Romiplostim in Management of the Thrombocytopenic Surgical Patient

Abstract Background: The thrombopoietin (TPO) mimetics are FDA-approved for the treatment of chronic immune thrombocytopenia (ITP) and have the potential for use in several additional clinical settings. At our institution, the TPO-mimetic romiplostim has been used to boost platelet counts in the perioperative setting. Objective: Use of romiplostim for perioperative thrombocytopenia was examined with regards to patient characteristics, dosing and duration of use, success in achieving platelet counts high enough for surgery, and clinical outcomes. Methods: A retrospective review of patients with thrombocytopenia who received romiplostim prior to an operative intervention in 2010-2014 was performed. Inclusion criteria included age 18 or older, thrombocytopenia (baseline platelet count <150,000/uL), administration of at least one dose of romiplostim, and documentation of platelet counts before and after administration of romiplostim. Results: 18 patients undergoing 22 procedures were included. Median age at surgery was 61 years (range 47-74). Etiologies of baseline thrombocytopenia (some patients had more than one) included mild ITP (not on romiplostim at baseline) in 8 patients, liver disease in 12 patients (5 with hepatitis C, 2 with hepatitis B, 2 with alcoholic cirrhosis, 1 with fatty liver, and 2 with hepatocellular carcinoma), hematologic malignancy in 4 patients (2 with lymphoma, 1 with MDS, and 1 with myeloma) and drug-related thrombocytopenia in 3 patients (2 chemotherapy induced and 1 antibiotic-related). 3 patients were Jehovah's witnesses. Median platelet count at time of romiplostim initiation was 46,500/uL (range, 11,000-120,000) and median starting dose of romiplostim was 2.5 mcg/kg (range 1-7.5). Patients remained on romiplostim for a median of 5 weeks prior to surgery (receiving doses on average once weekly) and while on therapy the dose of romiplostim was changed on average one time. Procedures performed included 5 orthopedic surgeries (3 total hip replacements, 1 total knee replacement, and 1 open reduction/internal fixation), 3 open cardiac surgeries, 2 cholecystectomies, 2 EGD/colonoscopies, 2 biopsies of masses, and 1 each of: angioplasty and stenting, dental extraction, eyelid resection, liver biopsy, lung resection, prostate surgery, spinal surgery, and a TACE procedure. Median platelet count at the time of surgery was 144,000/uL (range 28,000-370,000). All patients had a rise in platelet count between time of initiation of romiplostim and time of surgery (see Figure); median rise was 97,500/uL (range 17,000-252,000). There were no surgical delays or cancellations for thrombocytopenia. Four bleeding events occurred: one thigh hematoma (at a platelet count of 185,000/uL), one episode of hematemesis (at a platelet count of 98,000/uL), one episode of melena (at a platelet count of 88,000/uL), and one persistent oozing from a tooth extraction (platelets 82,000/uL). Four patients received perioperative platelet transfusions and 3 received perioperative red cell transfusions. One patient developed a Foley-catheter associated clot after prostate surgery. No other thromboembolic events were recorded during the time of romiplostim administration and for up to 30 days following the last dose. Conclusions: 18 patients with thrombocytopenia due to several conditions (primarily ITP and liver disease) received romiplostim prior to 22 surgical procedures. Romiplostim prompted a rise in platelet count in all patients, allowing all planned procedures to be performed without delays or cancellations for thrombocytopenia. Few patients received perioperative platelet transfusions. Four bleeding episodes occurred (none in the context of significant thrombocytopenia), and one patient developed a clot (likely procedure-related). Romiplostim may be of clinical utility in the preoperative management of thrombocytopenic patients, and further trials are indicated. Figure 1 Figure 1. Disclosures Off Label Use: Romiplostim (Nplate) used for periprocedural management of thrombocytopenia. Kuter:Amgen: 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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Characteristics and Financial Impact of Potentially Inappropriate Platelet Transfusion in the Inpatient Hospital Setting

Blood ◽

10.1182/blood-2019-125949 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2096-2096

Author(s):

Eric Mou ◽

Colin Murphy ◽

Jason Hom ◽

Lisa Shieh ◽

Neil Shah

Keyword(s):

