Factors associated with thrombo-hemorrhagic deaths in patients with Acute Promyelocytic leukemia treated with Arsenic Trioxide and all-trans retinoic acid.

Acute Promyelocytic Leukemia (APL) is associated with excellent long-term outcomes. However, early mortality due to coagulopathy remains a challenge. In this study we examined the bleeding and thrombotic manifestations, as well as incidence of Early Death secondary to thrombosis/hemorrhage (ED-TH) in patients with APL. Early death (ED) was defined as death occurring within 30 days of induction therapy. Two-hundred forty-eight patients were included in the study. Overall, 57 patients had evidence of a major bleed/thrombosis at presentation or during induction therapy, including 44 patients with a major bleed, 8 patients with thrombosis and 5 patients with both evidence of thrombosis and a major bleed. Forty patients (16.1%) had ED, of which 21 had ED-TH. The cumulative incidence of death due to thrombo-hemorrhagic complications at 30 days was 8.4%. On univariate analysis, increasing Prothrombin time (PT)(p-<0.001), white blood cell count (p < 0.001) and activated Partial thromboplastin time (aPTT) (p < 0.001) were statistically significantly associated with increased risk of ED-TH. However, on multivariate analysis, only increasing PT (p-0.025) and aPTT (p-0.041) were significantly associated with increased risk of ED-TH.

Granulomatous inflammation and hypogammaglobulinemia: Clinical conundrum of familial hemophagocytic lymphohistiocytosis type 5.

Familial hemophagocytic lymphohistiocytosis (HLH) is an inherited disorder characterized by systemic hyperinflammation caused by an uncontrolled immune response mediated by T-lymphocytes, natural killer (NK) cells, and macrophages. Most children with familial HLH present within first 2 years of life and can have fatal disease unless hematopoietic stem cell transplant (HSCT) is performed (1). However, few patients may have late presentation and prolonged survival. With increasing awareness and facilities to identify HLH these disorders are being identified beyond infancy (2-4). Clinical and laboratory features are often similar to other primary immune deficiency diseases and pose diagnostic challenges (4-6). We report two patients who presented beyond the first decade of life with HLH, granulomatous inflammation, hypogammaglobulinemia, reduced B cells and were diagnosed to have familial HLH type 5 due to defect in STXBP2 gene.

Molecular spectrum of inherited FVII deficiency in North India revealed a recurrent variant with a founder effect.

INTRODUCTION: Inherited Factor VII (FVII) deficiency is commonest among the rare bleeding disorders. A small number of patients present in infancy with severe bleeding, and many may remain asymptomatic but detected before surgery/invasive procedures. Genetic testing may be helpful in predictive testing/prenatal diagnosis in severe cases. AIM: Characterisation of clinical and genotypic spectrum of patients with inherited FVII deficiency. METHODS: Retro-prospectively, 35 cases with prolonged prothrombin time and FVII activity (FVII:C) <50 IU/dl were subjected to targeted resequencing. After in-silico analysis, variant/s were validated by Sanger sequencing in index cases and family members. Haplotype analysis was done for F7 polymorphisms. RESULTS: Severe FVII deficiency was found in 50% of patients (FVII:C ≤1 IU/dl), and 42.9% were asymptomatic. Clinical severity assessment revealed 17% severe, 17% moderate and 22.9% patients with mild bleeds. FVII levels ranged from .3 to 38 IU/dl. Molecular analysis revealed variants in 30/35 cases, of which 17 were homozygous, 10 were compound heterozygous and 3 were heterozygous. Twelve genetic variants were identified, one promoter variant c.-30A>C; seven missense (c.215C>G, c.244T>C, c.253G>C, c.904G>A, c.961C>T, c.1109G>T, c.1211G>A), two deletions (c.21delG, c.868_870delATC), and one each of nonsense c.634C>T and splice-site variant c.316+1G>A. Recurrent variants c.1109G>T and c.215C>G were found in 17 and 8 cases, 12 of the former cases were homozygous. They had the same haplotype, indicating the founder effect in North Indians. CONCLUSION: This is the largest cohort of FVII genotyping from India, confirming heterogeneity in terms of clinical manifestations, FVII activity and zygosity of the variants with a limited genotypic phenotypic correlation.

Carfilzomib-induced Thrombotic Microangiopathy: A Case Based Review.

Carfilzomib is an irreversible proteasome inhibitor currently approved for the treatment of relapsed multiple myeloma. It has been implicated as a cause of thrombotic microangiopathy (TMA) in several case reports. The incidence, risk factors, and treatment of carfilzomib-related TMA remain unclear. Here we describe the clinical presentation and outcome of a 58-year-old man with biopsy-proven TMA that occurred following treatment with carfilzomib-based therapy. We also reviewed the published literature with regard to the incidence, risk factors, treatment options, and outcome of carfilzomib-related TMA.

