Rebound Thrombocytosis Research Articles

Efficacy of venetoclax combined azacitidine in newly diagnosed acute myeloid leukemia unfit for standard chemotherapy: a single center experience

Objective: To investigate the effectiveness and safety of the VA regimen, which combines venetoclax with azacitidine in the treatment of patients with newly diagnosed acute myeloid leukemia (AML) who are not suitable candidates for conventional chemotherapy. Methods: In the Department of Hematology at the Second Hospital of Hebei Medical University, 66 AML patients who received venetoclax and azacitidine treatment from May 2020 to March 2022 were the subject of a retrospective study. The complete remission (CR) rate, cCR rate, ORR rate, MRD negative rate, the incidence of adverse events,1-year EFS, and OS were retrospectively analyzed. Patients subgroups with varying ages, ECOG scores, primary and secondary, risk stratifications, and gene mutation were compared for differences in efficacy and survival. Results: The median follow-up was 4.25 (0.9-19.9) months, and the median number of treatment courses was 2 (1-8) cycles. After the first cycle, the cCR rate was 78.8% , and the MRD negative rate was 51.9% . After prolonged treatment, the cCR rate was 81.8% and MRD negative rate was 66.7% . The median EFS and OS, respectively, were13.2 and 15.3 months. Secondary AML showed inferior efficacy and prognosis. IDH1/2 or NPM1 mutation groups had a significantly higher rate of CR than the control group (P<0.05) . The CR rate and MRD negative rate of patients with rebound thrombocytosis were significantly higher than those without rebound thrombocytosis (P<0.05) . Those who had epigenetic modification mutations (DNMT3, ASXL1, TET2) were more likely to benefit from ongoing therapy. The most common grade 3 and 4 adverse reactions were neutropenia, thrombocytopenia, and anemia. Conclusions: In real-world patients with newly diagnosed AML who are not candidates for standard chemotherapy, the VA regimen produces rapid deep remission. Primary AML patients, rebound thrombocytosis, IDH1/2, and NPM1 gene mutations are favorable factors for treatment benefit, and adverse reactions were tolerable.

THROMBOSIS DURING VENETOCLAX TREATMENT FOR ACUTE MYELOID LEUKEMIA WITH THE 3Q21Q26 SYNDROME: CRITICAL SURVEILLANCE URGENTLY NEEDED

Acute myeloid leukemia (AML) is associated with dismal outcomes, especially in older patients. The use of intensive chemotherapy currently represents the most common option for young/adult AML patients. Nevertheless, older patients are frequently ineligible for it or have a disease that is refractory to standard chemotherapy. As an alternative, azacitidine or decitabine monotherapy has been used, but hypomethylating agents have been associated with a low chance of survival. Since the results of Viale-A got published in August 2020, we have been living a new era in Hematology due to the possibility of treating elderly patients with AML suffering from comorbidities. The most frequent adverse events of the azacitidine-venetoclax combination were thrombocytopenia, neutropenia, and febrile neutropenia in 45%, 42%, and 42% of the cases, respectively. But now, in real clinical practice outside of a clinical trial, we have detected a few cases with rebound thrombocytosis during initial cycles of treatment. Describe an AML patient who presented thrombosis of the arm due to very high thrombocytosis of 1,550 x 109/L during the first cycle of azacitidine-venetoclax treatment. Our patient presented translocation involving the long arm of chromosome 3 at 3q26 in which myeloid disorders had already been identified as 3q21q26 syndrome. Very recently, Othman et al. reported the incidence of rebound thrombocytosis without clinical manifestation during azacitidine-venetoclax combination for AML treatment. No case presented had such high platelet count and thrombosis as presented herein. Othman et al. suggested rebound thrombocytosis would be due to the capability of blasts to hide thrombopoietin (TPO) via increased expression of TPO receptor MPL, but the mechanism underlying the thrombocytosis remains unclear. The 3q21q26 syndrome is rare but occurs in a high-risk myelodysplastic syndrome (MDS) or the setting of AML and is commonly associated with thrombocytosis. These chromosomal abnormalities result in aberrant expression of the protooncogene ecotropic virus integration site – 1 ( EVI1 ) located at 3q26.2, and through mechanisms not completely understood, myeloid and erythroid differentiation are profoundly suppressed while the megakaryocytic lineage shows marked hyperplasia. This case illustrates the importance of critical surveillance of platelet count during the initial cycle of venetoclax plus azacytidine.