Platelet Count ◽

Patient Care ◽

Platelet Transfusion ◽

Bypass Surgery ◽

Hospital Setting ◽

Financial Impact ◽

Platelet Counts ◽

Cardiac Bypass ◽

Platelet Defects ◽

Platelet Transfusions

Introduction Platelets are transfused prophylactically to prevent hemorrhage in a variety of patient populations. However, guidelines indicate that prophylactic platelet transfusions in patients with platelet counts above 50k/uL are usually not indicated, with notable exceptions including those undergoing neurological or cardiac bypass surgery. Common minor procedures such as paracentesis, central line placement, and lumbar puncture have been safely performed at platelet counts below 50k/uL. Despite this evidence, our institution incurred approximately 10 million dollars (USD) in direct platelet costs in 2017, with nearly 40% of platelet transfusions are occurring when the patient's platelet count exceeded 50k/uL. Given the significant financial impact of, and potential adverse effects associated with inappropriate platelet transfusion, we implemented a best practice advisory (BPA) in our electronic medical record (EMR) in order to better characterize patterns of platelet transfusion orders in patients with platelet counts >50k/uL. Methods An EMR-embedded BPA was activated in the inpatient hospital setting of a large, tertiary care academic medical center on May 1, 2019, and triggered whenever a platelet transfusion order was placed on an admitted patient whose most recent documented platelet count was >50k/ul. To inform the comparative impact of BPA alerts on provider behavior, alerts were randomized at the patient level to trigger either in standard or silent fashion. For standard alerts, the BPA appeared on-screen, informing the provider that their platelet transfusion order was potentially inappropriate and citing supportive evidence. Providers had the option of following or overriding the alert (Figure 1). In case of alert override, a pre-specified or free text justification was requested. Pre-specified options included upcoming neurosurgery, cardiac bypass surgery, known qualitative platelet defects, or patients taking antiplatelet drugs. Charge data were based on charges for platelet transfusion orders as listed in the hospital charge master. Results From May 1, 2019 to July 30, 2019, the alert fired 181 times (Figure 2). Alerts were silently triggered in 64 (35%) cases. Of the 117 active alerts, 23 (20%) were followed and 94 (80%) were overridden. The most common reasons for alert override included prophylactic transfusions ahead of non-cardiac and non-neurosurgical operations (18%), upcoming cardiac bypass surgery (18%), qualitative platelet defects (12%), active central nervous system (CNS) bleeding (12%), and active non-CNS bleeding (7%). The estimated cost savings associated with followed alerts was $18,170 USD. Discussion Our BPA was effective in reducing instances of platelet transfusion orders by 20% over a three-month period, translating to an estimated annual savings of nearly $70,000 USD in hospital charges. Conversely, the 80% alert override rate indicates that platelet transfusion in patients with platelet counts >50k/uL remains common, occurring in a variety of contexts. Potentially appropriate reasons for platelet transfusions included orders in the setting of cardiovascular bypass surgery, active CNS bleeding, or qualitative platelet defects, representing circumstances in which platelet thresholds are often set higher than 50k/uL. Alternatively, 25% of alert overrides occurred in potentially inappropriate contexts, including patients undergoing non-cardiovascular/non-neurosurgical procedures and patients with non-CNS active bleeding, settings where routinely targeting a platelet threshold >50k/uL is not supported by evidence. As a result of our study's randomized design, future directions include comparative analyses between patient care encounters in which alerts were silently versus visibly triggered, allowing for rigorous determination as to whether providers' interaction with our BPA influences subsequent rates of potentially inappropriate platelet utilization as compared to a control group. Overall, our findings show that platelets are frequently ordered in potentially inappropriate settings, and that reducing these orders imparts significant financial savings. These results provide an impetus for interventions directed at educating providers on appropriate platelet ordering practices, in order to further reduce unnecessary expenditures and optimize patient care. Disclosures No relevant conflicts of interest to declare.

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Thrombopoietin Receptor Agonists in Patients with Chronic Liver Disease

Seminars in Thrombosis and Hemostasis ◽

10.1055/s-0040-1715451 ◽

2020 ◽

Vol 46 (06) ◽

pp. 682-692

Author(s):

Saro Khemichian ◽

Norah A. Terrault

Keyword(s):

Liver Disease ◽

Chronic Liver Disease ◽

Invasive Procedure ◽

Bleeding Risk ◽

Chronic Liver ◽

Bleeding Complications ◽

Invasive Procedures ◽

Platelet Counts ◽

Receptor Agonists ◽

Platelet Transfusions

AbstractThrombocytopenia is one of the most common hematologic complications in cirrhosis. Despite limited data linking platelet count and bleeding risk in patients with cirrhosis, the use of platelets transfusions for invasive procedures has been a common practice. Recently, thrombopoietin (TPO) receptor agonists have been approved for use in patients with chronic liver disease (CLD) undergoing invasive procedures. The aim of this study was to review current literature on bleeding risk in patients with cirrhosis and the use of platelet transfusions and TPO receptor agonists in the context of invasive procedures. PubMed search was conducted to find articles relating to cirrhosis, thrombocytopenia, and new novel treatments for this condition. Search terms included CLD, cirrhosis, thrombocytopenia, bleeding, thrombosis, coagulopathy, hemostasis, and TPO receptor agonists. Romiplostim, eltrombopag, avatrombopag, and lusutrombopag are approved TPO receptor agonists, with avatrombopag and lusutrombopag specifically approved for use in patients with CLD undergoing invasive procedures. In patients with platelet counts < 50,000/mm3, avatrombopag and lusutrombopag increased the platelet counts above this threshold in the majority of treated patients and reduced the frequency of platelet transfusions. At the approved doses, incidence of thrombosis was not increased and therapies were well tolerated. Studies were not powered to assess whether risk of bleeding complications was reduced and the fundamental question of whether correction of thrombocytopenia is warranted in patients undergoing invasive procedures remains unanswered. The use of TPO receptor agonists has resulted in less requirement for platelet transfusions. In patients with cirrhosis undergoing invasive procedures for whom platelet transfusion is planned, TPO receptor agonists are an alternative and avoid the risks associated with transfusions. However, there is need for a thoughtful approach to manage bleeding risk in patients with cirrhosis undergoing procedures, with the consideration of a comprehensive hemostatic profile, the severity of portal hypertension, and the complexity of the invasive procedure to guide decisions regarding transfusions or use of TPO receptor agonists.

