Recurrence of acute lymphoblastic leukemia manifesting as serous retinal detachments and optic disc swelling.

PURPOSE: The aim of this case report is to describe a patient with acute lymphoblastic leukemia (ALL) who developed bilateral serous retinal detachments and unilateral optic disc swelling. METHODS: A 23-year-old woman with ALL presented to the ophthalmology clinic with bilateral subacute visual loss. RESULTS: Ophthalmologic examination revealed bilateral serous retinal detachments and unilateral optic disc swelling. Magnetic resonance imaging for differential diagnosis was inconclusive; however, cerebrospinal fluid sampling demonstrated leukemic involvement of the central nervous system. The patient's vision improved and fundus findings resolved with the institution of systemic and intrathecal chemotherapy. CONCLUSIONS: Serous retinal detachment and optic disc swelling are unusual ocular manifestations of ALL. They may occur due to leukemic infiltration of ocular structures and may indicate extramedullary recurrence of the disease. Early recognition and treatment is crucial to improve prognosis.

Aplastic anemia associated with oral terbinafine: a case report and review of the literature.

Onychomycosis (OM) is a common fungal infection of the toenails and/or fingernails that is highly prevalent in the general population and also responsible for significant morbidity. OM is caused by dermatophytes, nondermatophytic molds, or yeast. Today systemic antifungal agents are considered as the gold standard for all types of OM. Here we report a case of aplastic anemia associated with oral terbinafine use and a review of the literature on hematological toxicities associated with terbinafine.

The Relevance of Anti-PF4 Antibody Isotypes and Endogenous Glycosaminoglycans and their Relationship with Inflammatory Biomarkers in Pulmonary Embolism Patients.

INTRODUCTION: Previous studies have shown that inflammation may contribute to the interplay of endogenous glycosaminoglycans (GAGs) and anti-PF4 antibodies. In this study, we quantified the levels of anti-PF4 antibody isotypes and endogenous GAGs together with inflammatory biomarkers in pulmonary embolism (PE) patients to determine whether there is a relationship in between. Identification of this relationship may provide insight to the complex pathophysiology of PE and HIT and may also be useful for development of potential prognostic, diagnostic and therapeutic interventions. MATERIALS AND METHODS: Plasma samples from PE patients (n: 210) were analyzed for anti-PF4 antibody isotypes and various thrombo-inflammatory cytokines utilizing commercially available biochip array and ELISA methods. The endogenous GAG levels in PE patients' plasma were quantified using a fluorescence quenching method. The collected data analyzed to demonstrate the relationship between various parameters. RESULTS: The endogenous GAG levels were increased in the PE group (P < .05). The levels of anti-PF4 antibody isotypes were higher in varying levels in comparison to the normal group (P < .05). Inflammatory cytokines have shown varying levels of increase with IL-6, IL-8 and IL-10 showing the most pronounced values. Mortality outcome was related to increased GAGs and some of the cytokines. CONCLUSION: In this study, we demonstrated increased levels of anti-PF4 antibody isotypes, endogenous GAGs, and inflammatory biomarkers in a large patient cohort in PE. The levels of the endogenous GAGs and inflammatory biomarkers were associated with PE severity and mortality. More studies are needed to understand this complex pathophysiology.

Predictive Role of Blood Cellular Indices and Their Relationship with Endogenous Glycosaminoglycans as Determinants of Inflammatory Biomarkers in Pulmonary Embolism.

INTRODUCTION: In this study, we profiled the levels of blood cellular indices, endogenous glycosaminoglycans (GAGs) and inflammatory biomarkers in a cohort comprised of pulmonary embolism (PE) patients, to determine their inter-relationships. Identification of this relationship may provide insight to the complex pathophysiology of PE and the predictive role of blood cellular indices in acute PE patients. MATERIALS AND METHODS: Plasma samples from PE patients and healthy controls were analyzed for thrombo-inflammatory biomarkers (IL-2, IL-4, IL-6, IL-8, IL-10, VEGF, IFN-É£, TNF-α, IL-1α, IL-1ß, MCP-1, EGF, D-dimer, CRP and MMP-9) using biochip array and ELISA methods. The endogenous GAG levels were quantified using a fluorescence quenching method. The data regarding the blood cellular indices were collected through the review of patient medical records and analyzed to demonstrate their relationship. RESULTS: The levels of inflammatory biomarkers and endogenous GAGs were elevated in acute PE patients compared to controls (P < .05). Most of the blood cellular indices have shown significant differences in acute PE patients compared to controls (P < .05). The levels of inflammatory biomarkers, endogenous GAGs and the blood cellular indices have shown significant associations in correlation and multivariable analysis. While NLR, PLR and SII were significantly predicting the 30-day mortality, PNR, ELR and EMR were not sufficient to predict 30-day mortality in acute PE. CONCLUSION: Our results show that the increased thrombo-inflammatory response is associated with the release of GAGs and the changes in blood cellular indices. The predictive role of the blood cellular indices for mortality is dependent on their relationship with the inflammatory response.

