Improvement In Platelet Count Research Articles

GC1126A, a novel ADAMTS13 mutein, evades autoantibodies in immune-mediated thrombotic thrombocytopenic purpura

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening blood disorder characterized by the formation of blood clots in small blood vessels. It is caused by antibodies targeting the A disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13 (ADAMTS13), which plays a role in cleaving von Willebrand factor. Most patients with iTTP have autoantibodies against specific domains of the ADAMTS13 protein, particularly the cysteine-rich and spacer domains. This study aimed to identify ADAMTS13 muteins that are resistant to autoantibodies and maintain their enzymatic activity. A panel of muteins was generated using rational and random mutagenesis methods and screened for autoantibody binding and ADAMTS13 activity. The selected muteins were assessed for pharmacodynamic biomarkers and pharmacokinetic profiles in the iTTP-mimic and wild-type mice, respectively. GC1126A was the most effective variant for escaping autoantibodies and had a longer half-life than the wild-type ADAMTS13 fragment (MDTCS). In the iTTP-mimic mouse model, GC1126A treatment significantly improved platelet counts, lactate dehydrogenase levels, and ADAMTS13 residual activity. In addition, GC1126A outperformed recombinant human wild-type ADAMTS13 (rh WT-ADAMTS13) and caplacizumab in terms of platelet recovery and sustained effectiveness. Results from the ex vivo study using plasma from patients with iTTP showed that GC1126A exhibited higher residual activity than rh WT-ADAMTS13, particularly in patients with high autoantibody titers. These findings suggest that GC1126A could be a promising new treatment option for patients with iTTP.

Effectiveness of partial splenic embolization in colorectal cancer patients with chemotherapy-induced thrombocytopenia: results of a single institution retrospective study.

To evaluate the safety and efficacy of partial splenic embolization (PSE) in treating chemotherapy-induced thrombocytopenia (CIT) in patients with colorectal cancer who failed to respond to platelet growth factor therapy. 56 patients who underwent PSE were retrospectively analyzed. Based on the inclusion and the exclusion criteria, 29 patients were eligible for the study, of whom one underwent twice PSE procedures due to recurrent thrombocytopenia. The clinical characteristics were retrospectively analyzed with respect to efficacy, safety and outcome. 60.0% of patients restarted antineoplastic therapy after PSE. There was a positive correlation between difference value of platelet count and embolization material size (Eta Squared = 0.252, p < 0.05). The correlation between the absolute volume of spleen embolized and postoperative complications was analyzed, with a statistically significant result (p < 0.001). The mean preoperative spleen volume, the preoperative platelet count, postoperative platelet count and difference value of platelet count in the non-cirrhotic group were larger than those in the cirrhotic group (p < 0.001). The mean overall survival was 47.7 ± 7.7 months. PSE is safe and effective in the treatment of CIT patients with colorectal cancer. The larger the embolized particle, the more platelets grew. The severity of complication was also positively correlated with the absolute volume of spleen embolized. Therefore, large particle embolization materials can be used to improve the efficacy of PSE and reduce complications. For CIT patients with cirrhosis, PSE was less effective in improving platelet count than those without cirrhosis.

Brief communication: coagulation profiles of HIV positive patients on antiretroviral therapy (ART) at the Mampong Municipal Hospital, Ashanti-Region, Ghana: a case control study

This study aimed to ascertain how the current two ART regimens used in Ghana affected HIV patients’ coagulation profiles. A case-control study was conducted on 102 HIV positive patients at the Mampong Municipal Hospital. Coagulation parameters measured showed APTT was normal in majority of ART-experienced participants but prolonged in majority of ART-naïve participants. The mean platelet count was significantly higher in ART-experienced participants. No significant differences were found between the coagulation profiles of ART-experienced patients on two different drug regimens. In conclusion, current ART can enhance the coagulation profiles in HIV-infected patients, by improving platelet count and APTT.

Use of Eltrombopag to Improve Thrombocytopenia and Tranfusion Requirement in Anti-CD19 CAR-T Cell-Treated Patients.

Background/Objectives: Immune effector cell-associated hematotoxicity (ICAHT) is a frequent adverse event after chimeric antigen receptor (CAR)-T cell therapy. Grade ≥ 3 thrombocytopenia occurs in around one-third of patients, and many of them become platelet transfusion-dependent. Eltrombopag is a thrombopoietin receptor agonist (TPO-RA) able to accelerate megakaryopoiesis, which has been used successfully in patients with bone marrow failure and immune thrombocytopenia (ITP). Its role in managing thrombocytopenia and other cytopenias in CAR-T cell-treated patients has been scarcely addressed. Our aim was to report the safety and efficacy of this approach in patients included in the Spanish Group for Hematopoietic Transplantation and Cellular Therapy (GETH-TC) registry. Methods: This is a retrospective, multicenter, observational study. Patients who developed platelet transfusion dependence subsequently to CAR-T cells and received eltrombopag to improve platelet counts were recruited in 10 Spanish hospitals. Results: Thirty-eight patients were enrolled and followed up for a median (interquartile range [IQR]) of 175 (99, 489) days since CAR-T cell infusion. At the moment eltrombopag was indicated, 18 patients had thrombocytopenia and another severe cytopenia, while 8 patients had severe pancytopenia. After 32 (14, 38) days on eltrombopag, 29 (76.3%) patients recovered platelet transfusion independence. The number of platelet units transfused correlated with the time needed to restore platelet counts higher than 20 × 109/L (Rho = 0.639, p < 0.001). Non-responders to eltrombopag required more platelet units (58 [29, 69] vs. 12 [6, 26] in responders, p = 0.002). Nineteen out of twenty-three (82.6%) patients recovered from severe neutropenia after 22 (11, 31) days on eltrombopag. Twenty-nine out of thirty-five (82.9%) patients recovered red blood cell (RBC) transfusion independence after 29 (17, 44) days. Seven patients recovered all cell lineages while on treatment. No thromboembolic events were reported. Only two transient toxicities (cholestasis, hyperbilirubinemia) were reported during eltrombopag treatment, none of which compelled permanent drug withdrawal. Conclusions: Eltrombopag could be safely used to manage thrombocytopenia and accelerate transfusion independence in CAR-T cell-treated patients.