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Platelet Counts Following Eltrombopag Discontinuation in Patients with Chronic Immune Thrombocytopenic Purpura.

Blood ◽

10.1182/blood.v114.22.3517.3517 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3517-3517

Author(s):

Gregory Cheng ◽

Michael Tarantino ◽

Terry Gernsheimer ◽

Oliver Meyer ◽

Andres Brainsky ◽

...

Keyword(s):

Platelet Count ◽

Immune Thrombocytopenic Purpura ◽

Research Funding ◽

Rescue Medication ◽

Study Medication ◽

Bleeding Events ◽

Thrombocytopenic Purpura ◽

Baseline Platelet Count ◽

Platelet Counts ◽

Transient Decrease

Abstract Abstract 3517 Poster Board III-454 BACKGROUND Eltrombopag (PROMACTA®; GlaxoSmithKline, Collegeville, PA, USA) is an oral, small molecule (565 Da), thrombopoietin receptor agonist that has been approved in the United States for the treatment of patients with chronic immune thrombocytopenic purpura (ITP). It is also being studied in thrombocytopenic patients with chronic liver disease, hepatitis C, myelodysplastic syndromes, and cancer. Withdrawal of treatments that stimulate platelet production may theoretically result in recurrent thrombocytopenia below pretreatment levels (below baseline). OBJECTIVE: To determine whether worsening of thrombocytopenia (ie, platelet count decrease below baseline) occurs after discontinuation of eltrombopag in patients with chronic ITP. METHODS: The lowest median platelet counts during the first 4 weeks posttherapy were compared with median baseline platelet counts. Data from 369 patients treated in 3 randomized, double-blind, placebo-controlled studies were analyzed: TRA100773A and TRA100773B were 6-week studies, and RAISE was a 6-month study. For all 3 studies, a baseline platelet count <30,000/μL was required. Platelet counts, bleeding events, and the use of ITP medication were examined in the 4 weeks following the discontinuation of eltrombopag or placebo. A transient decrease in platelet counts (ie, worsening of thrombocytopenia) was defined as a platelet count below 10,000/μL and at least 10,000/μL below each patient's baseline platelet count (Bussel N Eng J Med 2006). RESULTS: Using pooled data from the 3 studies, no decreases below baseline median platelet counts (placebo, 16,300/μL; eltrombopag, 16,000/μL) were observed compared to the lowest median platelet counts within the first 4 weeks posttherapy (placebo, 14,000/μL; eltrombopag, 17,000/μL). Across the pooled studies, a total of 10/128 (8%) of placebo-treated patients and 20/241 (8%) of eltrombopag-treated patients had a transient decrease in platelet counts in the 4 weeks following discontinuation or interruption of treatment. None of the 10 placebo-treated patients had bleeding events associated with posttreatment platelet nadirs. Three of the 20 eltrombopag-treated patients had bleeding events and/or rescue treatment associated with the platelet nadir in the 4-week posttreatment period. One patient discontinued eltrombopag after achieving platelet counts >200,000/μL following on-therapy rescue medication (corticosteroid 0.5 mg/kg/day); 9 days after discontinuing study medication, the patient had grade 1 gum bleeding and resumed daily corticosteroids at an increased dose. The second patient had grade 3 menorrhagia and was administered vincristine (patient had a history of similar symptoms). The third patient had Henoch-Schoenlein purpura, interrupted eltrombopag due to platelet counts >400,000/μL, and 7 days after holding eltrombopag had a platelet count of 2000/μL, experienced grade 1 mouth hemorrhage and grade 2 petechiae, and did not require rescue medication. The patient continued in the study for the full 6 months and following permanent discontinuation of eltrombopag, this patient did not experience a transient decrease in platelet counts or any bleeding. CONCLUSION: Across 3 placebo-controlled studies, the incidence of transient decreases in platelet counts following discontinuation or interruption of study medication was similar in patients receiving eltrombopag or placebo. Therefore, these decreases may be unrelated to study medication and may represent normal fluctuations in platelet counts in patients with chronic ITP. Transient platelet count decreases were generally not associated with bleeding events. Disclosures: Cheng: GlaxoSmithKline: Research Funding. Tarantino:GlaxoSmithKline: Speakers Bureau; Lundbeck: Speakers Bureau; Baxter: Membership on an entity's Board of Directors or advisory committees. Gernsheimer:GlaxoSmithKline: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Meyer:GlaxoSmithKline: Consultancy, Honoraria. Brainsky:GlaxoSmithKline: Employment. Stone:GlaxoSmithKline: Employment.

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Evaluation of Bleeding-Related Episodes in Patients with Chronic Immune Thrombocytopenia (ITP) Treated with Romiplostim in Two Phase 3 Placebo-Controlled Clinical Trials.

Blood ◽

10.1182/blood.v114.22.891.891 ◽

2009 ◽

Vol 114 (22) ◽

pp. 891-891 ◽

Cited By ~ 1

Author(s):

Ilene Ceil Weitz ◽

Miguel A Sanz ◽

David H. Henry ◽

Martin Schipperus ◽

Bertrand Godeau ◽

...