An Update on the Status of Vaccine Development for SARS-CoV-2 Including Variants. Practical Considerations for COVID-19 Special Populations.

The progress in the development of various vaccine platforms against SARS-CoV-2 have been rather remarkable owing to advancement in molecular and biologic sciences. Most of the current vaccines and those in development focus on targeting the viral spike proteins by generating antibodies of varying spectrum. These vaccines represent a variety of platforms including whole virus vaccines, viral vector vaccines, nucleic acid vaccines representing RNA, DNA, and their hybrid forms.The therapeutic efficacy of these vaccines varies owing to their pharmacodynamic individualities. COVID-19 variants are capable of inducing different pathologic responses and some of which may be resistant to antibodies generated by current vaccines. The current clinical use of these vaccines has been through emergency use authorization until recently. Moreover, the efficacy and safety of these vaccines have been tested in substantial numbers of individuals but studies in special populations that better reflect the global population are pending results. These specialized populations include young children, immunocompromised patients, pregnant individuals, and other specialized groups. Combination approaches, molecularly modified vaccination approaches, and vaccines conferring longer periods of immunity are being currently being investigated, as well as pharmacovigilance studies.The continual transformation of SARS-CoV-2 and its variants are of concern along with the breakthrough infections. These considerations pose new challenges for the development of vaccination platforms. For this purpose, booster doses, combination vaccine approaches, and other modalities are being discussed. This review provides an updated account of currently available vaccines and those in advanced development with reference to their composition and mechanisms of action.A discussion on the use of vaccines in special populations including immunocompromised patients, pregnant women and other specialized populations are also included.

Differentiation of parenteral anticoagulants in the prevention and treatment of venous thromboembolism.

BACKGROUND: The prevention of venous thromboembolism has been identified as a leading priority in hospital safety. Recommended parenteral anticoagulant agents with different indications for the prevention and treatment of venous thromboembolism include unfractionated heparin, low-molecular-weight heparins and fondaparinux. Prescribing decisions in venous thromboembolism management may seem complex due to the large range of clinical indications and patient types, and the range of anticoagulants available. METHODS: MEDLINE and EMBASE databases were searched to identify relevant original articles. RESULTS: Low-molecular-weight heparins have nearly replaced unfractionated heparin as the gold standard antithrombotic agent. Low-molecular-weight heparins currently available in the US are enoxaparin, dalteparin, and tinzaparin. Each low-molecular-weight heparin is a distinct pharmacological entity with different licensed indications and available clinical evidence. Enoxaparin is the only low-molecular-weight heparin that is licensed for both venous thromboembolism prophylaxis and treatment. Enoxaparin also has the largest body of clinical evidence supporting its use across the spectrum of venous thromboembolism management and has been used as the reference standard comparator anticoagulant in trials of new anticoagulants. As well as novel oral anticoagulant agents, biosimilar and/or generic low-molecular-weight heparins are now commercially available. Despite similar anticoagulant properties, studies report differences between the branded and biosimilar and/or generic agents and further clinical studies are required to support the use of biosimilar low-molecular-weight heparins. The newer parenteral anticoagulant, fondaparinux, is now also licensed for venous thromboembolism prophylaxis in surgical patients and the treatment of acute deep-vein thrombosis; clinical experience with this anticoagulant is expanding. CONCLUSIONS: Parenteral anticoagulants should be prescribed in accordance with recommended dose regimens for each clinical indication, based on the available clinical evidence for each agent to assure optimal safety and efficacy.

Focal segmental glomerulosclerosis associated with idiopathic myelofibrosis.