Extreme Thrombocytosis: Influence of Care Setting and Likelihood of Occult Malignancy

IntroductionExtreme thrombocytosis (EXT) is defined as platelet count >1,000x109/L. The objectives of our study were: 1) to describe the causes of EXT in both the inpatient and outpatient settings, and 2) to determine the frequency of occult malignancy as a cause of EXT.MethodsWe conducted a retrospective chart review of adult patients (age≥18 years) with EXT seen at Mayo Clinic from 2011-2016. We included patients who had ≥2 platelet counts >1,000x109/L within 30 days. Patients who declined a bone marrow biopsy were excluded. For each patient, we determined potential contributing causes of EXT and identified the most likely dominant cause.ResultsWe identified 44,490 patients with thrombocytosis, of which 645 patients (1.4%) had EXT. We excluded 340 patients including 337 patients who did not meet the criteria for two readings of EXT, and 3 who did not undergo bone marrow biopsy. The remaining 305 patients included 109 outpatients (35.7%) and 196 inpatients (64.3%). The median age was 57 (range: 18-95 years) and the majority were females (52.1%). The median peak platelet count was 1,242x109/L (1,009x109/L -3,209 x109/L), and the median duration of EXT was 6 days (range: 2-389 days).The causes of EXT were as follows: 31.1% of all the patients had a previous or a new diagnosis of hematologic cancer, predominately myeloproliferative neoplasms; the remaining 68.9% had either recent surgeries or a variety of non-malignant medical conditions. Because 79.3% of patients had more than one identifiable causes of EXT, we assigned the dominant cause based on (1) the temporal association between the platelet trend and the factor and (2) the extent of platelet increase attributed to the factor. The dominant causes of EXT are shown in the Table 1. The majority (82.0%) of the EXT occurred in the setting of splenectomy, other surgeries, or hematologic cancers. In the absence of surgery or hematologic cancer, infection/inflammation was an infrequent cause of EXT (8.9%). While iron deficiency was relatively common (15.4%), it was never identified as the sole cause of EXT, and rarely (0.3%) as the dominant cause. In 2.3% of the patients, EXT was associated with rebound thrombocytosis after chemotherapy. The contributing causes of EXT varied according to the care setting as depicted in the Figure 1. Surgery and infection were the dominant causes in the inpatient setting. In contrast, hematologic cancers and iron deficiency were the major causes in the outpatient setting.During the evaluation of EXT, 38 (12.5%) patients were diagnosed with new malignancies. Of these, 33 (86.8%) were hematologic cancers (30 myeloproliferative neoplasms, 2 diffuse large B-cell lymphoma and 1 acute myeloid leukemia). In 5 patients, solid cancers were discovered (2 colon cancers, 1 ovarian cancer, 1 gastric cancer and 1 squamous cell carcinoma of the mandible). Outpatients were twice as likely to be diagnosed with new cancers as inpatients (18.4% vs 9.2%).ConclusionsIn our study, EXT was often multifactorial. Contributing factors varied by care setting. The most common causes were surgery (including splenectomy) in inpatients, and hematologic cancers in outpatients. EXT was a presenting manifestation of occult malignancy in over 10% of cases. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Cyclical Thrombocytopenia— a Rare but Fatal Imitator of Idiopathic Thrombocytopenia

AbstractLearning Objective 1: Recognize the patterns needed for diagnosing cyclical thrombocytopeniaLearning Objective 2: Distinguish the potentially life threatening features of cyclical thrombocytopenia as compared to idiopathic thrombocytopeniaCase Report: A 42 year old female of Eastern European origin, with a past medical history of systemic lupus erythematosis (SLE), was referred to outpatient hematology for management of her presumed diagnosis of idiopathic thrombocytopenia (ITP). Previous treatments including Aspirin, Eltrombopag, Azathioprine, Prednisone, Rituximab, Intravenous Immunoglobulin (IVIG) and splenectomy had been unsuccessful in raising her platelet count. The patient experienced symptoms of thrombocytopenia which included diffuse petechiae, mucosal petechiae, self-limiting epistaxis and significant menorrhagia which required hysterectomy. Symptoms were intermittent and occurred approximately once a month.Upon investigating the patient's previous lab work, a cyclic pattern of thrombocytopenia alternating with rebound thrombocytosis was revealed. A nadir of platelet count as low as 1000/mm3 with a peak count of as high as 2,000,000/mm3 was observed occurring approximately every 28 days. Interestingly, a similar pattern was noticed in the white blood cell levels. A correlation was also seen with her reproductive hormone levels, with luteinizing hormone running synchronously and estradiol cycling inversely to the platelet trends. This laboratory pattern, coupled with her lack of response to the aforementioned therapies, allowed us to make a diagnosis of cyclical thrombocytopenia (CT). Although the patient did not always experience symptoms during periods of rebound thrombocytosis, over the years, thrombotic events included lower extremity deep venous thrombosis and a myocardial infarction thought to be a result of peaked platelet levels.Treatment since the diagnosis of CT was made included Eltrombopag, Romiplostim, and Prednisone with dose adjustment at two-week intervals depending on her most recent platelet levels. Hormone therapy was trialed using Premarin, a conjugated estrogen therapy. Concurrent management of SLE with Belimumab was also held for a period of time. A combination of these interventions decreased the life threatening peaks but failed to inhibit platelet nadirs.Discussion: Cyclical thrombocytopenia is a rare but potentially life threatening condition. A recent literature review identified only 51 reported cases. Correlation with cyclical leukocytosis is found in a small subset of CT patients making it a more uncommon variant. Diagnosis is challenging and most patients are misdiagnosed with ITP. Differentiating CT from ITP is crucial to prevent life threatening thrombotic events. Differentiating factors include rebound cyclical thrombocytosis alternating with cyclical thrombocytopenia. These cycles typically occur every 28 days. CT patients may have a history of thrombotic events in addition to typical ITP symptoms and may fail to respond to conventional ITP therapies. CT predominantly affects pre-menopausal females, however, post-menopausal females and men may also be affected. The pathophysiology of CT is poorly understood. Multiple theories exist including intermittent autoimmune destruction of platelets, cyclical fluctuations of megakaryocytes, and abnormal biochemical signaling between cytokines and hematopoietic cells. An association with female reproductive hormones and a positive response to hormone therapy has also been documented in the literature. More research is needed to fully understand the pathogenesis of CT. Such an understanding may increase identification of the disease, provide better treatment modalities, and prevent poor outcomes in these patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