When it itches, dengue switches off: a retrospective case series

BackgroundDengue fever (DF) is a viral illness caused by the dengue virus transmitted by Aedes aegypti mosquitoe. It manifests with a range of symptoms, from mild DF to severe forms like dengue hemorrhagic fever and dengue shock syndrome. Common symptoms include fever, headache, rash, muscle and joint pain, and itching. The relationship between itching and clinical improvement in dengue patients remains unclear.Case presentationA retrospective analysis was conducted on hospital data from a tertiary care centre in South India from April 2021 to April 2023. Patients diagnosed with dengue fever (confirmed by Immunoglobulin (Ig) M and Non-Structural protein (NS) 1 positivity) who experienced itching were included. Clinical details, age, sex, and laboratory findings were collected. A total of 261 patients were examined. Itching typically occurred around day eight from fever onset and was associated with improved platelet count and hematocrit levels.ConclusionsDengue fever, caused by the dengue virus, presents with various symptoms, including itching during the recovery phase. Studies suggest a correlation between itching and clinical improvement in dengue patients, indicating itching as a potential prognostic marker. Possible mechanisms for itching include direct viral infection of skin cells and cytokine release. However, further research is needed to understand this association fully. Despite limitations such as retrospective analysis, these findings highlight the significance of itching in dengue prognosis and emphasise the need for large-scale studies.

Management of immune thrombotic thrombocytopenic purpura without therapeutic plasma exchange

AbstractImmune thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening autoimmune disorder caused by a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS13) deficiency. Caplacizumab, an anti–von Willebrand factor nanobody, is approved for iTTP treatment, reducing the need for therapeutic plasma exchange (TPE) and improving platelet count recovery and survival. We conducted a retrospective study on 42 acute iTTP cases in Austria and Germany, treated with a modified regimen aimed at avoiding TPE if platelet count increased after the first caplacizumab dose. Baseline characteristics and patient outcomes were compared with a control group of 59 patients with iTTP receiving frontline treatment with TPE, caplacizumab, and immunosuppression. The main outcome was the time to platelet count normalization. Secondary outcomes included clinical response, exacerbation, refractory iTTP, iTTP-related deaths, and the time to platelet count doubling. The median time to platelet count normalization was similar between the 2 cohorts (3 and 4 days; P = .31). There were no significant differences in clinical response, exacerbations, refractoriness, iTTP-related deaths, or time to platelet count doubling, reflecting the short-term treatment response. Four patients did not respond to the first caplacizumab dose, and TPE was subsequently initiated. Cytomegalovirus infection, HIV/hepatitis B virus coinfection, an ovarian teratoma with associated antiplatelet antibodies, and multiple platelet transfusions before the correct diagnosis may have impeded the immediate treatment response in these patients. In conclusion, caplacizumab and immunosuppression alone, without TPE, rapidly controlled thrombotic microangiopathy and achieved a sustained clinical response in iTTP. Our study provides a basis for TPE-free iTTP management in experienced centers via shared decision-making between patients and treating physicians.

Improving platelet function following prophylactic platelet transfusion in patients with hematological malignancies.

Platelet transfusion is a standard treatment to prevent bleeding in patients with hematological malignancies. Although transfusions can improve platelet count, their impact on platelet function remains controversial. We conducted flow cytometry to assess platelet function before and after transfusion and performed subgroup analyses to examine differences based on blood type, corrected count increment (CCI), and platelet microparticles. Overall, 50 patients who received prophylactic platelet transfusion were enrolled. CD42b expression increased, whereas CD41 expression decreased after transfusion. Apheresis platelets exhibited the lowest expression of PAC-1 and P-selectin when exposed to agonist stimulations. PAC-1 expression increased under high adenosine diphosphate (ADP) stimulation, while P-selectin expression increased under both high ADP and thrombin receptor-activating peptide stimulation. In the subgroup analysis, patients with a CCI >4500 and those with the same blood types exhibited a more significant increase in PAC-1 and P-selectin expression under agonist stimulation. When comparing apheresis platelets collected on different days, only the percentage of platelet-derived microparticles showed a significantincrease. Prophylactic transfusion improved platelet function. Platelet function significantly improved in patients with a CCI >4500, those with the same blood types as that of apheresis platelets, or those with platelet-derived microparticle levels <4.7%. No significant improvement in platelet function was noted after the transfusion of different blood types with acceptable compatibility or the transfusion of incompatible blood types. Our results suggest that transfusing platelets with the same blood type remains the optimal choice.

Improvement in Thrombocytopenia after Direct Acting Anti-Viral (DAA)Therapy in Patients with Hepatitis C Virus-Related Chronic Liver Disease in Pakistani Population-A Single Centered Study