A patient with idiopathic myelofibrosis with nephrotic syndrome is reported. Seven months after the initial diagnosis of myelofibrosis, the patient was presented with dyspnea, generalized edema, heavy proteinuria, massive pleural effusion, and ascites. Renal biopsy showed focal segmental glomerulosclerosis. After starting immunosuppressive therapy consisting of cyclosporine and steroids, his renal function and proteinuria improved and transfusion requirements decreased.

An update on the prevalence and characterization of H-PF4 antibodies in Asian-Indian patients.

Heparin is the second most widely used anticoagulant/antithrombotic agent besides warfarin and is commonly used for various purposes such as treatment and surgical indications. A significant adverse effect of heparin treatment can occur when heparin binds platelet factor 4 (H-PF4) to form a complex that results in formation of H-PF4 antibodies, which in turn leads to platelet/endothelial cell activation followed by heparin-induced thrombocytopenia (HIT). Based on the heparin-induced platelet aggregation and enzyme-linked immunosorbent assay tests, the H-PF4 antibody (HIT antibody) was diagnosed in 6% of Indian patients undergoing cardiovascular surgery who received unfractionated heparin, but the frequency of occurrence rose to 15% when the patients were tested with the (14)C-serotonin release assay. This highlights some methodological variations in the diagnosis of HIT antibodies. It was also found that all the HIT-positive patients were either homozygous or heterozygous for the FcgammaRIIa polymorphism, which also highlights the role of this polymorphism in the occurrence of HIT. Very recent studies show that increases in HIT antibody production may also be due to heparin contaminants. Although these antibodies do not result in thrombocytopenia, contaminants in heparin may be capable of triggering a differential immunogenic response in comparison with contaminant-free heparin. Here we discuss the methodological differences in diagnosing HIT, the potential impact of contaminants in heparin, as well as future considerations.

Comparison of immunogenic potentials of bovine thrombin preparations.

Using a membrane filtration step, bovine crude thrombin was purified into thrombin 4A and 4B preparations. The purpose of this study was to determine whether the improved purity of a bovine thrombin preparation can reduce its overall immunogenic potential and lower the risk of development of factor V antibodies. Bovine crude thrombin and its purified versions, thrombin 4A and 4B, were administered to individual groups of rabbits on days 0, 21, 42, 91, 123, and 151 using standard immunologic methods. Blood was drawn from each rabbit on days 30, 50, 105, 137, and 165, and the pooled antisera from individual groups were purified to obtain the Ig Gs using protein G affinity columns. Using Western blotting, the specificity of each immunoglobulin G collected at the first time point (day 30) and last time point (day 165) was determined. The results of Western blotting using the Ig Gs collected on days 30 and 165 were consistent; both demonstrating that thrombin 4B has the least immunogenic potential among the 3 thrombin preparations tested. Compared with the immunoglobulin Gs collected on day 30, the Ig Gs from day 165 did not show obvious difference regarding their ability to detect antigens in bovine thrombin samples. Neither showed cross-reactivity with human coagulation factors nor the recognition of bovine factor Va antigens. These results suggest that despite the presence of a trace amount of bovine factor Va antigen in bovine thrombin preparations, these contaminants failed to elicit the generation of antibodies against factor Va light chain in rabbit.

Structural and functional characterization of low-molecular-weight heparins: impact on the development of guidelines for generic products.

Low-molecular-weight heparins (LMWHs) are poly-pharmacologic drugs used to treat thrombotic and cardiovascular disorders. Recently, several generic versions of branded LMWHs have been introduced. Although generic versions of LMWHs exhibit similar profiles, marked differences in their biological and pharmacologic properties have been demonstrated. Several studies have demonstrated differences in terms of anti-Xa activity and tissue factor pathway inhibitor release. The current data emphasize the need to consider multiple functional parameters when defining bioequivalence of biologic drugs and also underscore the importance of further pharmacologic studies involving animal and human clinical trials. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) are currently developing guidelines for the acceptance of complex biological drugs including LMWHs. The US FDA considers these drugs as follow-on agents whereas the EMEA classifies these drugs as biosimilar agents. Until clear guidelines are developed, generic interchange of LMWHs may not be feasible.

Reduced immunogenic potential of membrane filtered bovine thrombin preparations for hemostatic application.

