Acute Severe Thrombocytopenia Research Articles

Long-Term Durability of Eltrombopag Clinical Benefit for Advanced Myelodysplastic Syndromes or Acute Myeloid Leukemia and Severe Thrombocytopenia (ASPIRE Part 3)

Thrombocytopenia is a common complication in patients (pts) with advanced myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) that is associated with significant morbidity, a clinically significant bleeding risk, and early death. There are only limited treatment options for this high-risk population. Previous trials (Frey et al. ASH 2012) of thrombopoietin receptor agonists (TPO-RAs) for thrombocytopenia treatment in these pts suggested reduced thrombocytopenia-associated bleeding. ASPIRE (NCT01440374) was a multicenter, phase 2 trial. Eligible pts were ≥18 years, with high-risk MDS or AML, thrombocytopenia (platelets ≤25 x 109/L) due to bone marrow insufficiency, bone marrow blasts ≤50%, and an Eastern Cooperative Oncology Group status of 0-2. Exclusion criteria included platelets ≤10 x 109/L for reasons other than bone marrow insufficiency; leukocyte count ≥25 x 109/L; previous TPO-RA treatment. Pts were severely ill, on no other anti-MDS/AML therapy, with an expected median survival of ~6 months on treatment. Part 1 was an 8-week open-label study of eltrombopag 100 mg/day with dose escalation up to 300 mg/day (Mittelman et al. ASH 2012). Part 2 was a 12-week randomized, double-blind trial, during which pts received eltrombopag or placebo (Mittelman et al. Lancet Haematol 2018). Pts who completed both parts continued to Part 3, an extension phase of 10 months (for pts from Part 1) and 9 months (for pts from Part 2) (Fig. 1A). In ASPIRE Part 2, eltrombopag reduced the frequency of clinically relevant thrombocytopenic events (CRTEs) (one or more ≥Grade 3 hemorrhagic adverse events [AEs], platelets ≤10 x 109/L, or platelet transfusions) compared with placebo during weeks 5-12 in pts with advanced MDS or AML. Here we present data on the long-term durability of clinical benefit, overall survival (OS) and progression-free survival (PFS) for Part 2 pts within Part 2 and Part 3, and safety and tolerability of eltrombopag monotherapy in pts with advanced MDS or AML. Mean pt age was 72.2 years. Pts received a median eltrombopag daily dose of 298.8 mg with a median exposure of 11.1 weeks. At baseline, 40% of pts had an abnormal karyotype and 68% were platelet transfusion-dependent. OS (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.64-1.48) and PFS (HR 0.99, 95% CI 0.68-1.43) were not significantly different between long-term eltrombopag and placebo to eltrombopag switchers in Part 3 (median OS of 4.3 months vs 4.6 months, respectively). Median PFS was 0.94 months and 1.08 months for the placebo and eltrombopag group, respectively. CRTEs were summarized by week with the proportion of pts plotted by visit. Pts experienced large variability in CRTEs during weeks 1-40 with inconclusive results due to low number of pts at some time points (Fig. 1B). Hematological improvement (HI) was defined as improvement (platelets, neutrophils, hemoglobin) on treatment compared with placebo (Cheson et al. Blood 2006). Overall, 33% of pts showed HI with long-term eltrombopag use, compared with 10% during the double-blind phase. However, HI did not reach statistical significance compared with placebo in the double-blind phase. 46% of pts completed treatment. The main reasons for treatment discontinuation were physician decision (24%) and AEs (22%). Overall, 97% of pts experienced an AE during the extension phase plus 30 days. The most common AEs (≥20% of pts) were pyrexia, nausea, diarrhea, and epistaxis. Overall, 56% of pts died, with the disease under study being the most common cause (36%), and 37% of pts had treatment-related AEs. 31% of pts experienced Grade 3 or 4 AEs. The most commonly reported (>5%) were pneumonia, febrile neutropenia, anemia, hypokalemia, and urinary tract infection. Overall, 66% of pts experienced a serious AE (SAE). The most common (≥10%) were pneumonia, pyrexia, febrile neutropenia, and sepsis. The most common fatal SAEs (≥5%) were sepsis, pneumonia, and cardiac failure. ASPIRE Part 3 did not identify any new safety signals. The most common AEs were consistent with those expected for the disease under study and with eltrombopag treatment. There was no evidence of reduced OS or PFS. More pts met the criteria for HI with long-term eltrombopag use compared with those in the double-blind phase. The large CRTE variability observed with eltrombopag during Part 3 requires further assessment in adequately powered trials of high-risk MDS or AML pts and in a less seriously ill population. Figure 1 Disclosures Mittelman: Novartis: Honoraria, Research Funding, Speakers Bureau. Platzbecker:Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Portella:Novartis: Employment. Zhu:Novartis: Employment. Selleslag:Celyad: Other: Clinical trial research (no honoraria recieved); Novartis: Consultancy, Honoraria, Speakers Bureau. OffLabel Disclosure: Eltrombopag is used for the treatment of thrombocytopenia in adult and pediatric patients 1 year and older with chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Eltrombopag is not indicated for the treatment of patients with myelodysplastic syndrome (MDS).