Background: Hepatitis C Virus (HCV) infection remains a significant global health challenge, often leading to chronic liver diseases such as cirrhosis and associated complications like thrombocytopenia. Directly acting antivirals (DAAs) have revolutionized HCV treatment due to their high efficacy and favorable safety profiles but the impact on thrombocytopenia, particularly in the Pakistani population, has been less studied. Objective: This study aimed to evaluate the effects of DAA therapy on platelet count and other laboratory parameters in chronic HCV patients with thrombocytopenia in Pakistan and to establish correlations between treatment outcomes and baseline laboratory values. Methods: A retrospective observational study was conducted at the Sindh Institute of Urology and Transplantation from January 2018 to December 2022. Patients with chronic HCV genotype 3a infection, compensated cirrhosis, and a baseline platelet count of less than 150 × 10^9/L were included. Exclusion criteria encompassed decompensated liver disease, liver cancer, and other specific conditions. The treatment regimens were Sofosbuvir plus Daclatasvir or Velpatasvir plus Ribavirin over three months. Parameters such as complete blood counts, serum creatinine, liver enzymes, and Child-Turcotte-Pugh (CTP) and Model for End-Stage Liver Disease (MELD) scores were recorded at baseline and post-treatment. Statistical analysis was performed using SPSS version 25, employing paired t-tests and Pearson correlation coefficients. Results: A total of 195 patients were studied, with a mean baseline platelet count of 100.7 × 10^9/L, which significantly increased to 122.2 × 10^9/L post-treatment (p &lt; 0.001). Improvements were also noted in mean serum creatinine (0.96 mg/dL to 0.87 mg/dL; p = 0.009), total bilirubin (1.6 mg/dL to 1.2 mg/dL; p &lt; 0.001), liver enzymes (ALT from 63.9 IU to 45.9 IU; p &lt; 0.001 and AST from 86.8 IU to 59.5 IU; p &lt; 0.001), and MELD scores (11.5 to 9.3; p &lt; 0.001). Hemoglobin levels and total leukocyte counts also showed significant improvements. Conclusion: DAA therapy significantly improves platelet counts and other laboratory parameters in chronic HCV patients with thrombocytopenia, suggesting a positive impact on liver function and patient management. This study highlights the importance of DAAs in the therapeutic regimen for HCV in the Pakistani population, contributing to better clinical outcomes and healthcare practices.

Therapeutic effects of Medicago sativa against cyclophosphamide-induced toxicity in rats.

Medicago sativa (M. sativa) has been traditionally used for treating anemia; therefore, M. sativa hydro-ethanolic extract therapeutic effects against cyclophosphamide (CP) -induced hematologic and liver toxicity were examined. Thirty male Wistar rats were randomly divided to control (saline); CP (100 mg/kg, day 1-3, subcutaneously); CP+ M. sativa 200 mg/kg (MS 200); CP+ M. sativa 400 mg/kg (MS 400); CP+ dexamethasone (0.1 mg/kg), (all groups n=6). Treated animals received M. sativa or dexamethasone by gavage from days 7-14. On days 0, 7, and 14, hematologic parameters, and on the 14th day, serum and liver tissue oxidative stress markers including nitric oxide, malondialdehyde (MDA) and total thiol levels, superoxide dismutase (SOD) and catalase (CAT) activities, serum lipids, and liver enzymes were measured. Animal weight, platelet, white blood cells, and red blood cells counts, hemoglobin and hematocrit as well as thiol, SOD, and CAT activities in serum and liver tissue were significantly reduced, but serum nitric oxide, MDA, total cholesterol, triglycerides, low-density lipoproteins levels, and liver enzymes were increased in the CP group compared to the control group (p<0.05 to p<0.001). Administering M. sativa extract (400 mg/kg) significantly enhanced platelet count, and SOD and CAT activities and inhibited all of the CP toxic effects, while dexamethasone improved platelet count and oxidative stress markers compared to the CP group (p<0.05 to p<0.001). The extract of M. sativa (400 mg/kg) showed therapeutic effects against the CP-induced myelosuppression and thrombocytopenia and improved oxidative stress markers which were comparable to the effect of dexamethasone.

Establish a Graded Method to Avoid HLA Class I Antibodies Corresponding Antigen and Combining HLAMatchmaker Application in Improving the CCI Value after Platelet Transfusion for Patients with IPTR

To establish a graded method to avoid mean fluorescence intensity (MFI) threshold of HLA Class I antibodies corresponding antigen, and the HLAMatchmaker program has been used to select the minimum mismatch value of donor-patient epitopes. Evaluate the application value of combining both methods in selecting HLA compatible platelets (PTL) for patients with immune platelet transfusion failure (IPTR) in improving platelet the corrected count increment (CCI). A total 7 807 PLT cross-matching compatible were performed by the solid-phase red cell adherence (SPRCA) method for 51 IPTR patients. The Luminex single antigen flow cytometry was used to detect HLA Class I antibodies in patients, and detected the MFI value for different specificity antigens of HLA Class I antibodies, was graded into strong positive group (MFI>4 000, level 1), medium positive group (1 000< MFI≤4 000, 2), weak positive group (500< MFI≤1 000, 3), and one negative control group (MFI≤500). The results of 7 807 SPRCA their negative/positive reaction wells were enrolled and statistically analyzed in different grades and the four groups, the statistical differences between the four groups were compared. Multiple applications for the select HLA Class I compatible donor events were made for patients in two cases, and HLAMatchmaker program was used to calculate the number of HLA Class I epitopes mismatches between the donors and patients. The donor with the minimum number of epitopes mismatches was selected, while avoiding the corresponding antigens of HLA Class I antibodies in levels 1 and 2, the provision of HLA compatible platelets for IPTR. After the transfusions, the CCI value of the platelet transfusion efficacy evaluation index was calculated, and the clinical evaluation of the transfusion effect was obtained through statistical analysis. There were statistically significant differences in the positive results of SPRCA immunoassay among the strong positive group, medium positive group, and weak positive group of 51 IPTR patients with different specific of HLA -I class antibodies and corresponding antigens(all P <0.001). The positive results showed a range from high to low, with strong positive group>medium positive group>weak positive group. There were a statistical difference among between the strongly positive or moderately positive groups and the negative control group(P <0.001). There was no statistical difference between the weakly positive group and the negative control group(P >0.05). The strong positive group was set as the corresponding specific HLA Class I site corresponding antigen grade 1 avoidance threshold, the medium positive group as the grade 2 avoidance thresholds, and the weak positive group as the grade 3 avoidance threshold. In the case of donor platelet shortage, it is not necessary to avoid the weak positive group. Avoiding the strategy of donor antigens and HLAMatchmaker program scores ≤7 corresponding to HLA Class I antibodies of levels 1 and 2, with CCI values>4.5×109/L within 24 hours, can obtain effective clinical platelet transfusion conclusions. When selecting HLA Class I compatible donors for IPTR patients, the grading avoids HLA Class I antibodies corresponding to donor antigens, and the donor selection strategy with the minimum scores of HLAMatchmaker program is comprehensively selected. The negative result confirmed by platelet cross-matching experiments has certain practical application value for improving platelet count in IPTR patients.