Keyword(s):

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Rescue Medication ◽

Bleeding Event ◽

Bleeding Events ◽

Phase 3 ◽

Advisory Committees ◽

Platelet Counts ◽

Chronic Itp

Abstract Abstract 891 Background: Chronic Immune thrombocytopenia (ITP) is characterized by low platelet counts and increased risk of bleeding. Rescue medications used to treat or prevent bleeding produce transient increases in platelet counts but may be associated with additional toxicities and costs. Romiplostim, approved for the treatment of adult chronic ITP, is a TPO mimetic peptibody protein that increases platelet production. Previously published data from phase 3 romiplostim trials showed that despite the increased use of rescue medication in the placebo arm, patient (pt) incidence of bleeding was reduced in the romiplostim arm vs placebo arm: 15% vs 34% (p = 0.02) for bleeding of grade ≥2 severity and 7% vs 12% (p=0.36) for grade ≥3 severity. Objective: To evaluate the effects of romiplostim treatment on bleeding outcomes in the phase 3 placebo controlled studies in chronic ITP pts with and without previous splenectomy. Bleeding events were captured as adverse events making it difficult to identify a single event reported multiple times versus persistent or recurrent bleeding. Further, we have developed a composite endpoint, termed bleeding-related episodes (BREs), which combines bleeding events and rescue medication administration to account for use of rescue medications to prevent bleeding. Methods: Adults with chronic ITP and a mean baseline platelet count <30 × 109/L were eligible. The previously published studies were conducted separately in splenectomized and nonsplenectomized populations. Pts were randomized (2:1) to receive romiplostim or placebo by subcutaneous injection once weekly for 24 weeks, with dose adjustments to maintain platelet counts between 50-200 × 109/L. Rescue medications were permitted to treat or prevent bleeding and included immunoglobulins, platelet transfusions, corticosteroids, or an increase in dose or frequency of a concurrent ITP medication. A BRE was defined as an actual bleeding event and/or the use of rescue medication. To collapse related events into episodes, events (bleeding events and/or the use of rescue medication) that occurred concurrently or within 3 days of each other were considered a single BRE. Bleeding events beginning 7 or more days after the start of the initial bleeding event were considered a new BRE. To account for differences in time spent on-study, rates of BRE per 100 pt-weeks were calculated. Results: A total of 125 pts (41 placebo, 84 romiplostim) were enrolled in the two studies. Baseline characteristics were well-balanced between the placebo and romiplostim-treated groups. During the treatment period, the rate of BREs was lower in the romiplostim group than in the placebo group, and results were consistent between splenectomized and nonsplenectomized pts (Table). Across both studies, the rate of BREs was reduced by 55% in pts receiving romiplostim compared to those receiving placebo (95% CI, 41% to 65%). BREs were more frequent at platelet counts <50 × 109/L (Table). BREs associated with hospitalizations were less common among romiplostim- than placebo-treated pts, and occurred at platelet counts <50 × 109/L in 10 of 11 cases. Corticosteroids (58 romiplostim, 38 placebo) and immunoglobulins (30 romiplostim, 73 placebo), were the most commonly used rescue medications and the rate of BREs including immunoglobulins was reduced by 88% in pts receiving romiplostim compared to placebo. Conclusions: In adults with chronic ITP, romiplostim was associated with a significant reduction in BREs compared to placebo. There was a marked reduction in BREs requiring immunoglobulins in the romiplostim arm compared to the placebo arm. Results were comparable in splenectomized and nonsplenectomized populations. The platelet count for a BRE starting ≥1 day after a platelet count measurement was calculated from the 2 proximal weekly measurements. Disclosures: Weitz: Amgen Inc.: Speakers Bureau. Sanz:Amgen Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Henry:Amgen Inc.: Research Funding, Speakers Bureau; Orthobiotech: Research Funding, Speakers Bureau; Watson Pharma: Research Funding, Speakers Bureau. Schipperus:Amgen Inc.: Membership on an entity's Board of Directors or advisory committees. Godeau:Amgen Inc.: Consultancy, Research Funding; Laboratoire Français de Fractionnement et de Biotechnologies (LFB): Consultancy; Roche: Research Funding. Gleeson:Amgen Inc.: Consultancy, Research Funding. Danese:Amgen Inc.: Consultancy, Research Funding. Deuson:Amgen Inc.: Employment, Equity Ownership.

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Romiplostim For Thrombocytopenia in Patients with Hepatitis C (HCV)-Associated Liver Disease: Preliminary Report Of An Ongoing Clinical Trial

Blood ◽

10.1182/blood.v122.21.3555.3555 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3555-3555

Author(s):

Howard Liebman ◽

Laurie Hornor ◽

Tse-Ling Fong ◽

Casey O'Connell ◽

Ilene C Weitz

Keyword(s):

