Expert Opinions on the Management of Hemophilia A in India: The Role of Emicizumab.

Hemophilia A (HA) is a genetic disorder of hemostasis associated with a deficiency or reduced activity of clotting factor VIII (FVIII). This disorder remains unacceptably underdiagnosed in India. Early diagnosis and appropriate management of HA can substantially prevent morbidity and mortality. Currently, HA is managed with regular replacement therapy using standard or extended half-life FVIII concentrates or non-factor drug products. The challenges associated with FVIII concentrates include plateauing of drug effect, issues with its administration and adherence to treatment, breakthrough bleeds, and the development of inhibiting antibodies against administered clotting factors. Emicizumab is a bispecific antibody, launched in India in April 2019, for managing patients with HA. To investigate the role of emicizumab in Indian patients with HA, opinions were sought from 13 eminent hematologists and experts from India on the effectiveness of emicizumab in preventing all bleeds, spontaneous bleeds, perioperative bleeds, and intracranial hemorrhage; resolving target joints; and reducing the rate of hospitalizations and fatality associated with HA in children and adults, with or without inhibitors. The benefits of emicizumab over traditional FVIII concentrates include the subcutaneous route of delivery, less frequent dosing, and a lack of inhibitor development, in addition to providing sustained hemostasis without in-depth monitoring. It is a safe and effective management option for all HA patients, especially for patients with certain archetypes, such as those with inhibitors, those with high annualized bleed rates, those living far away from hemophilia care centers, pediatric patients and infants with intravenous access challenges, and those with a history of life-threatening bleeding events.

Correction: Expert Opinions on the Management of Hemophilia A in India: The Role of Emicizumab.

[This corrects the article DOI: 10.7759/cureus.58941.].

Autoimmune Hemolytic Anaemias in Pregnancy: Experience in a Tertiary Care Hospital in South India.

BACKGROUND: Autoimmune hemolytic anaemia is very rare and there is limited data regarding their pregnancy outcomes. Hence we aimed to study the maternal and perinatal outcomes in pregnancies with autoimmune hemolytic anaemias (AIHA). METHODS: A retrospective descriptive study of pregnant women with AIHA, who delivered at SJMCH between January 2011 and January 2016 was carried out. Their antenatal and labour records were reviewed and demographic details noted.The primary outcome measures studied were-the prevalence of AIHA, gestational age at delivery, antepartum, intrapartum and postpartum complications, mode of delivery and requirement of transfusion of blood and blood products. The secondary outcome measures studied included neonatal outcomes such as low birth weight, intrauterine growth restriction and need for intensive care. The data is presented as descriptive statistics, including means and percentage. RESULTS: The prevalence of AIHA was (18/12,420) 0.14%. The mean gestational age at delivery was 34 weeks; 100%, 77% and 50% had antenatal, intra partum or postpartum complications, respectively. 44% had preeclampsia, 38% intrauterine growth restriction and 16% preterm labour. 83% required additional drugs for treatment of AIHA.72% had vaginal delivery; 28% had caesarean delivery; 33% were transfused antenatally and 22% postnatally; 50% of the babies were preterm and required intensive care, 66% had low birth weight. There was no maternal mortality. CONCLUSION: Multidisciplinary approach, early diagnosis and detection of autoimmune hemolytic anaemia and complications, good antenatal care, judicious transfusions and delivery at tertiary care centre are the keys to successful outcomes.

Innate Immune Cytokine Profiling and Biomarker Identification for Outcome in Dengue Patients.

Background: Early biomarkers of progression to severe dengue are urgently required to enable effective patient management and control treatment costs. Innate immune cells, which comprise the earliest responders to infection and along with the cytokines and chemokines they secrete, play a vital role in orchestrating the subsequent adaptive immune response and have been implicated in the enhancement of infection and "cytokine storm" associated with dengue severity. We investigated the early innate immune cytokine profile of dengue patients during acute phase of disease in a prospective blinded study that included subjects with acute dengue and febrile controls from four major hospitals in Bengaluru, India along with healthy controls. We used intracellular cytokine staining and flow cytometry to identify innate immune biomarkers that can predict progression to severe dengue. Results: Dengue infection resulted in enhanced secretion of multiple cytokines by all queried innate immune cell subsets, dominated by TNF-α from CD56+CD3+ NKT cells, monocyte subsets, and granulocytes along with IFN-γ from CD56+CD3+ NKT cells. Of note, significantly higher proportions of TNF-α secreting granulocytes and monocyte subsets at admission were associated with mild dengue and minimal symptoms. Dengue NS1 antigenemia used as a surrogate of viral load directly correlated with proportion of cytokine-secreting innate immune cells and was significantly higher in those who went on to recover with minimal symptoms. In patients with secondary dengue or those with bleeding or elevated liver enzymes who revealed predisposition to severe outcomes, early activation as well as efficient downregulation of innate responses were compromised. Conclusion: Our findings suggested that faulty/delayed kinetics of innate immune activation and downregulation was a driver of disease severity. We identified IFN-γ+CD56+CD3+ NKT cells and IL-6+ granulocytes at admission as novel early biomarkers that can predict the risk of progression to severity (composite AUC = 0.85-0.9). Strong correlations among multiple cytokine-secreting innate cell subsets revealed that coordinated early activation of the entire innate immune system in response to dengue virus infection contributed to resolution of infection and speedy recovery.

RhoC regulates radioresistance via crosstalk of ROCK2 with the DNA repair machinery in cervical cancer.