An Autopsy Case of Wiskott-Aldrich Syndrome Revealing "FDC-Only Lymphoid Follicles" in Lymphoid Tissue: A Morphologic Correlate of Defective Immune Synapse.

Wiskott-Aldrich Syndrome (WAS) is an inherited disorder characterized by the classical triad of eczema, micro-thrombocytopenia, and immune deficiency. This disease affects the hematopoietic cells to a variable extent. The spectrum of clinical and laboratory data for WAS has been well described in the literature though there is a paucity of its histopathologic and immunohistochemical correlates. The current case describes the autopsy findings of this rare entity in an 8-year old male child with specific recognition of altered histology noticed in the lymphoreticular tissues. The predominant morphological finding in lymphoid tissue was atretic hyalinized germinal centers labeled as "the follicular dendritic cell (FDC)-only lymphoid follicles." Immunohistochemistry revealed a reduction in germinal-center B-cells, T-follicular helper cells, attenuated mantle zone, FDC proliferation, and paracortical plasmacytosis. This case highlights the crippled immune cell population in WAS, ultimately leading to the morphology of atretic follicles rich in FDCs.

Feasibility and impact of screening for venous thromboembolism in treatment-naive lung cancer patients-Results of a prospective cohort study.

Background: Venous thromboembolism (VTE) in cancer remains underdiagnosed. This prospective study aimed to evaluate the feasibility of screening for VTE in lung cancer (LC) patients. We assess the incidence of VTE, its risk factors, and effects on overall survival (OS). Methods: Consecutive treatment-naive LC patients were screened for deep venous thrombosis (DVT) with compression ultrasonography and pulmonary thromboembolism (PTE) with computed tomography pulmonary angiography (CTPA) at diagnosis and after 3 months of treatment. The incidence rate of VTE (DVT and/or PTE) was calculated. Risk factors associated with VTE were assessed using logistic regression analysis. All participants were followed-up to 1 year after enrollment. OS was compared in LC subjects with and without VTE, using the Cox proportional hazard analysis. Results: Around 301 subjects with LC (stages IIIB-IV accounted for 83.1%) were enrolled, of which 16 had VTE (5.3%). The incidence rate of VTE was 90 per 1000 person-years (PY). PTE was asymptomatic in 27.3% of cases while all DVT episodes were symptomatic. The incidence rate of asymptomatic PTE identified during the screening was 17 per 1000 PY. The median duration from LC diagnosis to the VTE event was 96.5 days. Median OS was significantly less in VTE patients [161 versus 311 days; P = 0.007] and death was attributable to VTE in 50%. After adjusting for covariates, VTE (hazard ratio [HR] = 2.1), smoking (HR = 1.7), and Eastern cooperative oncology group performance status ≥2 (HR = 1.6) were independently associated with poor OS in LC. Conclusions: VTE occurs in approximately 1 in 20 newly-diagnosed patients with LC and is associated with decreased OS. Screening for PTE may be considered even in resource-limited settings.

Effect of tranexamic acid on blood loss, coagulation profile, and quality of surgical field in intracranial meningioma resection: A prospective randomized, double-blind, placebo-controlled study.

BACKGROUND: Resection of intracranial meningioma has been associated with significant blood loss. Providing a clear surgical field and maintaining hemodynamic stability are the major goals of anesthesia during meningioma surgery. Tranexamic acid has been used to reduce blood loss in various neurosurgical settings with limited evidence in literature. A randomized, double-blind, and placebo-controlled trial was conducted to evaluate the efficacy of tranexamic acid on blood loss, coagulation profile, and quality of surgical field during resection of intracranial meningioma. METHODS: Thirty patients aged 18-65 years undergoing elective meningioma resection surgery were given either tranexamic acid or placebo (0.9% saline), tranexamic acid at a loading dose of 20 mg/kg, and infusion of 1 mg/kg/h during surgery. The intraoperative blood loss, coagulation profile, and the surgical field using Likert scale were assessed. RESULTS: The patients in tranexamic group had significantly decreased intraoperative blood loss compared to the placebo group (616.42 ± 393.42 ml vs. 1150.02 ± 416.1 ml) (P = 0.02). The quality of the surgical field was better in the tranexamic group (median score 4 vs. 2 on Likert Scale) (P < 0.001). Patients in tranexamic group had an improved coagulation profile and decreased blood transfusion requirement (p=0.016). The blood collected in closed suction drain in 24 h postsurgery was less in the tranexamic acid group compared to placebo group (84.7 ± 50.4 ml vs. 127.6 ± 62.2 ml) (P = 0.047). CONCLUSION: Tranexamic acid bolus followed by infusion reduces perioperative blood loss by 46.43% and blood transfusion requirement with improved surgical field and coagulation profile in patients undergoing intracranial meningioma resection surgery.