CREB3L1 Overexpression Can Reliably Discriminate Ph-MPNs from Reactive Cases

Discrimination of Philadelphia-negative myeloproliferative neoplasms (Ph-MPNs) from reactive hypercytosis and myelofibrosis is imperative because treatment strategies differ greatly, and an exhaustive search for the underlying cause becomes mandatory in reactive cases. However, discrimination is not necessarily easy in the real-world setting, and a simple and universally utilizable method that can efficiently differentiate Ph-MPNs from reactive cases is awaited. We extracted platelet rich plasma (PRP) derived RNAs from 9 essential thrombocythemia (ET) patients (3 patients with JAK2V617F, 3 patients with MPLW515L/K, and 3 patients with CALR exon 9 frameshift mutation) and 6 patients with reactive thrombocytosis (3 cases due to chronic inflammation, and 3 cases due to rebound thrombocytosis) and performed RNA-seq to identify a gene expressed specifically in ET. RNA-seq analysis followed by differential expression and principal component analysis revealed that CREB3L1 had the highest impact in discriminating ET from reactive cases. Subsequently, expression levels of CREB3L1 in PRP were quantified by reverse transcription quantitative PCR and compared within patients with various Ph-MPNs harboring either JAK2, MPL, or CALR mutations, chronic myeloid leukemia (CML), and reactive cases, and found that CREB3L1 expression levels were significantly higher in 66 ET compared to 33 reactive thrombocytosis (p &amp;lt; 0.0001), 26 polycythemia vera (PV) compared to 23 reactive erythrocytosis (p &amp;lt; 0.0001), 22 primary myelofibrosis and 15 post-PV/ET myelofibrosis (MF) compared to 3 reactive MF (p &amp;lt; 0.001, and p &amp;lt; 0.01, respectively), and the entire cohort of 129 Ph-MPN compared to 5 CML patients (p &amp;lt; 0.001). A clear cut-off value discriminating Ph-MPNs and non-Ph-MPNs was determined, and sensitivity and specificity were both 1.0000. Furthermore, when we tested CREB3L1 expression levels of triple-negative cases with thrombocytosis, all patients with CREB3L1 overexpression were pathologically diagnosed as ET by bone marrow biopsy. We demonstrate that CREB3L1 overexpression can single-handedly and reliably discriminate Ph-MPNs from reactive hypercytosis, reactive myelofibrosis, and CML. Early utilization of this method in the diagnostic process can guide patients to an efficient diagnosis and free many patients from unnecessary testing. Disclosures Komatsu: Otsuka Pharmaceutical Co., Ltd., PharmaEssentia Japan KK, AbbVie GK, Celgene KK, Novartis Pharma KK, Shire Japan KK, Japan Tobacco Inc: Consultancy; Takeda Pharmaceutical Co., Ltd, Novartis Pharma KK, Shire Japan KK: Speakers Bureau; AbbVie: Other: member of safety assessment committee in M13-834 clinical trial.; PPMX: Consultancy, Research Funding; Otsuka Pharmaceutical Co., Ltd., Shire Japan KK, Novartis Pharma KK, PharmaEssentia Japan KK, Fuso Pharmaceutical Industries, Ltd., Fujifilm Wako Pure Chemical Corporation, Chugai Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Takeda Pharmaceutica: Research Funding; Meiji Seika Pharma Co., Ltd.: Patents &amp; Royalties: PCT/JP2020/008434, Research Funding.