The effect of recombinant human thrombopoietin (rhTPO) on sepsis patients with acute severe thrombocytopenia: a study protocol for a multicentre randomised controlled trial (RESCUE trial)

BackgroundSepsis is still a common critical disease with high morbidity and mortality in intensive care unit. Despite published guidelines for sepsis, development of antibiotic therapy and advanced organ support technologies, the mortality of sepsis patients is still 25% or more. It is necessary to distinguish the subtypes of sepsis, and the targeted therapy for the patients need to be explored. Platelets have various biological functions in hemostasis and thrombosis, host defense, inflammatory/immune responses and tissue repair/regeneration. Moreover, severe thrombocytopenia or sustained thrombocytopenia was closely associated with multiply organ dysfunction and higher mortality in sepsis patients. The clinical therapies for thrombocytopenia are platelet transfusion and platelet-elevating drugs. However, platelet transfusion has many defects in clinical practice in sepsis patients, and the impact of platelet-elevating drugs for sepsis patients is still unclear. RESCUE trial is aim to explore the effect of a platelet-elevating drug, recombinant human thrombopoietin (rhTPO), as an effective rescue therapy on sepsis patients with acute severe thrombocytopenia.MethodsIt is a randomized, open-label, multi-center, controlled trial in 5 tertiary academic hospitals including medical, surgical or general ICUs. In this study, a total of 200 sepsis patients with severe thrombocytopenia will be randomly assigned in a 1:1 ratio to the control and rhTPO group. The patients will be followed up to 28 days after randomization. All patients in two groups receive the same treatment based on the guideline of Surviving Sepsis Campaign. Primary outcome is 28-day mortality. Secondary outcomes are the changes of PCs, blood transfusion, biomarkers of infection and organ function, days free from advanced organ support, drug-related adverse events, the length of ICU and hospital stay.DiscussionRESCUE trial is the first randomized controlled trial to explore the impact of rhTPO for severe thrombocytopenia in sepsis patients diagnosed by sepsis-3.0 standard. Furthermore, RESCUE trial results will be of significant clinical value on the targeted therapy and add clinical evidence that rhTPO is an effective rescue therapy for these sepsis patients.Trial registrationClinicalTrials.gov: NCT02707497. Registered Date: March 3rd, 2016. Protocol Version 3. Protocol Date: January 25th, 2019.

Abnormal hemostasis in children with vascular anomalies, part I: Thrombocytopenias among different vascular anomalies

Long before the classification of vascular anomalies from the International Society for the Study of Vascular Anomalies (ISSVA) provided a framework to differentiate vascular anomalies, otherwise known as vascular birthmarks, it was recognized that patients with such lesions can present with acute life-threatening hemostatic and/or thrombotic complications, as well as chronic long-standing bleeding or thrombotic issues. Scenarios such as a rapidly growing vascular lesion with severe acute thrombocytopenia, a visceral hemorrhagic lesion, a lesion associated with repetitive and painful superficial thrombosis, and cases of unprovoked or post-procedural fatal pulmonary embolism highlight the wide spectrum of manifestations of abnormal coagulation in patients with vascular anomalies.The separation of vascular anomalies into two distinct groups, vascular tumors and vascular malformations, was followed by the characterization that their respective coagulopathies were due to either a derangement of platelets or to a disequilibrium of the patient's coagulation/fibrinolytic process. This configuration of coagulopathies will be the foundation for this two-chapter review series. In the initial review, coagulopathies where thrombocytopenia is the main feature will be characterized, whereas the second review will focus on vascular malformations that have a coagulation disorder secondary to some degree of coagulation consumption and/or fibrinolytic pathway derangement.