Wiskott Aldrich Syndrome: A Multi-Institutional Experience From India.

Background: Wiskott Aldrich syndrome (WAS) is characterized by bleeding manifestations, recurrent infections, eczema, autoimmunity, and malignancy. Over the last decade, improved awareness and better in-house diagnostic facilities at several centers in India has resulted in increased recognition of WAS. This study reports collated data across major primary immunodeficiency diseases (PID) centers in India that are involved in care of children with WAS and highlights the varied clinical presentations, genetic profile, and outcomes of patients in India. Methods: Request to share data was sent to multiple centers in India that are involved in care and management of patients with PID. Six centers provided requisite data that were compiled and analyzed. Results: In this multi-institutional cohort, clinical details of 108 patients who had a provisional diagnosis of WAS were received. Of these, 95 patients with 'definite WAS' were included Fourteen patients were classified as XLT and 81 patients as WAS. Median age at onset of symptoms of patients was 3 months (IQR 1.6, 6.0 months) and median age at diagnosis was 12 months (IQR 6,48 months). Clinical profile included bleeding episodes (92.6%), infections (84.2%), eczema (78.9%), various autoimmune manifestations (40%), and malignancy (2.1%). DNA analysis revealed 47 variants in 67 cases. Nonsense and missense variants were the most common (28.4% each), followed by small deletions (19.4%), and splice site defects (16.4%). We also report 24 novel variants, most of these being frameshift and nonsense mutations resulting in premature termination of protein synthesis. Prophylactic intravenous immunoglobulin (IVIg) was initiated in 52 patients (54.7%). Hematopoietic stem cell transplantation (HSCT) was carried out in 25 patients (26.3%). Of those transplanted, disease-free survival was seen in 15 patients (60%). Transplant related mortality was 36%. Outcome details were available for 89 patients. Of these, 37% had died till the time of this analysis. Median duration of follow-up was 36 months (range 2 weeks- 12 years; IQR 16.2 months- 70 months). Conclusions: We report the first nationwide cohort of patients with WAS from India. Bleeding episodes and infections are common manifestations. Mortality continues to be high as curative therapy is not accessible to most of our patients.

Successful Management of Catastrophic Thrombotic Storm in a Young Boy: A Case Report From Northern India.

Thrombotic storm is a rare clinical entity characterized by acute to subacute thrombosis developing at multiple sites over a few days to a few weeks. An 11-year-old boy presented with headache and facial nerve palsy. He was found to have cortical sinus venous thrombosis and was initiated on low molecular weight heparin, but rapidly progressed with thromboses involving the pulmonary arteries and deep veins of the legs. Thereafter managed on high-dose unfractionated heparin, he eventually stabilized after a hospital stay of 34 days. Genetic analysis showed potentially pathogenic variants in the factor V and stabilin-2 genes.

CD 34 Staining to the Rescue in an Incidental Capillary Hemangioma of the Bone Marrow.

Intraosseous hemangiomas are extremely rare and benign neoplasms of vascular origin, usually occurring in adults and involving skull bones, vertebra, ribs, sternum, long bones, patella and clavicle. Iliac or pelvic bone involvement is extremely rare. Hemangiomas of the marrow spaces are extremely uncommon. We report this rare neoplasm in a child that was incidentally detected on bone marrow examination for thrombocytopenia which mimicked a metastatic deposit. However, immunostaining with CD34 was successful in characterizing this solid vascular lesion as capillary hemangioma. This report emphasizes the importance of correctly identifying this lesion with the help of simple CD34 immunostaining since no specific therapy is required.

Recurrent Intracranial Bleed in 3 Siblings: Short of a Shot of Vitamin K!

We present a family who suffered recurrent sibling losses due to vitamin K deficiency bleed. The index child was asymptomatic at presentation, had normal clinical examination, and was investigated for coagulation disorders in view of previous 3 sibling losses as a result of intracranial hemorrhage. His investigations showed deranged coagulogram and clotting factors' assay. The baby was given vitamin K1 1 mg intramuscularly following which his coagulogram and clotting factors' assay returned to normal. The genetic analysis did not identify any inherited cause of bleeding tendency. The significant family history, exclusive breastfeeding, no diarrhea, failure to thrive or drug use, no prophylaxis with vitamin K at birth, recovery of clotting factors on vitamin K administration, and a corroborative molecular analysis confirmed diagnosis of vitamin K deficiency in the index child. This case gives a strong reminder not to miss birth dose of vitamin K in any neonate.