BACKGROUND: Radioresistance remains a challenge to the successful treatment of various tumors. Intrinsic factors like alterations in signaling pathways regulate response to radiation. RhoC, which has been shown to modulate several tumor phenotypes has been investigated in this report for its role in radioresistance. In vitro and clinical sample-based studies have been performed to understand its contribution to radiation response in cervical cancer and this is the first report to establish the role of RhoC and its effector ROCK2 in cervical cancer radiation response. METHODS: Biochemical, transcriptomic and immunological approaches including flow cytometry and immunofluorescence were used to understand the role of RhoC and ROCK2. RhoC variants, siRNA and chemical inhibitors were used to alter the function of RhoC and ROCK2. Transcriptomic profiling was performed to understand the gene expression pattern of the cells. Live sorting using an intracellular antigen has been developed to isolate the cells for transcriptomic studies. RESULTS: Enhanced expression of RhoC conferred radioprotection on the tumor cells while inhibition of RhoC resulted in sensitization of cells to radiation. The RhoC overexpressing cells had a better DNA repair machinery as observed using transcriptomic analysis. Similarly, overexpression of ROCK2, protected tumor cells against radiation while its inhibition increased radiosensitivity in vitro. Further investigations revealed that ROCK2 inhibition abolished the radioresistance phenotype, conferred by RhoC on SiHa cells, confirming that it is a downstream effector of RhoC in this context. Additionally, transcriptional analysis of the live sorted ROCK2 high and ROCK2 low expressing SiHa cells revealed an upregulation of the DNA repair pathway proteins. Consequently, inhibition of ROCK2 resulted in reduced expression of pH2Ax and MRN complex proteins, critical to repair of double strand breaks. Clinical sample-based studies also demonstrated that ROCK2 inhibition sensitizes tumor cells to irradiation. CONCLUSIONS: Our data primarily indicates that RhoC and ROCK2 signaling is important for the radioresistance phenotype in cervical cancer tumor cells and is regulated via association of ROCK2 with the proteins of DNA repair pathway involving pH2Ax, MRE11 and RAD50 proteins, partly offering insights into the mechanism of radioresistance in tumor cells. These findings highlight RhoC-ROCK2 signaling involvement in DNA repair and urge the need for development of these molecules as targets to alleviate the non-responsiveness of cervical cancer tumor cells to irradiation treatment.

Flap cover in a patient with severe haemophilia type A.

Haemophilia A is a rare haematological disorder due to deficiency of Factor VIII, causing an abnormal coagulation response to injury. In severe haemophilia A, Factor VIII level is < 1%, often manifesting with spontaneous bleeding into joints. Judicious use of recombinant Factor VIII therapy to maintain adequate levels in the intraoperative, immediate and late post-operative periods, together with adjuvant pro-coagulants, can ensure a safe outcome following surgery. We describe the successful management of one such patient suffering from Marjolin's ulcer of the right gluteal region, who needed wide local excision followed by flap cover. A protocol for management of such patients is also suggested. This is the first such case report from the Indian subcontinent, with only a few such published reports from the West.

SDH with Bleeding Diathesis-a Management Protocol.

Chronic subdural hematoma (SDH) is one of the leading causes of morbidity and mortality in elderly. Patients taking antiplatelets and/or anticoagulants have increased risk of bleeding during the perioperative period. Precise dose blood products and specific surgical technique have been effective in preventing hemorrhagic complications perioperatively. From Jan 2010 to Dec 2012, 25 patients who were on antiplatelets and/or oral anticoagulants underwent emergency surgery for chronic or acute on chronic SDH. Patients were divided into three groups: group I-patients on antiplatelets, group II-patients on oral anticoagulants, and group III-patients taking both. Of these, 21 patients underwent minicraniotomy with microsurgical membranectomy and 4 patients underwent burr hole craniostomy. Random donor platelet concentrate (RDPC) and fresh frozen plasma (FFP) were used depending on whether patient was on antiplatelets or oral anticoagulants. Results were evaluated on the basis of ease of intraoperative hemostasis, incidence of rebleeding in postoperative period, postoperative imaging, and reversal of neurological deficits. Group I, group II, and group III had 16, 4, and 5 patients, respectively. Group I received a mean of 7 units of RDPC. Group II received a mean of 4 units of FFP. Group III received a mean of 7 units of RDPC and 4 units FFPs. There was no problem with intraoperative hemostasis and no incidence of rebleeding. We suggest specific dose protocol for reversal of antiplatelet and anticoagulant effect and specific surgical procedure in preventing intraoperative bleeding and postoperative rebleeding in the above group of patients.

Theoretical and practical issues related to the management of severe and refractory psychotic illness complicated by pulmonary embolism.

Pulmonary embolism (PE) is a potentially fatal condition. We describe the educative case of a young adult male, with a longstanding history of schizophrenia, who was receiving anticoagulant treatment because of repeated episodes of PE in the past. He presented with severe exacerbation of psychosis and did not respond to oral and parenteral antipsychotic medication during inpatient treatment. He was taken up for electroconvulsive therapy (ECT) and received a single ECT uneventfully. The ECT course had to be interrupted because of the unexpected development of a 4-day febrile illness, after which he experienced sudden onset breathlessness, which was diagnosed as acute-on-chronic PE. After the crisis resolved with 4 days of intensive care, he was managed with clozapine. We discuss concerns associated with the psychiatric management of patients with PE; special issues include the use of restraints, parenteral antipsychotic medications, anticoagulants, and ECT.