Clinical Trial ◽

Platelet Count ◽

Viral Load ◽

Liver Disease ◽

Phase I ◽

Phase Ii ◽

Hcv Treatment ◽

Platelet Counts ◽

Hcv Therapy ◽

Cirrhotic Patients

Abstract Background Thrombocytopenia (Tp) is frequently observed in individuals with advanced cirrhotic liver disease. Patients with HCV may develop Tp even in the absence of significant liver disease. Decreased thrombopoietin production may also contribute to the Tp. The current management of HCV infection includes the use of the Peg-interferon α (IFN) and ribavirin (RIB), which can induce a sustained viral remission in 40 to 50% of treated patients. However, Peg-INF is a known inhibitor of megakaryocyte growth and maturation and can result in treatment related Tp. Therefore, patients presenting with platelet counts <70,000/mcl are frequently excluded from treatment or often fail treatment due to the development of critically low platelet counts. With this understanding, we initiated a clinical trial of the thrombopoietin receptor agonist, romiplostim, in HCV cirrhotic patients with Tp to determine if platelet count can be increased to >100,000/mcl to allow for HCV treatment with Peg-INF/RIB. Methods This is a two phase clinical trial of HCV infected patients with Child-Pugh class A liver disease. All patients were required to have platelet counts <70,000/µl and have liver biopsy confirmed early cirrhosis. Phase I is a double-blind placebo controlled trial of romiplostim given up to 8 weeks to raise platelets to >100,000/mcl before initiating Peg-INF treatment. There are separate 1 to 1 randomizations for patients with platelets 70 to 50,000/µl and patients with platelets<50,000/mcl. Initial treatment dose is 1 µg/kg with weekly progressive increases in dose. For patients who failed to obtain platelet counts >100,000/µl by week 8, blind is terminated and placebo patients can enter the romiplostim arm. Phase II is a dose escalation study of romiplostim during Peg-INF/Rib treatment up to week 24 of HCV treatment. If patients are viral load negative by week 24, romiplostim treatment is held to see if the patients can sustain a safe platelet count with continued HCV therapy. If not, romiplostim is continued until completion of HCV treatment. A protocol amendment allowed the addition of HCV protease inhibitors for genotype 1a patients. Results At the time of this report 21 patients (7F/14M; mean age 54.9 yrs, range 28-72yrs) have been enrolled in this trial; 13 with platelets 70 to 50,000/µl (Mean 62,000/µl; range 55 to 70,000µl) and 8 with platelet counts<50,000/µl (Mean 35,000/µl; range 25-46,000/µl). 17 patients have completed Phase I; 2 patients are ongoing, 1 patient withdrew at wk 5 with no platelet response (Blind remains) and one patient was withdrawn at wk 2 when review of the pre-randomization ultrasound found evidence of an old partial portal thrombosis. Five patients failed to obtain a platelet count of >100,000/ul by wk 8; all on placebo and were rolled over to romiplostim. The mean romiplostim dose for patients completing Phase I with platelets 70 to 50,000/µl was 2.2 mcg/kg and 3.1 mcg/kg for patients with platelets of<50,000/µl. During the 8 wk course of romiplostim there were no SAEs and no change in HCV viral load. Eleven patients have successfully completed Phase II with 24 wks of HCV treatment; with 4 patients on HCV treatment at wks 21, 20, 13 and 9. One patient was withdrawn at wk 14 due to intractable pancytopenia. 7/11 (64%) were HCV viral load negative at wk 24 and continued to completion of their HCV treatment. The mean romiplostim dose for the 11 patients completing Phase II with HCV treatment was 7µg/kg (3 to 10µg/kg). Three major SAEs occurred during Phase II. A 61 y.o. female developed pancytopenia at wk 14 unresponsive to growth factor support with a hypocellular bone marrow. She had a slow recovery of counts over several months. A 63 y.o. female developed portal vein thrombosis at wk 22 of HCV therapy. Her platelet count was 92,000/µl. She was treated with LMW heparin, continued HCV treatment with romiplostim off study and was viral load negative at wk 44 of treatment. A 50 y.o. female had a sudden death at home at wk 20 of HCV therapy. She has a platelet count of 32,000/µl on a clinic visit the day before her death and her romiplostim dose was 10µg/kg. No autopsy was performed. Conclusion In this interim analysis of ongoing clinical trial, romiplostim appears well tolerated and effective in increasing platelet counts in HCV cirrhotic patients and can maintain a safe platelet count in the majority of patients during HCV antiviral therapy with Peg-INF/RIB. This study was funded by a grant from AMGEN. Disclosures: Liebman: Amgen: Research Funding. Off Label Use: A clinical trial of romiplostim to treat hepatitis C-related thrombocytopenia performed under an FDA IND.

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Thrombocytopenia in Patients with Gastric Varices and the Effect of Balloon-occluded Retrograde Transvenous Obliteration on the Platelet Count

Journal of Clinical Imaging Science ◽

10.4103/2156-7514.131743 ◽

2014 ◽

Vol 4 ◽

pp. 24 ◽

Cited By ~ 3

Author(s):

W. E. Saad ◽

W. Bleibel ◽

N. Adenaw ◽

C. E. Wagner ◽

C. Anderson ◽

...

