Romiplostim for the Emergency Management of Severe Immune Thrombocytopenia with Intracerebral Hemorrhage

Gellens, Romain; Habchi, Sabrina; Freppel, S.; Couret, David; Iacobelli, Simona

doi:10.3389/fneur.2017.00737

Cited by 8 publications

(11 citation statements)

References 17 publications

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“…Romiplostim (Nplate V R ) is a thrombopoietin (TPO) receptor agonist (i.e., a thrombopoietin mimetic) approved to treat low platelet counts in adults with chronic immune thrombocytopenia (ITP), an autoimmune disease characterized by low platelet counts (NPLATE V R (romiplostim) [product monograph]: Thousand Oaks, CA: Amgen Inc). A recent report using romiplostim as a successful 'on demand therapy' for emergency management of severe ITP with life-threating bleeding further confirms the usefulness of romiplostim in life-threating bleeding situations (Gellens et al 2017).…”

Section: Introductionmentioning

confidence: 71%

Romiplostim (Nplate^®) as an effective radiation countermeasure to improve survival and platelet recovery in mice

Bunin

Bakke

Green

et al. 2019

International Journal of Radiation Biology

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2020) Romiplostim (Nplate ® ) as an effective radiation countermeasure to improve survival and platelet recovery in mice, International Journal of Radiation Biology, 96:1, 145-154, ABSTRACT Purpose: Rapid depletion of white blood cells, platelets, and reticulocytes are hallmarks of hematopoietic injury of acute radiation syndrome (H-ARS) and, if left untreated, can lead to severe health consequences including death. While the granulocyte colony stimulating factors (G-CSF) filgrastim (Neupogen V R ), pegfilgrastim (Neulasta V R ), and sargramostim (Leukine V R ) are approved to increase survival in patients exposed to a myelosuppressive dose of radiation, no medical countermeasure is currently available for treatment of the thrombocytopenia that also results following radiation exposure. Romiplostim (Nplate V R ), a thrombopoietin receptor agonist, is the first FDAapproved thrombopoiesis-stimulating protein for the treatment of low platelet (PLT) counts in adults with chronic immune thrombocytopenia. Herein, we present the results of an analysis in mice of romiplostim as a medical countermeasure to improve survival and PLT recovery following acute radiation. Materials and methods: Male and female C57BL/6J mice (11 À 12 weeks of age, n ¼ 21/sex/ group) were total body irradiated (TBI) with 6.8 Gy X-rays that reduces 30-day survival to 30% (LD70/30). Vehicle, romiplostim, and/or pegfilgrastim were administered subcutaneously beginning 24 h after TBI for 1-5 days. Evaluation parameters included 30-day survival, pharmacokinetics, and hematology. Results: Full or maximal efficacy with an $40% increase in survival was achieved after a single 30 mg/kg dose of romiplostim. No further survival benefit was seen with higher (100 mg/kg) or more frequent dosing (3 or 5 once daily doses at 30 mg/kg) of romiplostim or combined treatment with pegfilgrastim. Pharmacodynamic analysis revealed that the platelet nadir was not as low and recovery was faster in the irradiated mice treated with romiplostim when compared with irradiated control animals (Day 8 versus 10 nadir; Day 22 versus 29 recovery to near baseline). Platelet volume also increased more rapidly after romiplostim injection. Kinetic profiles of other hematology parameters were similar between TBI romiplostim-treated and control mice. Peak serum levels of romiplostim in TBI mice occurred 4 À 24 h (T max ) after injection with a t 1/2 of $24 h. Cmax values were at $6 ng/ml after 30 mg/kg ± TBI and $200 ng/ml after 300 mg/kg. A 10-fold higher romiplostim dose increased the AUC last values by $35-fold. Conclusion: A single injection of romiplostim administered 24 h after TBI is a promising radiation medical countermeasure that dramatically increased survival, with or without pegfilgrastim, and hastened PLT recovery in mice. ARTICLE HISTORY

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Section: Introductionmentioning

confidence: 71%

Romiplostim (Nplate^®) as an effective radiation countermeasure to improve survival and platelet recovery in mice

Bunin

Bakke

Green

et al. 2019

International Journal of Radiation Biology

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“…TPO (gene symbol THPO) is a humoral growth factor that stimulates platelet formation, reduces ischemic brain injury, and improves outcome partly by inhibiting MMP9 and BBB dysfunction [ 84 ]. TPO-receptor agonists are used to treat ICH associated with severe immune thrombocytopenia, a condition with accelerated platelet destruction and impaired platelet production [ 85 ]. Platelet aggregation was activated through the Thrombin Signaling Pathway in larger ICH and aPHE volumes.…”

Section: Discussionmentioning

confidence: 99%

Molecular Correlates of Hemorrhage and Edema Volumes Following Human Intracerebral Hemorrhage Implicate Inflammation, Autophagy, mRNA Splicing, and T Cell Receptor Signaling

Durocher

Knepp

Yee

et al. 2020

Transl. Stroke Res.