A Diagnostic Puzzle: New Liver Dysfunction with Severe Thrombocytopenia

Autoimmune hepatitis is a chronic disease characterized by inflammation and hepatocellular necrosis causing varying degrees of clinical and biochemical manifestations. A rare complication is the development of aplastic anemia defined by inability of hematopoietic stem cells to repopulate the bone marrow thus resulting in severe hypocellularity without other morphologic abnormalities. Treatment using immunosuppressive therapy drastically improves outcome. We present this case of a young adult with autoimmune hepatitis leading to aplastic anemia. A previously healthy 20 year old male presented with abdominal pain and vomiting. Workup revealed markedly elevated liver enzymes, hyperbilirubinemia, seronegative acute viral hepatitis panels, severe thrombocytopenia and moderate neutropenia. Initial bone marrow biopsy showed hypocellularity and mildly decreased megakaryocytes.Liver biopsy disclosed periportal and lobular inflammation with patchy necrosis. A course of steroids and IVIG resulted in improvement of transaminitis, but he developed progressive severe pancytopenia.5 weeks later, repeat bone marrow biopsy showed virtually acellular marrow confirming the diagnosis of hepatitis associated aplastic anemia. He was treated with antithymocyte globulin, steroids and cyclosporine. About 7 months later, he continued to have moderately severe neutropenia and mild thrombocytopenia without anemia. Currently the patient is a potential candidate for stem cell transplant. Hepatitis associated aplastic anemia (HAAA) is a rare complication of autoimmune hepatitis occurring mostly in children and young adults.Onset of aplastic anemia is usually within a few months of diagnosis of hepatitis and it evolves independently of successful treatment of hepatitis. Diagnosis criteria of HAAA is a combination of pancytopenia and bone marrow biopsy showing severe hypocellularity without other morphologic abnormalities in the cellular and stromal elements. Pathophysiology of HAAA is not well defined but it is widely believed that a decreased CD4:CD8 ratio, proliferation and activation of cytotoxic T-lymphocytes and release of cytokines all play important roles. If untreated, HAAA has a very high mortality rate. It must be promptly treated using immunosuppressive therapy and, in some cases of persistent severe cytopenia, allogeneic bone marrow transplant. Such an approach has been demonstrated to improve survival.

Exceptional microorganisms on blood smear.

A 67-year-old woman with metastatic pancreatic adenocarcinoma was referred for acute respiratory distress syndrome and severe sepsis. She had a totally implantable central venous access device for chemotherapy administration and home parenteral nutrition. Laboratory workup at admission revealed increased C-reactive protein (209 mg/L), mild normocytic anemia (hemoglobin 8.6 g/dL), and severe acute thrombocytopenia (platelet count 3 × 109/L, as compared to 257 × 109/L 8 days before). White blood cell count, absolute neutrophil count, and blood smear were normal. Laboratory tests excluded disseminated intravascular coagulation. The patient was treated with cefotaxime and metronidazole. Forty-eight hours later, blood smear examination done on a sample taken through the intravenous line revealed yeasts (Image 1, panels A-E-B-D). Moreover, some bacilli were also observed (Image 1, panels C-E). Yeasts and budding yeasts in monocyte and neutrophil cytoplasm, extracellular branching pseudohyphae (arrow, respectively panels A-E-B-D May–Grünwald–Giemsa stain, original magnification 100× and 20×). Extra- and intracellular bacilli (arrowhead, respectively panels C-E, May–Grünwald–Giemsa stain, original magnification 100×) This exceptional observation of microorganisms on blood smear led to microbiological tests, identifying Candida albicans and Klebsiella pneumoniae. Severe thrombocytopenia was most likely related to severe sepsis. The patient was admitted to a palliative care unit. Nothing to report.

Successful Use of Intravenous Immunoglobulin G to Treat Refractory Heparin-Induced Thrombocytopenia With Thrombosis Complicating Peripheral Blood Stem Cell Harvest.