Keyword(s):

Platelet Count ◽

Liver Disease ◽

Patient Survival ◽

International Normalized Ratio ◽

Gastric Varices ◽

Meld Score ◽

Disease Etiology ◽

Platelet Counts ◽

The Usa ◽

End Stage

Objectives: Gastric varices primarily occur in cirrhotic patients with portal hypertension and splenomegaly and thus are probably associated with thrombocytopenia. However, the prevalence and severity of thrombocytopenia are unknown in this clinical setting. Moreover, one-third of patients after balloon-occluded retrograde transvenous obliteration (BRTO) have aggravated splenomegaly, which potentially may cause worsening thrombocytopenia. The aim of the study is to determine the prevalence and degree of thrombocytopenia in patients with gastric varices associated with gastrorenal shunts undergoing BRTO, to determine the prognostic factors of survival after BRTO (platelet count included), and to assess the effect of BRTO on platelet count over a 1-year period. Materials and Methods: This is a retrospective review of 35 patients who underwent BRTO (March 2008–August 2011). Pre- and post-BRTO platelet counts were noted. Potential predictors of bleeding and survival (age, gender, liver disease etiology, platelet count, model for end stage liver disease [MELD]-score, presence of ascites or hepatocellular carcinoma) were analyzed (multivariate analysis). A total of 91% (n = 32/35) of patients had thrombocytopenia (<150,000 platelet/cm3) pre-BRTO. Platelet counts at within 48-h, within 2 weeks and at 30-60 days intervals (up to 6 months) after BRTO were compared with the baseline pre-BRTO values. Results: 35 Patients with adequate platelet follow-up were found. A total of 92% and 17% of patients had a platelet count of <150,000/cm3 and <50,000/cm3, respectively. There was a trend for transient worsening of thrombocytopenia immediately (<48 h) after BRTO, however, this was not statistically significant. Platelet count was not a predictor of post-BRTO rebleeding or patient survival. However, MELD-score, albumin, international normalized ratio (INR), and etiology were predictors of rebleeding. Conclusion: Thrombocytopenia is very common (>90% of patients) in patients undergoing BRTO. However, BRTO (with occlusion of the gastrorenal shunt) has little effect on the platelet count. Long-term outcomes of BRTO for bleeding gastric varices using sodium tetradecyl sulfate in the USA are impressive with a 4-year variceal rebleed rate and transplant-free survival rate of 9% and 76%, respectively. Platelet count is not a predictor of higher rebleeding or patient survival after BRTO.

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Treatment of Immune Thrombocytopenia (ITP) with Eltrombopag - Results of the 4 th Interim Analysis of the German Non-Interventional Trial RISA

Blood ◽

10.1182/blood-2021-146809 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3150-3150

Author(s):

Oliver Meyer ◽

Rudolf Schlag ◽

Thomas Stauch ◽

Bastian Fleischmann ◽

Marcel Reiser ◽

...

Keyword(s):

Platelet Count ◽

Interim Analysis ◽

Receptor Agonist ◽

Immune Thrombocytopenia ◽

Bleeding Complications ◽

Bleeding Events ◽

Interventional Trial ◽

Platelet Counts ◽

Thrombopoietin Receptor ◽

Thrombopoietin Receptor Agonist

Abstract Background: Immune thrombocytopenia (ITP) is an acquired autoimmune disorder with increased platelet destruction and impaired platelet production. Patients present with bleeding complications of various severity. Another common symptom of ITP is fatigue, which can severely affect patient's quality of life. Eltrombopag (EPAG) is an oral thrombopoietin receptor agonist, which is proved to be effective and safe in the treatment of ITP. In Europe, it is approved for the therapy of patients who were diagnosed with ITP at least 6 months ago and who have not responded to other treatments. Here we present data from the 4 th interim analysis of the RISA study. Methods: RISA is a prospective multicenter non-interventional trial in Germany. It was launched in December 2015, and it will be continued until December 2023. In accordance with the inclusion criteria, adults with persisting or chronic pITP (primary ITP) have been enrolled. Patients with pre-treatment could only be included if it was terminated 4 weeks prior to the patient's consent to participate in the study. Exclusion criteria comprised pregnancy, hepatitis C infection and severe aplastic anaemia. Dosage of EPAG and treatment of patients follows the SmPC and the routine of treating physicians. According to the study protocol, patient questionnaires must be completed at 0,1,3,6,9,12,18 and 24 months. Fatigue is assessed using the FACIT-F score, which includes a score range from 0 to 52, with score values <30 indicating severe fatigue. Statistical elaboration is predominantly descriptive. Calculations of confidence intervals and significance values are performed only for explorative purposes. Results: Data cutoff for this 4 th interim analysis was 23.02.2021. 275 patients were enrolled. 261 of them received at least one dose of EPAG and completed one post baseline assessment. Mean duration of participation was 5.2 years. Mean±SD age was 62.7±17.6 years. 54.8% of the patients were female. Median (range) duration of ITP at baseline was 5.3 (0.0-44.9) years. Comorbidity was present in 80.5% of all patients. 79 (28.7%) patients completed all scheduled visits before data cutoff. Median treatment duration was 395.0 days. Treatment with EPAG was carried out at a median dosage of 50 mg daily. In 255 patients, baseline platelet counts were available. The proportion of patients with a platelet count ≥50x10 9/L was 30.6% at baseline. With EPAG treatment, it increased to 75.4% within the first month (N=224) and to 89.0% within 24 months (N=73) from baseline. 12.6% of the patients who completed at least one assessment visit after baseline were pre-treated with the thrombopoietin receptor agonist romiplostim. Within this subgroup as well, platelet counts responded well to EPAG treatment. In 35.6% of patients, at least one bleeding event had occurred in the 12 months prior to baseline. During EPAG therapy, the incidence of bleeding events per patient year was reduced from 1.40 before baseline to 0.60 and 0.13 within the first and second treatment year respectively. This corresponds to a relative reduction in bleeding events of 57% and 91% respectively. Over the entire two years treatment period, the average incidence of bleeding events per patient year accounted for 0.44, which is 69% below the incidence at baseline. Bleeding events were mostly of low severity. (Tab.) Median FACIT-F score was 37.0 at baseline (N=202; mean 36.0±11.0) and 42.5 after 24 months (N=48; mean 38.1±12.1). This difference was not statistically significant. According to exploratory calculations, severity of fatigue was not correlated to platelet count, hemoglobin concentration or incidence of bleeding events. Discussion: In line with previously published randomized controlled trials (Birocchi et al. Platelets 2021), this non-interventional study confirmed the effectiveness of EPAG in adults with persistent or chronic ITP in a routine care setting. During treatment with EPAG, the prevalence and severity of thrombocytopenia, as well as the incidence of bleeding events, decreased. We could also confirm that fatigue is a significant issue in patients with ITP. A FACIT-F score of 37.0 is comparable to average score values in cancer patients (Montan et al. Value Health 2018). Under treatment with EPAG, we observed a decrease in fatigue that was clinically relevant but not statistically significant. Further research is needed to explore possible additional effects of EPAG, for example on fatigue. Figure 1 Figure 1. Disclosures Meyer: Swedish Orphan Biovitrum: Consultancy, Honoraria; Grifols: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Stauch: Novartis: Honoraria, Research Funding; Amgen: Honoraria. Willy: Novartis Pharma: Current Employment.