Role of granulocyte colony stimulating factor (G-CSF) in dengue patients with severe thrombocytopenia.

To determine the effects of granulocyte colony-stimulating factor in improving platelet count in patients with dengue fever. The retrospective, cross-sectional study was conducted at Northwest General Hospital and Research Centre, Peshawar, Pakistan, between January 2021 and October 2022, and comprised dengue fever inpatients regardless of age and gender who received granulocyte colony-stimulating factor subcutaneously. The impact of colony-stimulating factor on platelet and white blood cell counts as well as any unfavourable consequences was assessed. Convenient sampling was used and a structured format was used for data collection. Data was analysed using SPSS 21. Of the 100 patients, 67(67%) were males and 33(33%) were females. The largest age group was that of >55 years 31(31%), fever was present in all the 100(100%) cases, bleeding in 18(18%) and platelet count <30,000 in 83(83%) cases. Dengue fever was confirmed by rapid dengue nonstructural protein 1 antigen in 76(76%) cases, dengue immunoglobulin G antibody test 28(28%), and immunoglobulin M antibody test in 31(31%) cases. Overall, 72(72%) patients received only one dose of granulocyte colony-stimulating factor. Post-administration, a substantial rise in the median platelet and white blood cell counts was seen compared to the baseline (p<0.05) on day 2. Granulocyte colony-stimulating factor helped increase platelet and white blood cell counts quickly in dengue fever patients.

Phase II Study Assessing Safety and Preliminary Efficacy of High Dose Intravenous Ascorbic Acid in Patients with TET2 Mutant Clonal Cytopenias

Background: Clonal cytopenia(s) of undetermined significance ( CCUS) is defined as persistent cytopenias arising in the context of myeloid neoplasm ( MN)-associated somatic mutations ( MT) in hematopoietic stem cells. Patients ( PTs) with TET2MT CCUS have a high probability of progression to MN. To date, no FDA-approved therapies exist for CCUS, and PTs often have similar cytopenias/transfusion needs as those with myelodysplastic syndromes ( MDS). TET2 is an ascorbic acid (AA)-dependent dioxygenase that catalyzes the conversion of 5-methylcytosine ( 5mC) to 5-hydroxymethylcytosine ( 5hmC), providing rationale to study high-dose IV (HI)-AA in TET2MT CCUS. Here we report the final results of this pilot trial. Methods: This is an investigator-initiated, single-institutional, phase II trial assessing the safety and efficacy of HI-AA in PTs with TET2MT CCUS (NCT03418038). PTs≥ 18 years with ≥1 TET2MT with or without additional somatic MTs, without prior treatment, and with any of the following laboratory criteria: (1) hemoglobin ( Hb) ≤10g/dL, (2) absolute neutrophil count ( ANC) ≤1(10^9/L), (3) platelet count ( PLT)≤100 (10^9/L) were eligible. HI-AA (1g/kg, maximum 100g) was given 3 times weekly for 12 weeks. The primary endpoint was hematologic response rates determined by MDS IWG 2018 criteria at week 20. (Platzbecker Blood 2018) and reported as hematologic improvement ( HI)- erythropoietic ( HI-E), platelets ( HI-P), neutrophils ( HI-N). Secondary endpoints include safety and adverse events ( AEs), graded by NCI-CTCAE v4.03. Correlative studies include changes in TET2MT variant allele fraction ( VAF), in vitro colony formation and differentiation, global and sequence-specific DNA methylation/hydroxymethylation, and quantitative 5hmC estimated by IHC in bone marrow biopsy specimens. Results: Ten patients were enrolled, with a median age of 71.4 (range: 65, 79) years, 8 (80%) males. The median number of mutations was 3, with 9 (90%) having co-mutations. All PTs but one [-Y] had normal karyotype. Baseline Hb levels were normal in all but one who was red blood transfusion dependent. Five (50%) PTs were thrombocytopenic, and 5 (50%) PTs had ANC&amp;lt;1 (10^9/L). ( Table). HI-AA was well tolerated with the most common AEs being infusion-related polyuria (40%) and polydipsia (40%, 3 Grade 1, 1 Grade 2). One (10%) PT had constipation and headaches (both Grade 1), and 1 (10%) experienced dyspepsia. No treatment-related Grade 3 or 4 AEs' or deaths were reported. The median follow-up duration was 16.8 months (range: 9.4, 24.1). Overall, no PTs met the criteria for HI. There were no significant differences with regards to median Hb, PLT, and ANC values at baseline, week 20, and 1-year (median Hb: 13.3, 12.5, and 12.7 g/dL, p=0.93; PLT: 97 vs. 120 vs. 92.5X10^9/L, p&amp;gt;0.99, and ANC: 0.9 vs. 1.2 vs. 1.3X10^9/L, p=0.99). By CTCAE grading criteria for cytopenias, 3 (30%) PTs had an improvement in severity of cytopenias, while 2 had worsening. One (10%) PT had an improvement in PLT (baseline vs. week 20: 62 vs 192X10^9/L) but was morphologically deemed to meet criteria for CMML-1 at week 20. Four (40%) PTs met criteria for disease progression (PT_4, 7,8,10); CMML-1- 2 and MDS-2. The median time to progression was 5 months (95% CI: 4.9, unreached). Two PTs had mutational clonal evolution, with 1 (PT_8) acquiring a RUNX1 (VAF: 20%) and 1 (PT_9) acquiring 2 CBL mutations (both VAF:4%) at one-year follow-up. There were no significant differences regarding the clinical characteristics or the TET2 variants between PTs who had stable disease vs. progression. There were no significant differences in TET2 VAF at baseline, week 20, and 1-year (median: 39% vs. 43% vs. 42%, p=0.54). We profiled changes in 5-mC and 5-hmC (Ilumina EpicArray) in PTs pre- and post-IV AA treatment and did not observe global changes. However, we were able to highlight site-specific changes in differentially methylated regions, largely resulting in hypomethylation at enhancer sites and affecting actively transcribed states in PTs with an improvement in cytopenia(s) severity by CTACE criteria ( Figure). Conclusion: We report the final safety and efficacy analysis of HI-AA in PTs with TET2 MT CCUS. The trial data suggest that HI-AA is safe and well tolerated. Although there were no significant responses by IWG MDS criteria, alleviation in severity of cytopenias in a subset of PTs (n=3) along with correlative epigenetic changes in enhancer regions, needs further exploration.