Heparin-induced thrombocytopenia is a well-known, life-threatening complication that occurs in 5% of patients exposed to heparin. It causes thrombocytopenia in roughly 85% to 90% of affected individuals, with expected recovery in approximately 4 to 10 days following heparin withdrawal. However, there is an entity known as refractory heparin-induced thrombocytopenia with thrombosis in which patients have prolonged thrombocytopenia, refractory to the current standard of care. We present one such case of a 48-year-old male with R-ISS (Revised International Staging System) stage II kappa light chain multiple myeloma in stringent complete response status postinduction therapy. He developed heparin-induced thrombocytopenia with thrombosis during peripheral blood stem cell harvesting, manifesting as acute right coronary artery thrombus and severe thrombocytopenia. Although his clinical course was prolonged, he was ultimately successfully treated with intravenous immunoglobulin G 500 mg/kg/day over 4 days.

Eltrombopag for advanced myelodysplastic syndromes or acute myeloid leukaemia and severe thrombocytopenia (ASPIRE): a randomised, placebo-controlled, phase 2 trial

Thrombocytopenia is a life-threatening complication in patients with advanced myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). In this study (ASPIRE), we aimed to assess eltrombopag, an oral thrombopoietin receptor agonist, for thrombocytopenia (grade 4) treatment in adult patients with advanced MDS or AML. ASPIRE consisted of an open-label, double-blind phase for 8 weeks and a randomised, double-blind phase (parts 1 and 2, reported here) for 12 weeks, and an open-label extension (part 3). Eligible patients were men and women aged 18 years or older, with intermediate-2 or high-risk MDS or AML, with bone marrow blasts of 50% or less, and had either grade 4 thrombocytopenia due to bone marrow insufficiency (platelet counts <25 × 109 per L) or grade 4 thrombocytopenia before platelet transfusion, with 25 × 109 platelets per L or greater after transfusion. Additionally, eligible patients had at least one of the following within the screening period of 4 weeks: platelet transfusion, symptomatic bleeding, or platelet count of less than 10 × 109 per L. During part 1, patients received eltrombopag, and dose-escalation criteria for part 2 were determined. In part 2, we randomly allocated patients 2:1 using an interactive voice-response system to eltrombopag or placebo, stratified by baseline platelet count (<10 × 109 platelets per L vs ≥10 × 109 platelets per L) and disease (MDS vs AML). In parts 1 and 2, patients received supportive standard of care and initiated eltrombopag or placebo at 100 mg per day (50 mg per day for patients of east-Asian heritage) to a maximum of 300 mg per day (150 mg per day for patients of east-Asian heritage). The part 2 primary objective was assessed by a composite primary endpoint of clinically relevant thrombocytopenic events (CRTE) during weeks 5-12, defined as one of the following events, either alone or in combination: grade 3 or worse haemorrhagic adverse events; platelet counts of less than 10 × 109 per L; or platelet transfusions. Efficacy analyses were based on intention to treat; clinically meaningful efficacy was defined as 30% absolute difference between groups. This trial is registered with ClinicalTrials.gov, number NCT01440374. In part 1, 17 patients received eltrombopag and 11 patients completed treatment; four experienced significantly increased platelet counts, and ten had reduced platelet transfusion requirements. In part 2 we randomly allocated 145 patients to receive supportive care plus eltrombopag (n=98) or placebo (n=47); similar proportions had MDS (50 [51%] patients to eltrombopag, 22 (47%) patients to placebo) or AML (48 [49%] patients to eltrombopag, 25 [53%] patients to placebo). Average weekly CRTE proportions from weeks 5-12 were significantly lower with eltrombopag (54% [95% CI 43-64]) than with placebo (69% [57-80], odds ratio [OR] 0·20, 95% CI 0·05-0·87; p=0·032) although the difference between treatment groups was less than 30%. The most common grade 3 and grade 4 adverse events were fatigue (six [6%] in the eltrombopag group and one [2%] in the placebo group), hypokalaemia (six [6%] and two [4%]), pneumonia (five [5%] and five [11%]), and febrile neutropenia (five [5%] and six [13%]). Serious adverse events were reported in 56 (58%) eltrombopag-treated patients and 32 (68%) placebo-treated patients. Seven eltrombopag recipients and two placebo recipients had serious adverse events that were suspected to be study drug-related (eltrombopag: acute kidney injury, arterial thrombosis, bone pain, diarrhoea, myocardial infarction, pyrexia, retinal vein occlusion, n=1 each; placebo: vomiting, white blood cell count increased, n=1 each). Two eltrombopag recipients (arterial thrombosis n=1; myocardial infarction n=1) and no placebo recipients experienced fatal serious adverse events suspected to be study drug-related. No new safety concerns were noted with eltrombopag and the trial met the primary objective of a reduction in CRTEs; eltrombopag might be a treatment option for thrombocytopenic patients with AML or MDS who are ineligible for other treatment and who are not receiving disease-modifying treatment. Novartis Pharma AG.