English

BACKGROUND We wanted to evaluate the role of platelet indices in differentiating reactive and clonal thrombocytosis. METHODS This is a cross sectional observational study conducted for two years among 150 patients with platelet counts of 5 lac and above. Thrombocytosis and utility of platelet indices like Mean Platelet Volume (MPV), Platelet Distribution Width (PDW) for the differential diagnosis of thrombocytosis were done. RESULTS Out of total 150 cases, 144 (96 %) had reactive thrombocytosis, and 6 (4 %) had clonal thrombocytosis. Infectious aetiology is seen in 64 (42.6 %), tissue injury 35 (23 %), rebound thrombocytosis 22 (14.6 %), anaemia 13 (8.6 %), multiple causes 8 (5.3 %), clonal aetiology 6 (4 %), and inflammatory 2 (1.3 %). Patients with reactive thrombocytosis showed a lower mean platelet volume and platelet distribution width compared to primary thrombocytosis. In reactive thrombocytosis MPV range, 6.0 - 8.0 fl with mean MPV 6.5 fl and PDW ranges from 14.0 - 16.2 % with mean PDW 15.3 %. In clonal thrombocytosis MPV range, 6.9 - 8.5 fl with mean MPV 7.9 fl and PDW range was 15.9 - 17.2 % with mean PDW 16.4 %. CONCLUSIONS On analysing the platelet counts and indices, patients with high counts, low MPV and PDW suggested reactive aetiology and patients with high counts and high MPV and PDW suggested clonal aetiology. KEYWORDS Thrombocytosis, Mean Platelet Volume, Platelet Distribution Width

Rebound Thrombocytosis after Induction Chemotherapy Is a Strong Biomarker for Favorable Outcome in AML Patients

Background: Whereas the molecular events underlying acute myeloid leukemia (AML) are increasingly identified, dynamics of hematologic suppression and recovery following induction chemotherapy remain enigmatic. In addition, thrombocytopenia at diagnosis is related to deregulated cytokine expression in specific leukemia subtypes rather than on the degree of bone marrow infiltration per se. Similarly, recovery of platelets after the first induction cycle among individual patients can vary from incomplete to excess recovery even if morphologic remission is achieved. In particular, excess platelet rebound (EPR) with values exceeding 500 G/L can be observed in some patients. However, this clinical observation of EPR is poorly understood so far, and its prognostic relevance is unknown. Methods: We analyzed platelet recovery after the first induction cycle in 291 consecutive AML patients receiving at least one cycle of intensive "3+7" based induction treatment. We defined excess platelet rebound (EPR) as a platelet increase above 500 G/L during hematologic recovery after the first induction cycle. Results: We observed EPR in 120 (41.2%) patients. EPR+ patients had lower platelets at diagnosis, higher marrow infiltration, more frequently NPM1 mutations, and were associated with ELN favorable risk. Absence of EPR correlated with complex karyotypes, ELN intermediate-I and adverse risk, and therapy-related AML. Overall survival was better in EPR+ patients than EPR- (median 125 versus 41 months; P=0.04), as was disease-free survival (Figure 1). By multivariate analysis, achievement of EPR+ was an independent parameter associated with favorable survival. Plasma thrombopoietin (TPO) levels at diagnosis indicated EPR+ (p&lt;0.0001), while GATA-1, GATA-2 and MPL mRNA expression did not differ between EPR+ and EPR- patients. Finally, transcription factors blocking early megakaryopoiesis were upregulated in EPR- patients, while NFE2 involved in late megakaryocyte differentiation was increased in EPR+ patients. Conclusion: This study suggests that excess platelet rebound (EPR+) defined as platelets exceeding 500 G/L is a common event identified in AML patients after the first induction cycle. EPR+ was predominantly observed in ELN favorable risk AML, and it was associated with significantly better overall and disease-free survival as compared to EPR- patients. In addition, achievement of EPR+ represented an independent prognostic parameter for improved survival in a multivariate analysis, and may contribute to prognostic assessment in AML patients undergoing intensive treatment with intention to cure. Disclosures No relevant conflicts of interest to declare.

Abstract 360: Therapeutic potential of EC-18 as a chemotherapy adjuvant for 5-fluorouracil-induced neutropenia