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Intracerebral hemorrhage (ICH) and perihematomal edema (PHE) volumes are major determinants of ICH outcomes as is the immune system which plays a significant role in damage and repair. Thus, we performed whole-transcriptome analyses of 18 ICH patients to delineate peripheral blood genes and networks associated with ICH volume, absolute perihematomal edema (aPHE) volume, and relative PHE (aPHE/ICH; rPHE). We found 440, 266, and 391 genes correlated with ICH and aPHE volumes and rPHE, respectively (p < 0.005, partial-correlation > |0.6|). These mainly represented inflammatory pathways including NF-κB, TREM1, and Neuroinflammation Signaling—most activated with larger volumes. Weighted Gene Co-Expression Network Analysis identified seven modules significantly correlated with these measures (p < 0.05). Most modules were enriched in neutrophil, monocyte, erythroblast, and/or T cell-specific genes. Autophagy, apoptosis, HIF-1α, inflammatory and neuroinflammatory response (including Toll-like receptors), cell adhesion (including MMP9), platelet activation, T cell receptor signaling, and mRNA splicing were represented in these modules (FDR p < 0.05). Module hub genes, potential master regulators, were enriched in neutrophil-specific genes in three modules. Hub genes included NCF2, NCF4, STX3, and CSF3R, and involved immune response, autophagy, and neutrophil chemotaxis. One module that correlated negatively with ICH volume correlated positively with rPHE. Its genes and hubs were enriched in T cell-specific genes including hubs LCK and ITK, Src family tyrosine kinases whose modulation improved outcomes and reduced BBB dysfunction following experimental ICH. This study uncovers molecular underpinnings associated with ICH and PHE volumes and pathophysiology in human ICH, where knowledge is scarce. The identified pathways and hub genes may represent novel therapeutic targets.

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“…There are currently no clinical guidelines regarding the management of thrombotic events in ITP patients [ 14 ], and current literature is limited to case reports, case series, and small cohort studies involving the complex judgment of administering anticoagulation in a patient with impaired coagulation and increased risk of bleeding [ 15 - 19 ]. Thrombopoietic therapies have been pursued and utilized for management of ITP [ 20 ]; our findings specifically for ITP patients with ICH may raise caution for the administration of these agents given the significant risk for prothrombotic events in this population. Further research on the pathophysiology and management of this clinical challenge is needed.…”

Section: Discussionmentioning

confidence: 94%

Immune Thrombocytopenic Purpura and Intracerebral Hemorrhage, Incidence, and Mortality

Hallan¹,

Simion²,

Sciscent³

et al. 2022

Cureus

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Introduction: Intracerebral hemorrhage (ICH) is a devastating complication of immune thrombocytopenic purpura (ITP). Using a large database, we sought to determine its incidence and mortality. Methods: We used a de-identified database (TriNetX) to gather information on patients with ITP with subsequent ICH (cohort 1), propensity score-matched with patients with ITP and no ICH (cohort 2). Primary endpoint was mortality, with secondary endpoints of percutaneous endoscopic gastrostomy (PEG) placement, craniotomy, palliative care encounters, intensive care unit (ICU) management, seizure, falls, pulmonary embolism (PE), myocardial infarction (MI), deep venous thrombosis (DVT), ischemic stroke (IS), and other venous embolism and thrombosis (VTE). Results: Incidence of ICH in patients with ITP was 1.540% in all ages, and 0.774% in those under age 18. After matching, 942 patients from each cohort were identified. Mean age was 58.3 years versus 61.2 years in cohort 1 and 2, respectively. Mortality rate was 34.076% vs. 20.17% (p <0.0001, OR 2.046 with 95% CI 1.661,2.520) at five years. Thirty-day survival was 83.46% vs. 95.17% (p<0.0001), and 365-day survival 68.59% vs. 85.33% (p<0.0001). PEG placement was seen in 21 (2.229%) patients in cohort 1, and less than 10 patients (<1.062%) in cohort 2 (p<0.0464). 2.442% vs. 0% underwent craniotomy (p<0.0001), palliative care was involved in 15.711% vs. 7.962% (p<0.0001), ICU care was seen in 27.389% vs. 11.783% (p<0.0001), with a mean ICU stay of 8.075 vs. 5.812 days (p=0.0537). 6.582% vs. 3.715% had PE (p=0.0049), 7.643% vs. 7.113% experienced MI (p=0.6595), 9.236% vs. 4.883% had DVTs (p=0.0002), 23.673% vs. 5.732% had seizures (p<0.0001), 9.023% vs. 6.582% suffered falls (p=0.0482), 7.537% vs. 3.503% suffered IS (p<0.0001), and 15.074% vs. 8.174% experienced other VTE (p<0.0001). Conclusion: ICH occurs in approximately 1.54% of ITP patients, and is associated with a 34% mortality rate, increased PEG tube placement rates, palliative care involvement, ICU care, craniotomy, PE, IS, DVT, seizures, and falls.

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Romiplostim for the Emergency Management of Severe Immune Thrombocytopenia with Intracerebral Hemorrhage

Cited by 8 publications

References 17 publications

Romiplostim (Nplate^®) as an effective radiation countermeasure to improve survival and platelet recovery in mice

Romiplostim (Nplate^®) as an effective radiation countermeasure to improve survival and platelet recovery in mice

Molecular Correlates of Hemorrhage and Edema Volumes Following Human Intracerebral Hemorrhage Implicate Inflammation, Autophagy, mRNA Splicing, and T Cell Receptor Signaling

Immune Thrombocytopenic Purpura and Intracerebral Hemorrhage, Incidence, and Mortality

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Romiplostim for the Emergency Management of Severe Immune Thrombocytopenia with Intracerebral Hemorrhage

Cited by 8 publications

References 17 publications

Romiplostim (Nplate®) as an effective radiation countermeasure to improve survival and platelet recovery in mice

Romiplostim (Nplate®) as an effective radiation countermeasure to improve survival and platelet recovery in mice

Molecular Correlates of Hemorrhage and Edema Volumes Following Human Intracerebral Hemorrhage Implicate Inflammation, Autophagy, mRNA Splicing, and T Cell Receptor Signaling

Immune Thrombocytopenic Purpura and Intracerebral Hemorrhage, Incidence, and Mortality

Contact Info

Product

Resources

About

Romiplostim (Nplate^®) as an effective radiation countermeasure to improve survival and platelet recovery in mice

Romiplostim (Nplate^®) as an effective radiation countermeasure to improve survival and platelet recovery in mice