Neonatal outcome in meconium stained amniotic fluid: a hospital based study

Background: Amniotic fluid surrounds the baby in utero and provides a protective and low resistance environment and acts as a cushion for the baby. It is secreted by amniotic membranes, foetal skin and fetal urine. The objectives of this study was to identify the incidence of meconium stained amniotic fluid, perinatal outcome and the risks during pregnancy leading to in utero passage of meconium.Methods: A prospective study conducted in Sri Guru Ram Das University, Amritsar, between 1st December 2014 to 1st June 2016. All live births with meconim stained amniotic fluid without congenital malformation, twin or multiple organ dysfunction were taken as subjects of this study. Maternal obstetric history and risk factors were asked and foetal parameters including gestational age, fetal presentation, mode of delivery, birth weight, sex, Apgar score, age at onset of respiratory distress, treatment and outcome were observed.Results: Out of 1121 admissions in NICU, 12% of inborn and 9.6% of outborn were with MSAF, out of which 34% developed MAS. Majority of neonates were observed to be males (73.6%), term neonates (67.2%), weight 2.5-3.5 kg (76.9%) with mean weight being 2.701 kg±0.558 kg and 16% mortality including 9 inborn and 11 outborn neonates. Mean age at onset of respiratory distress was 18.43 minutes±11.52 minutes. Neonatal outcome was significantly related to weight, APGAR score at 5 mins, and development of complications like MAS, hypoxic ischemic encephalopathy, necrotizing enterocolitis, acute renal failure and severe thrombocytopenia. Culture proven septicaemia was seen in 21.6% cases. Mean duration of stay in NICU was 6.48 days±0.54 days.Conclusions: MSAF has significant effect on perinatal outcome and close observation is required to prevent and treat complications thus reducing mortality.

Chronic Use of Adalimumab as Potential Cause of Severe Thrombocytopenia in Psoriatic Arthritis Patient: The Need for Regular Monitoring of Cytopenias

Anti-tumor necrosis factor alpha (anti-TNFα) agents are used to treat inflammatory diseases with recognized safety and efficacy. Although they are rare, severe hematologic adverse effects are described and may be fatal. The current study describes the case of a patient presenting psoriatic arthritis, and under prolonged treatment with adalimumab. His condition worsened due to severe acute thrombocytopenia and severe hemorrhagic manifestations. Adalimumab was considered to be the probable cause of the thrombocytopenia and, therefore, its use was discontinued. The treatment consisted of corticosteroids, human immunoglobulin, rituximab and transfusion support. The regular monitoring of cytopenias in patients using anti-TNFα agents may be a safe measure for the early detection of severe hematologic adverse events. It is worth conducting additional studies to better characterize the interaction between anti-TNFα agents and the hematopoietic and immune systems.

A Case of Acute Severe Transient Thrombocytopenia Immediately after Cranioplasty using an Artificial Dura Mater

A Case of Acute Severe Transient Thrombocytopenia Immediately after Cranioplasty using an Artificial Dura Mater

Un cas de thrombopénie aiguë au rituximab dans la leucémie lymphoïde chronique

IntroductionRituximab is a chimeric anti-CD20 monoclonal antibody generally well tolerated. However, a severe but rare rituximab-related immune-toxic syndrome, associating fever, chills and thrombocytopenia can occur shortly after the infusion. Case reportWe report a case of severe acute rituximab-induced thrombocytopenia with favorable outcome in a patient with chronic lymphocytic leukemia and discuss the possible underlying mechanisms. ConclusionDespite the potential initial severity of rituximab-induced thrombocytopenia in CLL, chemotherapy should not be discontinued; tolerance might increase as the hematologic disorder is controlled.