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The Burden of Clinically Significant Bleeding, Thrombocytopenia and Platelet Transfusions in Myelodysplastic Syndromes

Blood ◽

10.1182/blood-2019-125273 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 719-719

Author(s):

Kathleen Pao Lynn Cheok ◽

Rakchha Chhetri ◽

Li Yan A Wee ◽

Arabelle Salvi ◽

Simon McRae ◽

...

Keyword(s):

Risk Factors ◽

Antiplatelet Therapy ◽

Myelodysplastic Syndromes ◽

Cumulative Incidence ◽

Platelet Transfusion ◽

Severe Thrombocytopenia ◽

Bleeding Events ◽

Platelet Counts ◽

Immune Mediated ◽

Platelet Transfusions

Aim: Although 40-65% of myelodysplastic syndromes (MDS) patients are thrombocytopenic and require platelet transfusions, there is limited literature on the risk factors predictive of bleeding and the burden of immune mediated platelet refractoriness (PLT-R). Objectives: To evaluate the prevalence of thrombocytopenia, incidence of bleeding events, platelet transfusion dependency (PLT-TD) and immune-mediated platelet refractoriness (PLT-R) in MDS patients. Methods: A retrospective analysis of 754 MDS patients enrolled in the South Australian MDS (SA-MDS) registry was performed. Platelet counts <100, <50 and <20 (x109/L) were used to define mild, moderate and severe thrombocytopenia respectively. The severity of bleeding events was classified according to the International Society of Thrombosis and Haemostasis (ISTH) classification. PLT-TD was defined as transfusion of at least one unit of platelets each month for four consecutive months. All other patients were classified as transfusion independent (PLT-TI). Immune mediated PLT-R was defined if a patient had HLA-class I or HPA antibodies, poor platelet increments and required HLA-matched platelets. Medication history with regards to anticoagulation and/or antiplatelet therapy was also collected. Results: At diagnosis, 332 (45%) patients had thrombocytopenia and 106 (14%) patients had moderate to severe thrombocytopenia. During the study period, 249 bleeding events were recorded in 162 (21%) patients with a cumulative incidence of 33% (Fig 1A). Of the 249 bleeding events, 85 (34%) were major and 164 (66%) were clinically relevant minor bleeding. Notably, 16, 90 and 5 bleeding events were intracranial, gastrointestinal, intraocular respectively. While 41% (96/235) bleeding events occurred in the setting of moderate to severe thrombocytopenia, 21% and 38% (Fig 1B) of bleeding events occurred at platelet counts of >50-100 and >100x109/L respectively. Twenty-eight percent (69/249) bleeding events were associated with concomitant anticoagulation and/or antiplatelet therapy and importantly, platelets counts were >50x109/L and >100 x109/L in 57 (83%) and 46 (67%) at the time of bleeding events, respectively. During the disease course, 393 (52%) patients required at least one unit of platelet transfusion. 106 (14%) patients were PLT-TD and had significantly poor overall survival (OS) compared to PLT-TI (26 vs 42 months, p<0.0001). In total, 30/393 (7%) required HLA-matched platelet transfusions. 20/30 (66%) of PLT-R patients were female receiving disease modifying therapy (DMT). This was substantiated by cox regression analysis, demonstrating that females (HR=5.32, p=0.0006), older age (HR=0.97, p=0.028) and haemoglobin (Hb) at diagnosis (HR=1.03, p=0.009) were independent risk factors for PLT-R. Importantly, 20/76 (25%) female patients receiving platelets and DMT developed immune mediated PLT-R requiring HLA matched platelets. Conclusions: In our cohort of MDS patients, cumulative incidence of bleeding is 33% and 59% of the bleeding events occurred at platelet counts >50X109/L. For all bleeding events that occurred while on anticoagulation and/or antiplatelet therapy, 83% events occurred with platelet counts >50 x 109/L. Therefore, guidelines for anticoagulation and/or antiplatelet therapy are required for MDS patients. We also showed that development of PLT-TD is associated with poor OS. Importantly, 1 in 4 female MDS patients receiving platelets and DMT required HLA-matched platelets. Platelet transfusions practices should be optimised for these high-risk groups. Disclosures No relevant conflicts of interest to declare.