Avatrombopag Safe and Effective in Treatment of Severe Refractory Thrombocytopenia in a Pediatric Patient with Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia Following Allogeneic Hematopoietic Stem Cell Transplantation

Background: Persistent thrombocytopenia following allogeneic stem cell transplantation (alloHSCT) leads to an increase in morbidity and mortality. Causes of severe thrombocytopenia following HSCT include poor graft function, graft-versus-host disease (GVHD), infections, drug toxicities, underlying autoimmune diseases and relapse of underlying disease. Treatments can include thrombopoietin receptor agonists (TPO-RA), immunomodulators, and stem cell boost. Avatrombopag is a second generation TPO-RA approved for the treatment of primary chronic immune thrombocytopenia (ITP) in adult patients with poor response to standard treatments or in patients with chronic liver disease (CLD) associated thrombocytopenia requiring surgical interventions. Phase III clinical trials have shown greater platelet responses in chronic ITP and reduced transfusion needs in patients with CLD. Avatrombopag differs from other TPO-RA medications due to majority of elimination occurring in the gut, thus avoiding hepatic toxicity. Additionally, it does not require dietary restrictions. As there is limited literature in pediatric patients following alloHSCT, we describe the use of avatrombopag in a pediatric patient with chronic severe thrombocytopenia (&amp;lt;10 x10 3/uL) post HSCT. Objective: To describe the use of avatrombopag for severe refractory thrombocytopenia in a pediatric alloHSCT recipient. Case Presentation: We present a 14-year-old Hispanic male with Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) who received a maternal haploidentical HSCT with myeloablative conditioning and post-transplant cyclophosphamide. His post HSCT course was complicated by adenoviremia, hepatic variant GVHD, Enterobacter cloacae bacteremia and poor graft function. Seven months following HSCT, patient was found to be severely pancytopenic. Bone marrow morphology demonstrated 20-30% cellularity without evidence of leukemia relapse or GVHD. Lab evaluation was not consistent with transplant associated thrombotic microangiopathy. He received a stem cell boost for presumed poor graft function. Patient demonstrated partial response by resolution of neutropenia and anemia; however, severe thrombocytopenia persisted. Multiple bone marrow evaluations remained negative for disease with full donor chimerism and negative TCR clonality. CXCL9 was noted to be elevated at 4270 and Immature Platelet fraction was elevated at 8.8. Platelet antibodies remained negative and all findings consistent with persistent severe ITP. Multiple treatments including romiplostim; eltrombopag; high dose immune globulin (IVIG); rituximab; methylprednisolone; and decitabine were not successful in improving platelet count (Figure 1). Evaluation for severe thrombocytopenia remained negative. During the course of severe thrombocytopenia, patient required several hospitalizations for symptomatic thrombocytopenia, requiring multiple platelet transfusions. Due to the severity of disease, he was granted a compassionate use investigational new drug (IND 165837) for avatrombopag and began on day +332. Dosing was initiated at 20 mg daily with a dosage adjustment to achieve platelet recovery to &amp;gt;50 x10 3/uL free from transfusion. The dose was titrated per manufacturer to maximum dose of 40 mg daily with response to platelet count &amp;gt;100 x10 3/uL in approximately 6 weeks time. By three months of treatment, dose was titrated down 40 mg three times a week and 20 mg on alternating days. Patient continues to maintain platelets above 100 x10 3/uL with no medication toxicities or adverse events noted. Patient has been able to return to his pre-alloHSCT lifestyle including contact sports and re-immunizations.