There is concern that exposure to bovine thrombin can result in the development of antibodies, usually against factor V/Va, which can lead to hemostatic abnormalities. It is thought that purer preparations of bovine thrombin might be less immunogenic. Utilizing newer methods including a membrane filtration step, bovine crude thrombin is further purified into thrombin 4A and 4B preparations which exhibit a higher specific activity and are devoid of some of the protein contaminants. Bovine crude thrombin and its purified versions were administered intravenously to individual groups of rabbits using standard immunologic protocols. Antiserum was drawn from each rabbit and the pooled antisera were purified to obtain the IgGs using protein G affinity columns. The results suggest that the reported purification process, including filtration, resulted in the removal of most of the antigens found in crude thrombin, and that none of these preparations generated any detectable antibodies against bovine factor V related antigens.

Increased prevalence of antiheparin platelet factor 4 antibodies in patients may be due to contaminated heparin.

During the period of November 2007 to January 2008, an increased prevalence of adverse reactions to heparin was noted. These adverse events have been attributed to the presence of purposeful contaminant, oversulfated chondroitin sulfate (OSCS) from April 2007 to May 2008. An analysis of dialysis patients' plasma obtained in 2006 and 2007 consistently had a low (5%) prevalence of AHPF4 antibodies. Blood samples from 78 patients on maintenance hemodialysis, who were potentially exposed to OSCS-contaminated heparin, were analyzed for the presence of all AHPF4 antibodies using a commercially available ELISA kit from GTI. Although there was no change in the platelet count of these patients, 15 of 78 patients (19.2%) studied had an increased prevalence of AHPF4 antibodies. Subtyping of the all platelet factor 4 (PF4) antibodies documented showed a higher prevalence of immunoglobulin G antibodies as compared to their previously determined antibodies. These observations suggest that the OSCS contaminant in the recalled heparin triggers an immunogenic response not seen with OSCS-contaminated free heparin.

Pregnancy outcome in women with antiphospholipid antibodies: report on a retrospective study.

Antiphospholipid syndrome (APS) represents a serious risk factor in pregnancy resulting in several complications, leading to fetal loss and hemostatic complications. In this dedicated report, we describe our experiences in the treatment of pregnancies in patients with APS. The retrospective data from 140 pregnant women were investigated, and the treatment results of 121 patients were recorded. We studied two groups of patients receiving different treatment. The first group (N = 78) received the standard therapy with low-weight-molecular heparin (dalteparin 5000 U or certoparin 3000 U daily) and aspirin (100 mg daily) and in the second group (N = 43) an additional 0.2 g/kg intravenous immunoglobulin (IVIG). Outcomes were 74.3% and 83.7% live births in the first group and in the second group, respectively. The abortion rate was similar in both groups (11.5% vs. 11.6%). The late complication rate was lower in the second group (5.8% vs. 14.1%, P < 0.05) than in the group with standard therapy. Interestingly, we found a trend to higher percentage (> 12%) of natural killer (NK) cells in patients with pregnancy complications (60% vs. 12%, P < 0.05). Our retrospective data shows an improvement of late pregnancy complications by additional use of IVIG. It is possible that IVIG influences higher NK cell activity in patients with previous pregnancy complications.

Are all low molecular weight heparins equivalent in the management of venous thromboembolism?

Low molecular weight heparins are replacing unfractionated heparin in a number of clinical indications because of their improved subcutaneous bioavailability and more predictable antithrombotic response. Clinical trials have demonstrated that low molecular weight heparins are at least as safe and effective as unfractionated heparin for the initial treatment of venous thromboembolism, and unfractionated heparin and warfarin for primary and secondary thromboprophylaxis. The mechanism behind the antithrombotic action of low molecular weight heparins is not fully understood but is likely to involve inhibition of coagulation factors Xa and IIa (thrombin), release of tissue-factor-pathway inhibitor, and inhibition of thrombin activatable fibrinolytic inhibitor. Different low molecular weight heparins have been shown to have various effects on coagulation parameters. Seven low molecular weight heparins are currently marketed worldwide, each demonstrated distinct chemical entities with unique pharmacokinetic and pharmacodynamic profiles. Each low molecular weight heparin is approved for specific indications based on the available efficacy and safety data for that product. The relative efficacy and safety of the low molecular weight heparins are unclear because there have been very few direct comparisons in randomized clinical trials. While recommending low molecular weight heparins for the prevention and treatment of venous thromboembolism, clinical guidelines have not specified individual agents. National and international organizations recognize that low molecular weight heparins are distinct entities and that they should not be used interchangeably in clinical practice. Each low molecular weight heparin should be used at the recommended dose when efficacy and safety data exist for the condition being treated. When these data are not available, the dosing and administration of low molecular weight heparins must be adapted from existing data and recommendations.