A Case of Brucellosis Admitting with Bleeding

During the course of an acute brucellosis infection, severe thrombocytopenia, ITP and bleeding are rarely seen and can be misleading for hematological diseases. Our case was a 20-year-old male patient. He had admitted to the Emergency Room with the complaints of gingival bleeding and bleeding of his pimples. His platelet count was 1.6 x 10³ /µL and he was hospitalized with the preliminary diagnoses of ITP or hematological malignancy. Despite steroids and IV immunoglobulin treatment, his thrombocytopenia did not improve and he further developed melena. A bone marrow biopsy was planned. No significant pathology was detected in the examination of bone marrow aspiration. Brucella tube agglutination test had been ordered to identify the etiology of thrombocytopenia. Its result was reported as 1/160 (+) leading to an hemoculture. The hemoculture resulted in the growth of Brucella mellitensis. Therefore the patient was diagnosed as Brucellosis. Steroid has stopped, with the administration of antimicrobial treatment, his platelet count started improving from second day onwards. All his hemotological findings improved with this treatment. The fact that the patient had findings of severe thrombocytopenia and bleeding resulted in considering a preliminary diagnosis of hematological malignancy. In our country which is endemic for Brucellosis, the differential diagnosis of several patients admitting with different hematological presentations should definitely include Brucella.

Cryopreserved Platelets: From in Vitro Thrombin Generation Potential to in Vivo Safety

Background: Cryopreservation of platelets (PLTs) at -80°C with dimethyl sulfoxide (DMSO) can extend their shelf life up to 2 years. Cryopreserved PLTs (CRY-PLTs) are reported to have a greater in vivo hemostatic effect than liquid-stored PLTs. Aims of this study were: i. to evaluate the thrombin generation potential of buffy coat derived cryopreserved PLTs (CRY- BC PLT) in comparison with fresh buffy coat derived platelets concentrates; ii. to determine the efficacy and safety of CRY-PLTs transfusion in hematological patients with severe thrombocytopenia.Materials and methods: BC PLTs were obtained from 5 buffy coats and pooled. The final PLTs concentrates were leukoreduced by filtration and transferred to a 650 mL patented cryopreservation kit (Promedical ®) which allowed mixing with DMSO 25% in a closed system and following removal of supernatant without further manipulations. BC-PLTs were washed prior freezing, suspended in homologous plasma from 1 of the 5 donors to a final concentration of 200 mL and frozen at - 80°. CRY- BC PLTs were preserved at -80°C with 6% DMSO. A system of 3 accessory bags directly connected to the mother bag was adopted for the in vitro study, to avoid repeated freezing/thawing of samples. In vitro assays were performed before freezing and at 3,6 and 9 months after thawing. Before assay, CRY-BC PLT were thawed at 37°C and diluted in plasma to adjust to 300× 109/L PLTs. Fresh BC PLTs underwent the same dilution to adjust to 300 ×109/L PLTs. Thrombin generation (TGA) was tested in CRY BC-PLTs and compared to TG potential of fresh BC PLTs. TGA was triggered by the addition of 0.5 pmol/L of recombinant human tissue factor. Endogenous thrombin potential (ETP) and peak height (PH) were determined. Flow Cytometry assays for PLTs activation markers and thromboelastography were also determined on each sample.CRY-BC PLTs, separately prepared according to the above described method for in vivo study, were infused in five hematological patients with acute leukemia (AL) and severe thrombocytopenia (PLTs <10 ×109/L) participating to the trial NCT02032134.CRY-BC PLTs were transfused to control epistaxis (n=2) and for prophylaxis (n=3). Patients were observed up to 7 days after infusion and the occurrence of any side effect was registered. An increase in PLTs count was observed only in one case, under prophylaxis, but bleeding was successfully controlled or prevented in all cases. Plasma from patients transfused with CRY-BC PLTs was tested for TGA pre-treatment and 24 hours after treatmentResults Fourty nine BC-PLTs from 245 healthy volunteer donors (145 males and 100 females, mean age: 48.16.±18.91) were prepared, cryopreserved and analyzed up to 9 months after storage. Cryopreserved PLTs show a good thrombin generation potential that is stably maintained up to 9 months after cryopreservation [ETP (nM min): 529.25±98.64 at T0, 558.82±114.67 at T3, at 548.57±93.38 T6 and 533.04±103.15 at T9 months, respectively; PH(nM): 132.77±44.9 at T0, 103.4±44.9 at T3, 108.0±36.7 at T6 and 132.0±44.6 at T9 months, respectively]. At TGA, fresh BC-PLTs (n=35) had a mean ETP of 760.13±130.11, PH was 138.9±40.2. Thrombin generation of CRY-BC PLTs is comparable to fresh BC-PLTs, even if slightly decreased. Infusion of CRY-BC PLT (1U) was effective in controlling mucosal bleeding (epistaxis) in two patients with AL and severe thrombocytopenia. CRY-PLT were also effective when administered for prophylaxis in 3 patients with very low platelets count secondary to chemotherapy. In vivo, thrombin generation is stably maintained up to 24 hours after infusion of 1 Unit of CRY-BC PLTs, without any adverse effect (mean ETP pre-treatment was: 414.13±160.60, 24 hours after transfusion: 326.95±152.54). CRY-BC PLTs were safe and they did not determine any thrombotic event.At flow-cytometry, CRY-BC PLTs expressed higher activation markers (CD62P,CD63) than fresh BC PLTs. CRY-BC PLTs are able to significantly decrease the time to clot formation and clot strength, as measured also by thromboelastography. CRY-BCPLTs activation/deterioration is accompanied by an effective hemostatic in vivo function.Conclusions: Cryopreserved PLTs have an enhanced hemostatic activity and a good thrombin generation potential. They are effective and safe in preventing and controlling bleeding, being available in emergency/urgency settings also for patients with acute leukemia and severe thrombocytopenia. DisclosuresReina:Promedical: Consultancy.