Abstract Chemotherapy-induced neutropenia (CIN) is a complication that arises during cancer treatment and necessitates dose reduction. Preventing CIN and maintaining absolute neutrophil counts (ANC) is critical for successful chemotherapy because a rapid decline of neutrophils increases susceptibility to infection. Here, we investigated whether administration of EC-18 has therapeutic effects on the treatment of CIN in 5-fluorouracil (5-FU)-induced neutropenia mouse model. A single injection of 5-FU 100mg/kg reduced the ANC in the control, EC-18 125 and EC-18 250mg/kg-treated cohort from pre-injection values to &amp;lt;500 cells/μL by 5.2±0.45, 5.8±0.45 and 5.8±0.45 days, respectively. The administration of EC-18 in 5-FU-injected mice resulted in significant reduction in the duration of neutropenia and the time to recovery of ANC &amp;gt;1000 cells/μL. EC-18 125 or 250mg/kg significantly reduced the duration of neutropenia from 7.4±1.14 days to 2.6±0.55 or 3.0±0.71 days, respectively. Moreover, the ANC of all individuals in the control cohort fell to severely neutropenic range (ANC &amp;lt;100 cells/μL), while only 20% of individuals in both EC-18 125 and 250mg/kg-treated cohorts experienced severe neutropenia. EC-18 also reduced the duration of severe neutropenia from 5.2±1.48 days to 2 days. EC-18 125 or 250mg/kg administration significantly increased the mean nadir after 5-FU injection from 2.0±4.47 cells/μL to 236±4.47 or 158±11.32 cells/μL, respectively. The time of recovery to an ANC ≥500 or 1000 cells/ μL was significantly reduced in EC-18 125 and 250 mg/kg-treated cohorts. Besides neutropenia, a single treatment of 5-FU induced the reduction of blood monocytes and eosinophils, similar to the pattern of the decrease of neutrophil counts. The administration of EC-18 125 or 250mg/kg in 5-FU-injected mice remarkably prevented the reduction of blood monocytes and eosinophils. In this study, thrombocytopenia is defined as a 50% or greater reduction in platelet count from baseline, and 2-fold or greater increase of platelet count from baseline for thrombocytosis. 5-FU treatment induced the moderate thrombocytopenia from 4 to 6 days and followed by a more pronounced and prolonged rebound thrombocytosis. EC-18 significantly reduced the extreme change in platelet counts, thus preventing 5-FU-induced thrombocytopenia and thrombocytosis. Moreover, EC-18 effectively prevented a constant reduction of red blood cell (RBC) count induced by 5-FU treatment. Based on the observations in this study, we concluded that EC-18 has therapeutic potential as a chemotherapy adjuvant for the treatment of 5-FU-induced CIN as well as chemotherapy-associated other hematologic disorders. Citation Format: Yong-Jae Kim, Jinseon Jeong, Ki-Young Sohn, Do Young Lee, Sun Young Yoon, Jae Wha Kim. Therapeutic potential of EC-18 as a chemotherapy adjuvant for 5-fluorouracil-induced neutropenia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 360.

Rebound Thrombocytosis after Induction Chemotherapy is a Strong Biomarker for Favorable Outcome in AML Patients.

Whereas the molecular events underlying acute myeloid leukemia (AML) are increasingly identified, dynamics of hematologic recovery following induction chemotherapy remain mysterious. Platelet recovery may vary between incomplete and excess recovery among patients achieving remission. We analyzed platelet recovery after the first induction cycle in 291 consecutive AML patients. We defined excess platelet rebound (EPR) as platelet increase above 500 G/L. We observed EPR in 120 (41.2%) patients. EPR+ patients had lower platelets at diagnosis, higher marrow infiltration, more frequently NPM1 mutations, and were associated with ELN favorable risk. Absence of EPR correlated with complex karyotypes, ELN intermediate-I and adverse risk, and therapy-related AML. Overall survival was better in EPR+ patients than EPR- (median 125 vs 41 months; p = 0.04), as was disease-free survival. By multivariate analysis, EPR+ was an independent parameter associated with favorable survival. Plasma thrombopoietin (TPO) levels at diagnosis indicated EPR+ (p < 0.0001), while GATA-1, GATA-2, and MPL mRNA expression did not differ between EPR+ and EPR- patients. Finally, transcription factors blocking early megakaryopoiesis were upregulated in EPR- patients, while NFE2 involved in late megakaryocyte differentiation was increased in EPR+ patients. Our work identifies mechanisms involved in platelet recovery after induction chemotherapy.

A guideline for the management of specific situations in polycythaemia vera and secondary erythrocytosis: A British Society for Haematology Guideline.

The previous BSH guideline for the management of erythrocytosis was published in 2005 (McMullin et al, 2005) and amended in 2007 (McMullin et al, 2007). Here, we re‐evaluate the literature formulate guidance on the management of specific situations encountered in polycythaemia vera (PV) and the management of the other types of secondary erythrocytosis. Recommendations for the diagnostic pathway of investigation of an erythrocytosis, risk stratification and management of PV are in the accompanying guideline (McMullin et al, 2018). We review evidence and outline guidance on management of acute thrombotic events and secondary prevention of thrombosis in PV. The unusual thrombotic events, splanchnic vein and cerebral vein thromboses are discussed and haemorrhage. The specific situations of surgery and pregnancy and guidance on management of pruritus are included. The evidence for the management of other causes of erythrocytosis, including idiopathic erythrocytosis, congenital erythrocytosis, hypoxic pulmonary disease and post‐transplant erythrocytosis, is reviewed and recommendations made.

PKC-epsilon deficiency alters progenitor cell populations in favor of megakaryopoiesis.