The Use of Caplacizumab in COVID-19-Related TTP

Introduction Thrombotic Thrombocytopenic Purpura (TTP) is a rare but feared hematological disorder encountered in the inpatient setting. COVID-19-associated TTP is a lesser understood phenomenon, with slightly different symptomology and clinical course. Prompt identification is essential since TTP is a medical emergency which carries a 90% risk of mortality if untreated. Several aspects of treatment, including the use of agents like caplacizumab as monotherapy and therapy duration, are poorly defined in the literature. In this case report, we discuss one such case of post-COVID TTP and explore the therapeutic challenges that clinicians should be aware of when using caplacizumab. Case A 49-year-old female presented with brief changes in mentation and confusion, as well as an associated headache, sore throat, myalgias, and fever for 10 days. The patient tested positive for the COVID-19 antigen 3 days prior to presentation. The patient was hemodynamically stable on arrival, although tachycardic to 94 beats per minute. Initial labs revealed acute normocytic anemia (Hb 7.4 g/dl from a baseline of 12.1 g/dl) and acute, severe thrombocytopenia (9 K/ul from a baseline of 217 K/ul) with schistocytes present on peripheral blood smear. Elevated lactate dehydrogenase (LDH) and low haptoglobin suggested hemolysis. PT, INR, PTT, d-dimer, fibrinogen, and fibrin degradation product (FDP) did not suggest disseminated intravascular coagulation (DIC). TTP was highly suspected with a PLASMIC score of 7. Therapeutic plasma exchange (TPE) was started emergently on day of admission. Additional treatments that were administered include methylprednisolone (1g daily for 3 days), rituximab (375mg/m2), and caplacizumab (11mg before and after TPE on Day 1, then 11 mg daily thereafter). Caplacizumab was administered daily through Day 4, then stopped because our hospital pharmacy could not procure the drug. Nevertheless, by day 4, platelets had improved to &amp;gt;150 K/ul and LDH to &amp;lt;200 IU/l for 2 consecutive days. From Day 4 to Day 10, TPE was given every other day. However, on day 10 the platelets decreased to 11 K/ul. Both daily TPE and caplacizumab was re-initiated. ADAMTS 13 level was &amp;lt;2% at admission and Day 9, later increased to 54.1% on Day 15. ADAMTS 13 antibody levels were &amp;gt;164 U/ml on the day of admission, 67 U/ml on Day 9, and undetectable on Day 15. The patient was discharged on Day 22 and completed a 30-day course of caplacizumab. Follow-up showed sustained remission at 2.5 months with ADAMSTS13 level of 90.8%, platelet count 130 K/ul and the LDH level of 136 U/l. Discussion Caplacizumab is a bivalent anti-VWF immunoglobulin approved in 2019 for treating acquired TTP in conjunction with TPE and other immunosuppressive therapies. The TITAN trial showed significantly lower 30-day exacerbations in the caplacizumab group compared to the placebo group, but a higher rate of relapse in the caplacizumab group in the following month. Patients in the caplacizumab group received fewer TPE sessions overall. Paradoxically HERCULES trial showed 67% lower recurrence in the caplacizumab group. These results in the HERCULES trial were attributed to caplacizumab treatment lengths that could be expanded based on ADAMTS13 activity &amp;lt;10%. In our case, given the high bleeding risk and lack of cost-effectiveness while inpatient, caplacizumab was discontinued and TPE decreased to alternate day dosing following adequate clinical response. It is difficult to predict whether premature discontinuation of caplacizumab or early weaning of TPE triggered recurrence, since both therapies were discontinued on Day 5. This case demonstrates a clinical conundrum of whether caplacizumab can lead to early discontinuation of TPE with inadequate clearance of ADAMTS13 antibody, leading to early relapses. A review of current literature and our experience suggest that Caplacizumab may be very effective in improving platelet count and reducing relapse rates, especially when decisions to discontinue the drug are based on ADAMTS-13 levels. However, lack of cost-effectiveness is a limiting factor, and high bleeding risks must be considered before deciding to start caplacizumab in patients with refractory or severe TTP.

Platelet Response in Pacritinib-Treated Patients with Cytopenic Myelofibrosis: A Retrospective Analysis of PERSIST-2 and PAC203 Studies

Background: Myelofibrosis (MF) is a myeloid malignancy characterized by clonal hematopoisis, bone marrow fibrosis (BMF) and ineffective extramedullary hematopoiesis, resulting in progressive cytopenias. Thrombocytopenia is both prognostic of poor outcomes and predictive of treatment intolerance with the JAK1/2 inhibitor ruxolitinib, which exacerbates cytopenias. Pacritinib is a JAK1-sparing inhibitor of JAK2/IRAK1/ACVR1 that can be administered at full dose to patients regardless of baseline platelet count (PLT). While prior studies have shown that pacritinib is associated with PLT stability in most patients, PLT improvement has not been described outside of a recently published case report ( Yacoub A, et al. JCO Precis Oncol. 2023;7:e2200523). Here, we report rates of hematologic improvement in PLTs (HI-P) with pacritinib across two clinical trials. Methods: Patients with baseline PLT ≤100x10 9/L on the pacritinib 200 mg BID arms of the phase 3 PERSIST-2 study (randomized ≥12 weeks prior to study termination) or the phase 2 dose-finding PAC203 study were included. HI-P was defined per International Working Group (IWG) criteria (baseline PLT &amp;lt;20x10 9/L: increase to &amp;gt;20x10 9/L and by at least 100%; baseline PLT 20-100 x 10 9/L: absolute increase of ≥30x10 9/L) in the absence of PLT transfusions, sustained over any 8 weeks while on treatment. Efficacy outcomes (reduction in spleen volume, symptom score, and BMF) were compared between HI-P responders vs non-responders (those who did not meet IWG criteria). Rates of PLT improvement were also analyzed on the best available therapy (BAT) arm of the PERSIST-2 study over the treatment period (end of study treatment). Results: Of 117 patients randomized to pacritinib (75 from PERSIST-2, 42 from PAC203), 16% (n=19) experienced HI-P on study (as defined in methods). Additionally, 14 of the 19 HI-P patients had sustained platelet improvement over ≥12 weeks). By contrast, only 5% (4/77) of patients on BAT achieved HI-P response prior to end of study treatment. HI-P responders on pacritinib compared to non-responders, had numerically higher median baseline PLT count (63 vs 45x10 9/L) and hemoglobin (Hb; 10.3 vs 8.8 g/dL). A similar percentage had prior (&amp;lt;30 days) JAK2 inhibitor exposure (68.4% vs 66.3%) and JAK2V617F mutation (78.9 vs 74.5%); median JAK2 allele burden was low in both responders and non-responders (26.7% vs 36.9%). Among HI-P responders with prior ruxolitinib exposure, most (85%, 11/13) had recent exposure within the prior 30 days, with median dose of 10 mg BID. PLT improvement was noted within the first 12 weeks in most HI-P responders, whereas PLT count remained stable, on average, among non-responders ( Figure 1a). To evaluate if recent ruxolitinib exposure and washout of drug was responsible for HI-P, we analyzed the subset of patients with ruxolitinib exposure in previous 30 days (11/19). The mean platelet count increased from 56 to 141x10 9/L at week 12. In the remaining 8/19 patients without recent ruxolitinib exposure (n=6 were treatment naïve), platelets increased from 59 to 102 x 10 9/L at week 12. While there was no difference in the magnitude of spleen volume or symptom score reduction in HI-P responders vs non-responders, a correlation with change in BMF was noted. Among the 36 patients with available bone marrow data from baseline and week 24, HI-P responders were numerically more likely to have BMF reduction (67%, n=4/6) compared to non-responders (23%, n=7/30, P=0.057, Figure 1b). There was no difference in the rate of hemorrhagic events (by standardized MedDRA queries) in PLT responders vs non-responders (47% vs 46%), though grade ≥3 bleeding was observed at lower frequency in responders compared to non-responders (10.5% vs 16%). Other commonly reported adverse events with pacritinib occurred at similar frequency between responders and non-responders. Discussion: PLT improvement meeting IWG criteria occurs in a subset of MF patients treated with pacritinib and does not seem to be explained by changes in spleen volume. Further studies are warranted to assess the correlation between hematologic improvement and BMF reduction with pacritinib. It is possible that pacritinib's unique mechanism of action as an IRAK1 inhibitor could result in modulation of the bone marrow microenvironment and thrombopoiesis. Study funded by CTI BioPharma Corp., a Sobi company.