Acute renal failure and severe thrombocytopenia in a young boy with vivax malaria

This 7-year-old boy presented with acute renal failure associated with Plasmodium vivax infection. In addition, he had severe thrombocytopenia. These apparently serious manifestations are rare in P. vivax malaria but respond favorably to antimalarials and supportive therapy.

Acute renal failure and severe thrombocytopenia associated with metamizole

Metamizole or dipyrone is a pyrazolone derivative that belongs to the non-steroidal anti-inflammatory drugs. Its main side-effect is hematological toxicity. Thrombocytopenia due to metamizole is rare and is usually associated with the involvement of the two other blood series. Drug-induced thrombocytopenia is more frequently related to immune mechanisms, and the diagnosis is still largely made by exclusion of other causes and by correlation of timing of thrombocytopenia with the administration of drug. Metamizole may cause acute renal failure due to hemodynamic renal failure/acute tubular necrosis and/or acute tubulointerstitial nephritis. We report a case of acute renal failure and severe thrombocytopenia after metamizole. As far as we know, this combination of adverse effects from this drug has not been reported previously.

Rituximab-Induced Acute Severe Thrombocytopenia: A Case Series in Patients With Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is a B-cell lymphoma that accounts for 3% to 10% of the non-Hodgkin forms of lymphoma. MCL almost universally expresses CD 20, the target of the monoclonal antibody rituximab. Therapy frequently combines rituximab with other chemotherapeutic agents. Administration of rituximab intravenously is well tolerated but frequently causes infusion reactions. Hematologic toxicity is seen less commonly but is well defined. Neutropenia, anemia, and thrombocytopenia have been described and often occur in the 10to 14-day window after rituximab infusion, similar to that seen with conventional chemotherapeutic agents. Isolated cases of acute severe thrombocytopenia after rituximab infusion for treatment of MCL have been reported, but this toxic event is uncommon. We identified 5 cases of acute severe thrombocytopenia occurring within 3 days of the administration of rituximab, suggesting that this toxic event might occur more frequently than previously recognized. Our series shows that acute severe thrombocytopenia is not always associated with infusion reactions, suggesting that the pathogenesis of these two toxic events might be different. Acute severe thrombocytopenia is reported more commonly in MCL than in other lymphomas treated with similar regimens. Four of the 5 patients received platelet transfusion. Subsequently, all the patients exhibited rapid recovery from thrombocytopenia without bleeding complications. Because acute severe thrombocytopenia appears to be transient, unpredictable, and not associated with bleeding complications, we would caution against the cessation or dose reduction of rituximab when treating MCL.