BackgroundIt has long been postulated that Protein Kinase C (PKC) is an important regulator of megakaryopoiesis. Recent contributions to the literature have outlined the functions of several individual PKC isoforms with regard to megakaryocyte differentiation and platelet production. However, the exact role of PKCε remains elusive.ObjectiveTo delineate the role of PKCε in megakaryopoiesis.Approach and resultsWe used a PKCε knockout mouse model to examine the effect of PKCε deficiency on platelet mass, megakaryocyte mass, and bone marrow progenitor cell distribution. We also investigated platelet recovery in PKCε null mice and TPO-mediated signaling in PKCε null megakaryocytes. PKCε null mice have higher platelet counts due to increased platelet production compared to WT littermate controls (p<0.05, n = 8). Furthermore, PKCε null mice have more bone marrow megakaryocyte progenitor cells than WT littermate control mice. Additionally, thrombopoietin-mediated signaling is perturbed in PKCε null mice as Akt and ERK1/2 phosphorylation are enhanced in PKCε null megakaryocytes stimulated with thrombopoietin. Finally, in response to immune-induced thrombocytopenia, PKCε null mice recovered faster and had higher rebound thrombocytosis than WT littermate control mice.ConclusionsEnhanced platelet recovery could be due to an increase in megakaryocyte progenitor cells found in PKCε null mice as well as enhanced thrombopoietin-mediated signaling observed in PKCε deficient megakaryocytes. These data suggest that PKCε is a negative regulator of megakaryopoiesis.

Changes in novel haematological parameters following thermal injury: A prospective observational cohort study

The mortality caused by sepsis is high following thermal injury. Diagnosis is difficult due to the ongoing systemic inflammatory response. Previous studies suggest that cellular parameters may show promise as diagnostic markers of sepsis. The aim of this study was to evaluate the effect of thermal injury on novel haematological parameters and to study their association with clinical outcomes. Haematological analysis was performed using a Sysmex XN-1000 analyser on blood samples acquired on the day of the thermal injury to 12 months post-injury in 39 patients (15–95% TBSA). Platelet counts had a nadir at day 3 followed by a rebound thrombocytosis at day 21, with nadir values significantly lower in septic patients. Measurements of extended neutrophil parameters (NEUT-Y and NEUT-RI) demonstrated that septic patients had significantly higher levels of neutrophil nucleic acid content. A combination of platelet impedance count (PLT-I) and NEUT-Y at day 3 post-injury exhibited good discriminatory power for the identifying septic patients (AUROC = 0.915, 95% CI [0.827, 1.000]). Importantly, the model had improved performance when adjusted for mortality with an AUROC of 0.974 (0.931, 1.000). A combination of PLT-I and NEUT-Y show potential for the early diagnosis of sepsis post-burn injury. Importantly, these tests can be performed rapidly and require a small volume of whole blood highlighting their potential utility in clinical practice.

Rebound thrombocytosis and persistence of clinical symptoms after recovery from dengue hemorrhagic fever

Rebound thrombocytosis and persistence of clinical symptoms after recovery from dengue hemorrhagic fever

Platelet Counts and Genetic Polymorphisms of Alcohol Dehydrogenase-1B and Aldehyde Dehydrogenase-2 in Japanese Alcoholic Men.

Thrombocytopenia during intoxication, rebound thrombocytosis during 1 to 3weeks of abstinence, and subsequent normalization of the platelet count are common in alcoholics. We evaluated 989 Japanese alcoholic men to identify the effects of genetic polymorphisms of alcohol dehydrogenase-1B (ADH1B; rs1229984) and aldehyde dehydrogenase-2 (ALDH2; rs671) on platelet counts during an 8-week in-hospital abstinence period. Thrombocytopenia (<15×104 /μl) was observed in 25.9% of the subjects upon admission. The platelet counts increased from 21.4±0.3×104 /μl (mean±SE) to 27.6±0.3×104 /μl, and a rebound platelet increase of ≥10×104 /μl was observed in 28.6% of the patients during the first 2weeks after admission. By 4weeks, the mean platelet counts had returned to intermediate levels and remained stable thereafter. The reversible suppression and rebound increase in the platelet counts were more prominent in the slow-metabolizing ADH1B*1/*1 group than in the fast-metabolizing ADH1B*2 group. Throughout the 8weeks, the mean platelet counts of the active ALDH2*1/*1 group were consistently lower than those in the inactive ALDH2*1/*2 group. Cirrhosis was a strong determinant of a lower platelet count. After adjustments for nongenetic factors including cirrhosis, multiple linear regression analyses showed that the ADH1B*1/*1 genotype was associated with a lower platelet count (partial regression coefficient=-1.3×104 /μl) on the admission day, but subsequently had a positive effect on the platelet count at 1 and 2weeks after admission (+1.5 and +3.8×104 /μl, respectively). The ALDH2*1/*1 genotype was associated with a lower platelet count (-2.1 to -3.9×104 /μl) consistently throughout the 8weeks. Multiple logistic regression analyses showed that the ADH1B*1/*1 genotype increased the risk of thrombocytopenia upon admission (odds ratio [95% confidence interval]=1.61 [1.14 to 2.27]) and of a rebound platelet increase during the first 2weeks (3.86 [2.79 to 5.34]). The ALDH2*1/*1 genotype increased the risk of thrombocytopenia upon admission (1.73 [1.06 to 2.82]). In alcoholics, the ADH1B*1/*1 genotype increased the risk of thrombocytopenia upon admission and of a rebound platelet increase 2weeks thereafter, while the ALDH2*1/*1 genotype was associated with lower platelet counts throughout the 8-week hospital stay.

