of the ITP patients with each IL-10 promoter polymorphism were compared using X2-tests and student t-tests. Probability values <0.05 were considered statistically significant. Results: The platelet count was at an initial diagnosis ranged from 1×109/L to 98 ×109/L, with a median of platelet count of 15×109/L. Thirty-five patients (35%) had severe thrombocytopenia. Steroid treatment was given to 68 patients (68%), while splenectomy was used in 11 patients (11%).The frequencies of the genotypes were as follows: AA (34%), AC (57%), and CC (9%) for -607; GG (77%), GC (21%), and CC (2%) for -137 loci. The frequencies of each haplotype were as follows: C-G/C-G haplotype (9%), A-G/C-G haplotype (47%), A-C/C-G haplotype (10%), A-G/A-G haplotype (21%), A-G/A-C haplotype (11%) and A-C/A-C haplotype (2%). No significant differences in the genotype or haplotype frequencies demonstrated between chronic ITP patients and control group. However, patients with -137CC genotypes showed severe thrombocytopenia at initial diagnosis compared to those with -137GG/GC genotypes (5×109/L vs. 22×109/L, p=0.002). Furthermore, patients with A-C/A-C haplotype showed severe thrombocytopenic state (5×109/L vs. 22×109/L, p=0.002) compared to those without A-C/A-C haplotype. No significant difference of treatment response was observed according to IL-18 polymorphism. Conclusion: No significant differences in the genotype or haplotype frequencies demonstrated between chronic ITP patients and control. However, -137CC genotypes or AA/CC haplotype was associated with severity of chronic ITP. Our data suggest that the group with low IL-18 inducibility (i.e. -137CC genotype, A-C/A-C haplotype) may have more severe thrombocytopenia. Disclosures: No relevant conflicts of interest to declare.

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The Cytokine Polymorphisms Affect the Severity of Thrombocytopenia at Diagnosis in Chronic Immune Thrombocytopenia.

Blood ◽

10.1182/blood.v120.21.2194.2194 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2194-2194

Author(s):

Takayuki Saitoh ◽

Chiaki Ushie ◽

Atsushi Iwasaki ◽

Norihiko Moriyama ◽

Tomonori Takani ◽

...

Keyword(s):

Polymerase Chain Reaction ◽

Platelet Count ◽

Clinical Features ◽

Immune Thrombocytopenia ◽

Steroid Treatment ◽

Severe Thrombocytopenia ◽

Bleeding Tendency ◽

Chain Reaction ◽

Chronic Itp ◽

Polymerase Chain

Abstract Abstract 2194 Introduction: The severity of immune thrombocytopenia (ITP) depends on the degree of the thrombocytopenia and the extent of bleeding. Some investigators have reported the association between the thrombocytopenia and cytokine dysregulation in ITP. We investigated the association between the severity of thrombocytopenia at diagnosis in ITP patients and several cytokine polymorphisms, including IL-10-1082A/G, -819T/C, -592A/C, IL-17F-7488T/C and IL-18-607A/C, −137G/C. Patients and methods: We examined 102 patients (male/female, 24/78; median age, 42) diagnosed with chronic ITP. The definition, response criteria, including complete response (CR)and response (R), loss of CR,and “corticosteroid-dependence” were assessed according to the criteria of the ITP International Working Group. ITP with severe thrombocytopenia (ST group)was defined as thrombocytopenia (platelet count < 10×109/L) at the initial diagnosis of ITP. Genotyping of IL-10 (rs1800870 − 1082 A/G, rs1800871 − 819 T/C, and rs1800872 − 592 A/C) and IL-17F (rs763780, 7488 T/C) polymorphisms were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and the genotyping of the IL-18 polymorphism (rs187238 −137G/C and rs1946518−607 A/C) was determined by the allelic specific polymerase chain reaction technique. To confirm the accuracy of the assay, amplification products of several individuals were sequenced using an ABI Prism Genetic Analyzer. Genotype and allele frequencies were compared between the study groups using χ2-test. The characteristics and laboratory features of ITP patients with each polymorphisms were compared using χ2-tests and student t-tests. Odds ratios (OR) and 95% confidence intervals (CIs) were estimated for each study. All patients were provided written information about the study. This study was approved by the Institutional Research Board of Gunma University Hospital. Results: Clinical features of chronic ITP: The platelet count ranged from 1×109/L to 98×109/L with a mean of platelet count of 32×109/L at the initial diagnosis. Fifty seven patients (49%) had bleeding tendency. Steroid treatment was given to 68 patients (66.7%) and eradication of Helicobacter pylori (H. pylori) was performed in 32 patients (31.4%), while splenectomy was performed in only 11 patients (10.8%). Clinical features of ST group vs. non-ST group in chronic ITP: Of these 102 patients, 17 (16.7%) had severe thrombocytopenia (platelet count < 10×109/L) (ST group). ST group were significantly older (ST group: median 59 years vs. non-ST group: 41 years, p<0.01) and had more severe bleeding tendency (ST group: 100% vs. non-ST group: 54%, p<0.0001). Steroid treatment was frequently given to ST group than to non-ST group (ST group: 100% vs. non-ST group: 59.5%, p<0.001). Though the response to corticosteroids treatment was not significantly different between ST group and non-ST group (CR rate, ST group: 50% vs. non-ST group: 51.0%, p=0.94), corticosteroid-dependent patients in ST group was significantly higher than in non-ST group (76.9% vs. 25.3%, p<0.005). Polymorphism study of ST group vs. non-ST group in chronic ITP: The frequencies of genotypes of cytokines in patients with chronic ITP according to the definition of criteria of ST were as follows: AA (93.3% vs. 97.1%) and AG (6.7% vs. 2.9%, p=0.48) for IL-10–1082; TT (46.7% vs. 33.3%), TC (33.3% vs.55 %) and CC (20% vs. 11.7%) for IL-10–819; AA (46.7% vs. 33.3%), AC (33.3% vs.55 %) and CC (12.2% vs. 11.5%) for IL-10–592; TT (100% vs. 81%) and TC (0% vs. 19%) for IL-17F; GG (82.4% vs. 74.4%), GC (17.6% vs. 23.2%) and CC (0% vs. 2.4%) for IL-18–137; AA (35.3% vs. 34.1%), AC (58.8% vs. 53.7%) and CC (5.9% vs 12.2%) for IL-18–607 loci (ST group vs. non-ST group, respectively). No significant difference was observed between ST group and non-ST group according to IL-10–1082A/G, −819T/C, −592A/C, and IL-18–607A/C, −137G/C polymorphism. However, the numbers of IL-17F 7488TT genotype (higher function type) in ST group were significantly higher than in non-ST group (ST group: 100% vs. non-ST group: 81% p<0.05). Conclusion: These findings suggest that severe thrombocytopenia at diagnosis have an impact of bleeding tendency and corticosteroid-dependency of chronic ITP. Furthermore, IL-17F polymorphism may affect the severity of thrombocytopenia of chronic ITP. Disclosures: No relevant conflicts of interest to declare.

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