Fatal hemolytic uremic syndrome associated with day care surgery and anaesthesia: a case report

BackgroundThrombotic angiopathies, i.e. haemolytic uremic syndrome and thrombotic thrombocytopenic purpura, are thought to occur in patients with a combination of risk factors (e.g., an infection with shiga-toxin-producing Escherichia coli (E. coli) or low activity of the metalloproteinase Adamts-13) and a pathophysiological trigger (e.g., anti-endothelial antibodies, cytokines or activation of chemokine receptor 4). To our knowledge, this is the first report describing an association between haemolytic uremic syndrome and routine surgery and anaesthesia.Case presentationWe present a case in which a 67-year-old Caucasian female developed fatal haemolytic uremic syndrome in the immediate postoperative period of uncomplicated day care surgery. The patient had suffered gastrointestinal symptoms followed by confusion approximately two weeks before surgery, but had been without any symptoms in the week before surgery. Haemolytic uremic syndrome with cerebral symptoms ranging from initial anxiety to subsequent seizures and coma developed within a few hours after the end of surgery. In addition, acute kidney failure and severe thrombocytopenia occurred about the same time. During intensive care, the patient was found to be positive for enterohaemorrhagic E. coli (EHEC) in faeces.ConclusionAnaesthesiologists should be notified that haemolytic uremic syndrome is an uncommon differential diagnosis in patients with postoperative seizures and coma. Patients with a recent enterohemmoragic E.Coli infection should be followed postoperatively for signs of haemolytic uremic syndrome.

Simvastatin and amlodipine induced thrombocytopenia in the same patient: double trouble and a literature review

Drug-induced thrombocytopenia (DITP) may be a fatal adverse reaction to many drugs. It is often misdiagnosed as primary immune thrombocytopenia (ITP), and thus diagnosis can be delayed and patients can be treated inappropriately. Amlodipine a calcium-channel blocker, and simvastatin, a statin, have very rarely been implicated in DITP. We report on an investigation of the causal relationship of amlodipine and simvastatin with thrombocytopenia occurring in the same patient, and review the literature. We present the case of a 78-year-old female hypertensive diabetic patient with three successive DITPs. The first attack of acute severe thrombocytopenia occurred after a 2-week course of amlodipine, and was initially misdiagnosed as ITP. Her platelet count normalized after the amlodipine was discontinued. The second attack followed her restarting simvastatin 3 weeks later. She had stopped it 2 months earlier having previously taken it for over 5 years. Again, she recovered once the simvastatin was discontinued. The third DITP attack occurred when she accidently took a single dose of amlodipine 9 months later. We provide clear evidence of a causal association of amlodipine with thrombocytopenia, and probable evidence of a causal association of simvastatin with thrombocytopenia. This is the first reported case of DITPs occurring with two of the most widely prescribed drugs in the same patient. Many hypertensive patients need to take multiple drugs in order to achieve their treatment goals and this increases their risk of drug-induced adverse reactions and makes identification of the causal drug (or drugs) extremely difficult.

Protamine‐induced immune thrombocytopenia

Protamine is widely used to reverse the anticoagulant effects of heparin. Although mild thrombocytopenia is common in patients given protamine after cardiac procedures, acute severe thrombocytopenia has not been described. We encountered a patient who experienced profound thrombocytopenia and bleeding shortly after administration of protamine and performed studies to characterize the responsible mechanism. Patient serum was studied for antibodies that recognize protamine, heparin-protamine complexes, and platelets (PLTs) treated with protamine using flow cytometry, enzyme-linked immunosorbent assay, and serotonin release from labeled PLTs. A high-titer immunoglobulin G antibody was detected in patient serum that recognizes protamine in a complex with heparin or PLT surface glycosaminoglycans (GAGs) and activates PLTs treated with protamine at concentrations achieved in vivo after protamine infusion. The antibody is distinctly different from those found in patients with heparin-induced thrombocytopenia on the basis of its failure to recognize heparin in a complex with PLT factor 4 (PF4) and to release serotonin from labeled PLTs in the absence of protamine. Findings made suggest that the patient's antibody is specific for conformational changes induced in protamine when it reacts with heparin or a PLT surface GAG. Development of severe thrombocytopenia after treatment of this patient with protamine defines a previously undescribed mechanism of drug-induced immune thrombocytopenia. Patients given protamine who produce this type of antibody may be at risk of experiencing thrombocytopenia if given the drug a second time while antibody is still present.

Acute Severe Thrombocytopenia Following Non-Ionic Low-Osmolarity Intravenous Contrast Medium Injection

Intravenous contrast medium (ICM) rarely induces anaphylactic reactions, including urticaria, hypotension and respiratory failure. Even the most modern ICM may cause such adverse events. Thrombocytopenia has been reported as an extreme rare consequence of ICM. Here we report on a case of a 72-year-old male patient with a self-limiting severe acute thrombocytopenia following administration of intravenous non-ionic low-osmolarity contrast medium. No such low platelet count has ever been reported. We also present a review of the literature.