A case of Cauda Equina syndrome in a leukemic patient due to intrathecal methotrexate.

The leukemias may cause neurologic dysfunction through either direct invasion of the nervous system or indirectly through cytopenias, or it may occur as a result of the necessarily vigorous treatment programs for leukemia. We report here a 24-year-old acute lymphoblastic leukemia patient who in her second cycle of hyper-CVAD chem therapy regimen (high-dose Ara-C and high-dose methotrexate) received intrathecal methotrexate and two days afterwards was diagnosed as having Cauda Equina syndrome (CES). A lumbo-sacral MRI imaging with gadolinium was performed and there was a remarkable enhancement in the Cauda Equina region, suggesting either leukemic involvement or a type of neurologic complication associated with intrathecal methotrexate treatment. To rule out leukemic involvement, a lumbar puncture was performed and the CSF was free of leukemic cells. There are cases of CES developing after spinal anesthesia reported in the literature, but this is the first report of CES due to intrathecal methotrexate.

Complete heart block in a neutropenic patient with invasive aspergillosis.

A patient with leukemia who developed complete heart block after the diagnosis of pulmonary aspergillosis is reported. The patient had probable invasive pulmonary aspergillosis with a sudden tachypnea, dyspnea, fever, bilateral pulmonary infiltrates and acute respiratory insufficiency after chemotherapy. On the sixth day of antifungal therapy, she developed complete atrioventricular block. Complete heart block has not been reported during liposomal amphotericin B (LAMB) therapy. Local or hematogenous involvement of the myocardium with aspergillosis may be the most likely explanation of the complete heart block.

Myelodysplastic syndrome with pseudoreticulocytosis.

A patient with myelodysplastic syndrome (MDS) with refractory anemia who had marked reticulocytosis in the absence of hemolytic anemia and/or blood loss is reported. Erythrocyte survival test showed that more than 50% of the patient's reticulocytes were still present on day seven. This should be due to the prolongation of reticulocyte maturation in MDS, and is known as pseudoreticulocytosis. This phenomenon which mimicks hemolytic anemia is an unusual presentation of myelodysplastic syndrome, with only 7 patients with pseudoreticulocytosis being reported previously.

Amifostine treatment in patients with myelodysplastic syndrome.

Myelodysplastic syndrome (MDS) is a clonal disorder that is characterized by peripheral cytopenia and the induction of apoptosis is thought to be partially responsible for pathological haematopoiesis in MDS. Amifostine is a cytoprotective and antioxidant agent, and it may prolong the survival of progenitor cells in MDS by delaying apoptosis. The study has been carried out with 9 MDS cases. Four of them were diagnosed as refractory anemia (MDS-RA), two as refractory anemia with ring sideroblasts (MDS-RARS) and the remaining three as refractory anemia with excess blasts (MDS-RAEB) according to the French-American-British (FAB) classification. Amifostine was given in a dose of 400 mg/m2, as an IV infusion administered in 5-6 minutes, three times a week for 4 consecutive weeks. Three of the cases (33.3%), two with MDS RARS and one with MDSRA, showed a significant improvement in the number of total leukocyte, neutrophil and reticulocyte counts and a decrease in the requirement of erithrocyte transfusions. In clinically responsive cases, all hematological parameters returned back to pre-treatment values two weeks after the cessation of therapy. We conclude that Amifostine can be used in a selected group of patients with MDS-RA and MDS-RARS.

Hairy cell leukemia in father and son.

Hairy cell leukemia (HCL) is an uncommon B cell disorder, and familial HCL is rarely encountered among the first degree relatives of HCL patients. A father and son, both of whom developed hairy cell leukemia, is presented in this report. The HLA haplotype shared by the father and son was A2, B18, BW6, CW7, DR3, DR10, and DQ8. Among these haplotypes, HLA A2 and Bw6 have previously been reported.