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Transfusion Practice Following Intracranial Hemorrhage in Acute Leukemia: An Institutional Review

Blood ◽

10.1182/blood-2018-99-112718 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4740-4740

Author(s):

Shannon Nixon ◽

Dawn Maze ◽

Eshetu G Atenafu ◽

Danielle Brandys ◽

Cindy Susan Murray ◽

...

Keyword(s):

Platelet Count ◽

Retrospective Study ◽

Acute Leukemia ◽

Intracranial Hemorrhage ◽

Platelet Transfusion ◽

Transfusion Practice ◽

Rank Test ◽

Transfusion Threshold ◽

Platelet Counts ◽

Platelet Transfusions

Abstract Background: Intracranial hemorrhage (ICH) is a common complication in acute leukemia that is associated with significant morbidity and mortality. While evidence supports prophylactic platelet transfusions at a threshold < 10 x 109/L to reduce the risk of bleeding in acute leukemia, there is little data to guide platelet transfusion practice in patients following ICH. The objectives of this study were to characterize the clinical features and outcomes of acute leukemia patients with ICH and to understand current platelet transfusion practice following ICH. Methods: This was a retrospective study conducted at a large, quaternary, academic cancer centre. We included all adult patients with a diagnosis of acute leukemia who had a documented ICH at our centre between January 1, 2009 and December 31, 2016. We assessed demographics, medications, infection and bleeding history in the week preceding ICH, characteristics of ICH including site of bleed, acute management, transfusion practice in the first 90 days, and clinical outcomes. Radiologic scans were re-assessed by neuroradiology to determine if the ICH was stable or if new or progressive bleeding had developed. Transfusion practice following the ICH was compared between the two groups with longitudinal data analysis using platelet counts as outcome. Kaplan-Meier product limit method was used to estimate overall survival (OS) rates as well as to obtain median survival; log-rank test was used to compare OS among those without new or progressive ICH vs. those with progression. Results: During the study period, of 2576 patients diagnosed with acute leukemia, 101 suffered from ICH and were included in the study. Most patients (94) had AML, of which 9 had APL, 6 had ALL, and 1 had MPAL. At the time of ICH, 61 patients were newly diagnosed or receiving induction chemotherapy, 33 had relapsed disease and 7 were in complete remission. Spontaneous ICH occurred in 76 patients. Within the week preceding ICH, 7 patients were on medications known to increase bleeding risk and 39 were on tranexamic acid. Sixty-four patients had clinical evidence of bleeding elsewhere and 22 had evidence of infection. On the day of ICH, the median platelet count was 16 x 109/L (range 0- 433 x109/L). Thirty-one patients had a platelet count < 10 x 109/L and 10 of these patients received a platelet transfusion prior to the bleed. Seventy patients had a platelet count ≥10 x109/L and 17 of these received a platelet transfusion prior to the bleed. Six patients (6%) exhibited evidence of platelet transfusion refractoriness. In the 90 days following ICH, 21% of platelet transfusions were given for a platelet count < 10 x 109/L, 55% were given with a platelet count between 10-29 x109/L, and 24% were given with a platelet count ≥ 30 x 109/L. New or progressive ICH occurred in 28 patients. The median platelet transfusion threshold was 19 x 109/L (range 0-114 x 109/L) for those without new or progressive ICH and 21 x 109/L (range 0-93 x 109/L) for those with progression (p=0.04; Figure 1). Of the 101 study patients, 79 have died. Median OS was 5.6 months for those without new or progressive ICH and 2.9 months for those with progression (p=0.002) (Figure 2). Cause of death was attributed to non-ICH causes in the majority of patients 65/79 (82%). Conclusions: In this retrospective study, we evaluated the outcomes of 101 patients with acute leukemia and ICH. At the time of the bleed, the majority of patients had active disease and more than two thirds had platelet counts of 10 x 109/L or higher. During 90 days of follow-up, nearly one third of patients developed new or progressive ICH. Platelet transfusion practice was variable and the median threshold was, in fact, higher in those who subsequently developed new or progressive bleeding. The reasons for this were unclear from our chart review, but we hypothesize that these patients may have had additional risk factors, e.g. fever, infection. The outcomes of patients with acute leukemia and ICH are poor. Factors other than platelet transfusion threshold likely contribute to secondary ICH events and the overall poor prognosis. Disclosures Maze: Novartis: Consultancy, Honoraria.

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