Firstline Treatment with Ruxolitinib Versus Best Available Therapy in Patients with Polycythemia Vera: Pre-Specified Interim Analysis of the Randomized Phase 2b Ruxobeat Clinical Trial of the German Study Group for Myeloproliferative Neoplasms (GSG-MPN)

Introduction: Polycythemia vera (PV) is characterized by trilineage blood cell expansion, PV-associated symptoms, and the risk of thromboembolic complications, progression to post-PV myelofibrosis, and acute leukemia. Cytoreductive treatment with hydroxyurea (HU) or ropeginterferon-alpha is approved in EU for the treatment of high-risk patients (pts) with PV. In addition, ruxolitinib (RUX) is approved for HU-intolerant/-resistant PV. However, RUX vs. best available therapy (BAT) has not been investigated as first-line treatment of pts with untreated PV. We hypothesized that RUX may have higher efficacy in such early-line PV pts. Methods: The clinical trial entitled “Ruxolitinib versus Best Available Therapy in pts with high-risk PV or high-risk ET” (RuxoBEAT; NCT02577926) is a multicenter, open-label, two-arm phase-IIb trial with a target population of 190 pts in each stratum. Crossover from BAT to RUX is possible in eligible pts after 6 months. Pts with PV in the RUX arm received a starting dose of 10 mg BID and may increase their dose up to 20 mg BID. The primary endpoint is the clinicohematologic complete response (CR) rate at month 6, as defined by Barosi et al (Blood 2009), using a strict score of zero for the four symptoms by patient-reported outcome measures (PROM, Table 2) and an adjusted level alpha = 0.005 at a power of 80%. Secondary endpoints include overall response rate (CR+PR), freedom from phlebotomy, changes in blood counts, spleen size, and PROM, using p values descriptively. The interim trial data were recently reviewed by the DMC, and, due to the low likelihood of reaching the primary endpoint (CR rate improvement), the DMC has recommended that the trial should continue without recruitment of new pts. Therefore, this pre-specified interim analysis was performed after 78 (instead of 95) PV pts were randomized 1:1 to RUX vs. BAT. A maximum of 6 weeks of previous PV-directed therapy was allowed. Differences between RUX and BAT at month 6 and between baseline and end of month 6 data for each treatment were calculated using Fisher´s exact test/ McNemar Test (for unpaired/ paired binary variables) or the Mann-Whitney-U test/ Wilcoxon signed-rank test (for unpaired/ paired ordered or continuous variables). Results: 78 first-line pts (33% were pre-treated for a median of 22 days [range 1-42]) were included in the intention-to-treat set (n=44 vs 34 randomized to RUX vs. BAT, resp.) and analyzed at the 6-month time point. Baseline characteristics are listed in Table 1. In pts on RUX or BAT, CR rates at 6 months were comparable (2.3% and 2.9%, p=1.0), while overall response (CR+PR) rates were 77.3% with RUX and 55.9% with BAT (p=0.054). Also, at month 6 (Table 2), pts on RUX showed significantly lower hematocrit (40.8% vs 42.1%, p=0.046), and PROM symptom points for pruritus (1 vs 4, p=0.001) and fatigue (2.5 vs 5, p=0.031), and a trend towards less headache, abdominal discomfort, and weight loss, while the number of platelets was lower with BAT vs. RUX (254/nl vs 386/nl, p=0.013). There was no difference between RUX and BAT in the number of white blood cells (WBC), spleen size, or other symptoms at this time point. When each treatment arm was analyzed separately for changes between baseline and month 6, RUX treatment significantly reduced platelet counts, WBC, hemoglobin and hematocrit, phlebotomy rates, spleen size and fraction of pts with splenomegaly (Table 2), and significantly improved PROMs for pruritus, early satiety, and quality of life. During the same time period, BAT significantly reduced platelet counts, WBC, hematocrit, and phlebotomy rates, but failed to impact on hemoglobin, spleen size, fraction of pts with splenomegaly, or any of the symptoms (Table 2). Safety analysis revealed 301 adverse events (AE) in both assigned treatment groups, including 153 AE in the RUX and 148 AE in the BAT group (11.8% and 8.1% grade ≥3, resp.). There was no significant difference in the percentage of grade ≥3 AE between both groups (p=0.358), and there were no consistent patterns of grade ≥3 AE in either of the two arms. Conclusion: In this interim analysis, first-line treatment with ruxolitinib for 6 months in high-risk pts with PV led to clinically meaningful improvements in overall response, hemoglobin and hematocrit, phlebotomy rates, splenomegaly, and patient-reported pruritus and fatigue severity, while BAT only improved platelet counts, WBC, hematocrit, and phlebotomy rates, without having an impact on symptoms.