Clotting disorder in severe acute respiratory syndrome coronavirus 2.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel human respiratory viral infection that has rapidly progressed into a pandemic, causing significant morbidity and mortality. Blood clotting disorders and acute respiratory failure have surfaced as the major complications among the severe cases of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection. Remarkably, more than 70% of deaths related to COVID-19 are attributed to clotting-associated complications such as pulmonary embolism, strokes and multi-organ failure. These vascular complications have been confirmed by autopsy. This study summarizes the current understanding and explains the possible mechanisms of the blood clotting disorder, emphasizing the role of (1) hypoxia-related activation of coagulation factors like tissue factor, a significant player in triggering coagulation cascade, (2) cytokine storm and activation of neutrophils and the release of neutrophil extracellular traps and (3) immobility and ICU related risk factors.

JAK2V617F Mutation in Patient with Splanchnic Vein Thrombosis.

Splanchnic vein thrombosis is an uncommon life-threatening form of venous thrombosis. It is one the common complication among MPN's. In the western studies the prevalence of JAK2V617F mutation among SVT patient is high and ranges from 7 to 59%. The frequency of this mutation among Indian SVT patients is heterogenous. This was a prospective case control study. A total 52 cases of SVT and 40 controls were screened for JAK2V617F mutation along with other routine thrombophilic risk factors. Out of total 52 cases, 10 had BCS, 2 had MVT and rest 40 were of PVT/EHPVO. The JAK2V617F mutation was seen in two cases and not in controls. Among the thrombophilic markers, heterozygous FVL mutation, PC, PS and presence of APA were seen in 2, 3, 1 and 3 cases respectively. In addition, eight cases also showed deranged risk factors (5 inherited and 3 acquired), however the repeat testing was not performed due to loss of follow up. Among controls, one person showed presence of APA and one person showed multiple thrombophilic risk factor deficiency. JAK2V617F mutation was observed in 3.8% among north Indian SVT patients. The frequency of mutation is on the lower side as compared to the available Indian data. The other thrombophilia markers (both inherited and acquired) are more frequent (18%) and patients should be routinely screened for these thrombophilia markers.

Antiphospholipid Antibodies Are Not Associated with Clinical Parameters or Prognostic Outcomes in Patients with Non-Hodgkin's Lymphoma.

BACKGROUND: Antiphospholipid antibodies (APAs) are found quite frequently in patients with non-Hodgkin's lymphoma (NHL). However, the clinical significance of these antibodies is largely unknown. This study aims to delineate the clinical and prognostic role of APAs in NHL patients. PATIENTS AND METHODS: Consecutive patients of NHL were screened for lupus anticoagulant (LA), IgG/IgM anticardiolipin antibody, and IgG/IgM anti-ß2-glycoprotein I at the time of diagnosis. Baseline investigations, staging, and treatment were done as per institutional protocol. Patients were followed up until the last known outpatient visit or death. All were screened at each visit for any thromboembolic event. The association of APA status with baseline NHL characteristics and treatment response was evaluated by univariate analysis. Kaplan-Meier survival analysis was used to compare the final outcome in patients with or without APAs. Patients who were initially APA positive were retested for the corresponding antibody at the end of chemotherapy. RESULTS: Twenty-four out of 105 patients (22.8%) were APA positive at diagnosis. The presence of APA was not significantly associated with NHL stage, histology, International Prognostic Index score, activated partial thromboplastin time, or treatment response. The median duration of follow-up was 15 months. Only four patients developed venous thrombosis; none was APA positive. There was no statistically significant difference in overall survival between the two groups (p = 0.471). Patients, who were APA positive initially, tested negative at the end of treatment, irrespective of treatment response. CONCLUSION: APAs are encountered more frequently in NHL patients than in the general population. However, APAs do not correlate with disease severity, thrombosis risk, treatment outcome, or overall survival.

Familial macro thrombocytopenia: role of genetics where morphology fails.

: Myosin heavy chain 9 (MYH9)-related disorders are rare inherited platelet disorders that are accompanied by a wide variety of systemic abnormalities. The persistent thrombocytopenia is usually asymptomatic and these patients are often misdiagnosed and treated as immune thrombocytopenia. MYH9 gene has been studied in association with solid organ malignancies. We report a young girl with family history of thrombocytopenia and hearing loss who presented with kidney dysfunction and later developed acute lymphoblastic leukemia. She lacked the characteristic inclusion bodies in her blood granulocytes, however a diagnosis of MYH9-related Epstein syndrome was confirmed on genetic testing. In the background of known causal association of MYH9 gene in solid organ malignancies, the role of MYH9 gene variant in malignant transformation in the index case remains conjectural.