Cyclic thrombocytopenia associated with menorrhagia

We studied a 17-year-old female P0 + 0 who presented with menorrhagia and cyclic thrombocytopenia (CTP). Cyclic changes were observed in platelet count in phase with menstruation with a nadir of 4–30 × 109/L and a rise of above 600 × 109/L noted over the 4 months period of the observation. Thrombocytopenia was associated with menorrhagia, gum bleeding and epistaxis, followed about 14 days later by normal or elevated platelet counts. Presenting packed cell volume (PCV), platelet count, and white blood cell (WBC) count were, 0.25 L/L, 4 × 109/L, and 6.8 × 109/L respectively, WBC and PCV all remain stable all through the period of study; antinuclear antibody, direct and indirect antiglobulin test was negative while flow cytometry for Gp IIb/IIIa and Ib were not done. Bone marrow examinations performed at the time of reduced platelet counts showed increased megakaryopoiesis. The patient was monitored and observed with only hematinics prescribed over the follow-up period, and menstrual suppression with combined oral contraceptives. CTP should always be suspected when a diagnosis of idiopathic thrombocytopenic purpura is entertained especially when there is a history of menorrhagia, thrombocytopenia, and rebound thrombocytosis.

Rebound Thrombocytosis following Induction Chemotherapy Is an Independent Predictor of a Good Prognosis in Acute Myeloid Leukemia Patients Attaining First Complete Remission

There are very few data about the relationship between acute myeloid leukemia (AML) prognosis and bone marrow recovery kinetics following chemotherapy. In this study, we aimed to assess the prognostic importance and clinical associations of neutrophil and platelet recovery rates and rebound thrombocytosis (RT) or neutrophilia (RN) in the postchemotherapy period for newly diagnosed AML patients. De novo AML patients diagnosed between October 2002 and December 2013 were evaluated retrospectively. One hundred patients were suitable for inclusion. Cox regression analysis using need for reinduction chemotherapy as a stratification parameter revealed RT as the only parameter predictive of OS, with borderline statistical significance (p = 0.06, OR = 7; 95% CI 0.92-53), and it was the only parameter predictive of DFS (p = 0.024, OR = 10; 95% CI 1.3-75). In order to understand whether RT or RN was related to a better marrow capacity or late consolidation, we considered neutrophil recovery time and platelet recovery time and nadir-first consolidation durations in all patients in the cohort. Both the marrow recovery duration and the time between marrow aplasia and first consolidation were shorter in RT and RN patients. To our knowledge, this is the first study to report a correlation between RT/RN and prognosis in AML.

Rebound Thrombocytosis Is an Independent Predictor of Good Prognosis in AML Patients Attaining First Complete Remission

We investigated the prognostic importance and clinical associations of neutrophil and platelet recovery rates and rebound thrombocytosis (RT) or neutrophilia (RN) in post-chemotherapy newly diagnosed AML patients. De novo AML patients who were diagnosed between October 2002 and December 2013 were evaluated retrospectively. The patients who attained first complete remission (CR) after one or two induction therapies were selected and their marrow aplasia periods preceding CR were considered. The patients who were transplanted were excluded. Neutrophil (NRT) and platelet recovery times (PRT) were accepted as the periods between neutrophil nadir and ³1000/µl neutrophil count and platelet nadir and ³50000/µl platelet count, respectively. The platelet nadir-to-first consolidation (PCT) and neutrophil nadir-to-first consolidation times (NCT) were computed. RN and RT thresholds were accepted as 7000/µl and 450000/µl respectively.There were 100 patients suitable for inclusion. The frequency of RT was 11/31, 6/19, 5/50 in patients with favorable ELN cytogenetic categories, normal karyotype, other cases, respectively (p=0.1). Cox regression analysis using need of reinduction therapy as stratification parameter revealed RT as the only parameter predicting both OS (p=0.06) and DFS (p=0.024). After understanding that RT525 (threshold 525000/ µl) is an independent prognostic parameter in AML patients, we tried to find its prognostics value in subgroups. There were 15 APL patients. Prognostic value of RT525 could not be determined due to low event rates. Only two patients experienced an event. Both events were mortalities during consolidation. There was one mortality in RT525 and no- RT525 groups each. There were 16 CBF-type AML patients. Four patients experienced an event. All events were relapses. All four events occurred in 12 cases without RT525 while none of four patients with RT525 experienced an event. However, statistical significance was not observed between groups in DFS (figure 1) and OS comparisons due to low event rates (p=0.17 and p=0.18 respectively). In other AML patients, there were 35 events (25 relapse, 10 deaths in CR). All of the events occurred in no-RT525 group. All RT525 cases in this group were living with CR at last follow-up. Both DFS (median [95% confidence interval] not reached versus 13.2 (6.1 - 20.2) months, p=0.004) (figure 2) and OS (not reached versus 17.0 (0 - 34.6) months, p<0.001) rates were higher in RT525 cases. In order to understand whether RT or RN were related to better marrow capacity or late consolidation, we considered NRT and PRT and nadir-first consolidation durations in all patients cohort. For RT group, the PRT was 10.3±5.2 days whereas it was 12.8±8.5 days for no-RT group (p=0.43). The NRT was 15.8±7.8 and 20.3±9.7 days in RN and no-RN groups respectively (p=0.07). For RT group, the PCT was 27.8±7.9 whereas it was 29.1±15.2 days for the group with no-RT (p=0.07). NCT was 30.2±11.2 and 34.6±18.2 days for RN and no-RN groups respectively (p=0.12). Both the marrow recovery duration and the time between marrow aplasia and first consolidation were shorter in RT and RN patients.To our knowledge, this is the first study that reports a correlation between RT/RN and prognosis in AML. Interestingly, RT was the only significant independent parameter in multivariate analyses also including classical prognostic risk factors for OS and DFS. The favorable prognosis associated with RT525 was evident in AML patients other than APL and CBF-type disease. However it could not be demonstrated in APL and CBF-type disease probably due to low event rates. In accordance with this suggestion there was a trend towards statistical significance in CBF-type disease (0/4 versus 4/12 relapses in RT525 and no-RT525 cases respectively, p=0.17). The marrow recovery time and the duration between marrow aplasia and first consolidation were shorter in RT and RN cases indicating better healthy hematopoiesis/marrow capacity in this group. As RT and RN are very easy to detect, they can be used as prognostic indicators in countries with limited laboratory facilities. These findings should be confirmed in other patient cohorts and preferably prospective studies. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Protein kinase C δ deficiency enhances megakaryopoiesis and recovery from thrombocytopenia.