Early initiation of second-line therapy in primary immune thrombocytopenia: insights from real-world evidence

To compare patients with primary immune thrombocytopenia (ITP) prescribed early (within 3 months of initial ITP treatment) second-line treatment (eltrombopag, romiplostim, rituximab, immunosuppressive agents, splenectomy) with or without concomitant first-line therapy to those who received only first-line therapy. This real-world retrospective cohort study of 8268 patients with primary ITP from a large US-based database (Optum® de-identified Electronic Health Record [EHR] dataset) combined electronic claims and EHR data. Outcomes included platelet count, bleeding events, and corticosteroid exposure 3 to 6 months after initial treatment. Baseline platelet counts were lower in patients receiving early second-line therapy (10‒28 × 109/L) versus those who did not (67 × 109/L). Counts improved and bleeding events decreased from baseline in all treatment groups 3 to 6 months after the start of therapy. Among the very few patients for whom follow-up treatment data were available (n = 94), corticosteroid use was reduced during the 3- to 6-month follow-up period in patients who received early second-line therapy versus those who did not (39% vs 87%, p < 0.001). Early second-line treatment was prescribed for more severe cases of ITP and appeared to be associated with improved platelet counts and bleeding outcomes 3 to 6 months after initial therapy. Early second-line therapy also appeared to reduce corticosteroid use after 3 months, although the small number of patients with follow-up data on treatment precludes any substantive conclusions. Further research is needed to determine whether early second-line therapy has an effect on the long-term course of ITP.

EFFECT OF ASSOCIATION OF THROMBOCYTOPENIA WITH ANEMIA ON FETO-MATERNAL OUTCOME

Objectives: To find out effect of association of thrombocytopenia with anemia on feto-maternal outcome. Background: Thrombocytopenia is defined as platelet count less than 150,000/mm3. It is a second common hematological disorder in pregnancy, anemia being the most common. The exact mechanism of Anemia and Thrombocytopenia is not well understood. There is scarcity of literature on association between Anemia and Thrombocytopenia. Pubmed mostly revealed case reports and case series with only a few studies related to our topic. It is pertinent to mention here that most of the studies have been conducted on Paediatric age group. Therefore, the present study is planned to evaluate the effect of association of thrombocytopenia with anemia on feto-maternal outcome. Methodology : The study was conducted after taking informed consent from the patients in the Department of Obstetrics and Gynaecology, with the collaboration of Department of Pathology and Department of Pediatrics, JNMCH, AMU, Aligarh (U.P) on 360 pregnant women at 26-32 weeks of gestation. Complete Blood Count (CBC) and Red cell indices were calculated by Automated Haemotology (H3D Premier Diagnova) Analyzer. Type of anemia was determined on the basis of general blood smear and on indices. Appropriate therapy was given and response seen after 4 to 6 weeks. During labour and after delivery, feto-maternal outcome was evaluated. All the qualitative variables were analyzed using Pearson Chi square test while all quantitative variables were analyzed using independent sample test and Kruskal-Wallis one-way ANOVA test. Results: The association of thrombocytopenia with anemia was highest in cases of dimorphic anemia and lowest in cases of megaloblastic anemia while only 15% of control were having thrombocytopenia in the present study. The maternal outcome in terms of preterm labor, PPH, duration of hospital stay after delivery, maternal sepsis, DIC, bleeding from any other site between cases and controls was not significant. Fetal outcome between cases and controls in terms prematurity, birthweight, neonatal infections, NICU admissions, intracranial hemorrhage, still births was not statistically significant. Only the mean 1 minute Apgar score was lower in cases as compared to controls and this was statistically significant. Conclusion : It can be concluded that there is an association that exists between hemoglobin and platelet count. Appropriate therapy corrects anemia and improves platelet count. Timely detection and correction of anemia with thrombocytopenia reduces intrapartum and postpartum complications. In order to reduce maternal and neonatal morbidities, careful surveillance is required of all pregnancies for early detection and treatment of anemia.

Concurrent Occurrence of Nasopharyngeal and Disseminated Cutaneous Rhinosporidiosis: A Rare Presentation.

Concurrent Occurrence of Nasopharyngeal and Disseminated Cutaneous Rhinosporidiosis: A Rare Presentation.

Efficacy of phytotherapy as nutritional supplements in patients with refractory immune thrombocytopenia

IntroductionThe management of refractory immune thrombocytopenia (ITP) is challenging and difficult. The treatment was mainly comprised of cytotoxic and immunosuppressed drugs that rarely lead to long-term remission but potentially cause severe and dangerous side effects. Our current study is a retrospective clinical analysis of refractory ITP patients who underwent phytotherapy as nutritional supplements. MethodsA retrospective clinical analysis of 15 refractory immune thrombocytopenia (ITP) patients aged 12–64 with ITP history for more than 24 months before the enrollments. All patients presented with low platelet count (< 30 × 109/L) and moderate to severe bleeding symptoms such as extensive petechiae, bruising, epistaxis, prolonged menses, rectal bleeding, and hematuria. The patients underwent supportive phytotherapy as nutritional supplements using herbal extracts with hemostatic, immunomodulating, and platelet function augmenting functions ResultsThe 6-month retrospective clinical evaluation indicated that phytotherapy might offer an effective and safe solution for controlling bleeding symptoms and improving platelet counts for refractory ITP patients. Moreover, phytotherapy also significantly improved patients' red cell count, hemoglobulin, and liver enzyme levels compared to baseline data. ConclusionsIn individual cases and economically disadvantaged regions, investigating and applying an appropriate combination of phytotherapy based on scientific knowledge and traditional folk medical experiences might offer an effective, inexpensive, and safe solution for refractory ITP and other bleeding disorders.