We previously determined that protein kinase C δ (PKCδ) regulates platelet function. However, the function of PKCδ in megakaryopoiesis is unknown. Using PKCδ(-/-) and wild-type littermate mice, we found that deficiency of PKCδ caused an increase in white blood cells and platelet counts, as well as in bone marrow and splenic megakaryocytes (P<0.05). Additionally, the megakaryocyte number and DNA content were enhanced in PKCδ(-/-) mouse bone marrow after culturing with exogenous thrombopoietin compared with wild-type (P<0.05). Importantly, thrombopoietin-induced signaling was also altered with PKCδ deletion because both extracellular signal-regulated kinase and Akt308 phosphorylation were heightened in PKCδ(-/-) megakaryocytes compared with wild-type. Finally, PKCδ(-/-) mice recovered faster and had a heightened rebound thrombocytosis after thrombocytopenic challenge. These data suggest that PKCδ is an important megakaryopoietic protein, which regulates signaling induced by thrombopoietin and represents a potential therapeutic target.

Severe romiplostim-induced rebound thrombocytopenia after splenectomy for refractory ITP.

To report a case of severe rebound thrombocytopenia after temporary discontinuation of romiplostim during splenectomy in the context of refractory immune (idiopathic) thrombocytopenic purpura (ITP). A 65-year-old man with a history of severe refractory ITP failing multiple treatments was considered for romiplostim therapy. He was initiated on 1 µg/kg and titrated upward to 4 µg/kg to elevate and stabilize his platelet levels prior to splenectomy. On day 74 of his clinical course, his platelets increased to 434 × 10(9)/L, and his scheduled dose of romiplostim was withheld on day 75 for fear of romiplostim-induced postsplenectomy rebound thrombocytosis. On day 78, his platelets dropped precipitously to 9 × 10(9)/L, and he experienced multiple episodes of epistaxis. He was reinitiated at 5 µg/kg and soon recovered. He later missed a scheduled dose of romiplostim, and his platelets fell to 23 × 10(9)/L. After resuming romiplostim at 8 µg/kg, his platelets continued to recover. Romiplostim, a thrombopoietin mimetic is directly regulated by megakaryocytes and existing circulating platelets via a negative feedback mechanism. This explains the theoretical risk of rapid clearance of romiplostim caused by an increased platelet pool. Clinically, alternative causes of his severe postoperative thrombocytopenia were considered and deemed unlikely. The rebound effect was observed after romiplostim was withdrawn on 2 occasions, and platelet counts improved after restarting romiplostim. The Naranjo Adverse Drug Reaction Probability Score of 7 suggests a probable adverse drug reaction. Physicians using romiplostim as a bridge to splenectomy should be cautious about withholding a scheduled dose around the time of surgery.

Plateletpheresis for postsplenectomy rebound thrombocytosis in a patient with chronic immune thrombocytopenic purpura on romiplostim

Immune thrombocytopenic purpura (ITP) is an autoimmune disease in which IgG-coated platelets are removed from circulation by the spleen, and platelet production is impaired due to increased thrombopoietin (TPO) clearance. Romiplostim, a novel TPO-mimetic agent, is approved for patients with ITP that are unresponsive to traditional treatments. However, there is little experience when using this drug before splenectomy. We describe herein the case of a young female with chronic ITP who was treated with romiplostim, underwent splenectomy shortly thereafter, and required plateletpheresis for postoperative rebound thrombocytosis with concomitant neurologic symptoms.