Clinical Profile of Congenital Factor XIII Deficiency in Children.

OBJECTIVES: Congenital Factor 13 Deficiency (FXIIID) is a rare bleeding disorder (RBD) of autosomal recessive inheritance, with an incidence of 1 in 3-5 million. The clinical symptomatology, diagnosis, and management of FXIIID are described. METHODS: A retrospective chart review of children with FXIIID was performed from January 2000 through October 2021 at a tertiary care center in Southern India. The diagnosis was performed by the Urea clot solubility test (UCST) and Factor XIII antigen assay. RESULTS: Twenty children (representing 16 families) were included. Male: Female ratio was 1.5:1. The median age of symptom onset was 6 mo, and the median age of diagnosis was 1 y, demonstrating a delay in diagnosis. Consanguinity was present in 15 (75%) with 4 children having affected siblings. Clinical symptomatology ranged from mucosal bleeds to intracranial bleeds and hemarthrosis, with many children having a history of prolonged umbilical bleeding in their neonatal period. Fourteen children were on cryoprecipitate prophylaxis. Four children had breakthrough bleeds due to irregular prophylaxis, including one intracranial bleed due to a delay in cryoprecipitate prophylaxis during the covid pandemic. CONCLUSIONS: Congenital FXIIID presents with a wide range of bleeding manifestations. The high prevalence of consanguinity in Southern India can be a cause of FXIIID's high prevalence in this region. There is a propensity for intracranial bleeding with a significant number having this at first presentation. Regular prophylaxis is required and feasible to prevent potentially fatal bleeds.

Transfusion burden following reduced intensity allogeneic hematopoietic cell transplantation: Impact of donor type.

BACKGROUND: Transfusions are essential for allogeneic hematopoietic cell transplant (HCT), yet they are influenced by graft, donor, and other factors. STUDY DESIGN: We analyzed transfusions in 165 adult reduced intensity HCTs (2016-2019): HLA matched sibling donor (MSD) (n = 59), matched URD (n = 25), UCB (n = 33), and haploidentical (haplo, n = 48) detailing the cumulative incidence of platelet and RBC transfusion independence, total transfusions (day-10 to day+100) plus transfusion densities (per week) over 110 days. RESULTS: Platelet recovery to 20 × 109 /L by 6 months occurred in 39/48 (81.25%) haplo recipients (median 33 [range, 0-139]) days vs. 58/59 (98.3%) MSD (median 10 [0-37]), 21/25 (84%) matched URD (median 20 [0-153]), and 29/33 (87.87%) UCB (median 48 [29-166]) days, p < .01. Regression analysis demonstrated a lower likelihood of prompt platelet recovery in matched URD, UCB, or haplo HCTs vs. MSD. Recovery to platelet independence was quickest in MSD (median 8 days [range 0-94]), vs. URD (median 16 days [0-99]), UCB (median 57 [0-94]), or haplo (median 45 [12-97]) days, p < .01. Platelet needs were unaffected by age, conditioning, or acute GVHD. RBC transfusion independence was achieved in 78% of MSD, 64% URD, and 82% UCB, though less frequent (58%) and slowest in haplo recipients, p < .01. All haplo and UCB recipients required platelet transfusions vs. only 51% of MSD and 76% of URD. RBC needs were highest in UCB and haplo HCTs. DISCUSSION: The transplant donor influences the transfusion burden with greater platelet and RBC needs in haplo and UCB HCT which directly contributes to increased cost of care.

Exovesicular-Shh confers Imatinib resistance by upregulating Bcl2 expression in chronic myeloid leukemia with variant chromosomes.

Chronic myeloid leukemia (CML) patients with complex chromosomal translocations as well as non-compliant CML patients often demonstrate short-lived responses and poor outcomes on the current therapeutic regimes using Imatinib and its variants. It has been derived so far that leukemic stem cells (LSCs) are responsible for Imatinib resistance and CML progression. Sonic hedgehog (Shh) signaling has been implicated in proliferation of this Imatinib-resistant CD34(+) LSCs. Our work here identifies the molecular mechanism of Shh-mediated mutation-independent Imatinib resistance that is most relevant for treating CML-variants and non-compliant patients. Our results elucidate that while Shh can impart stemness, it also upregulates expression of anti-apoptotic protein-Bcl2. It is the upregulation of Bcl2 that is involved in conferring Imatinib resistance to the CD34(+) LSCs. Sub-toxic doses of Bcl2 inhibitor or Shh inhibitor (<

Pharmacokinetics, surrogate efficacy and safety evaluations of a new human plasma-derived fibrinogen concentrate (FIB Grifols) in adult patients with congenital afibrinogenemia.

BACKGROUND AND AIMS: Congenital afibrinogenemia is a rare coagulation disorder resulting from a deficiency in fibrinogen. This study assessed the pharmacokinetics, surrogate efficacy and safety of FIB Grifols, a new human plasma-derived fibrinogen concentrate, to treat congenital afibrinogenemia. METHODS: Eleven adult patients from a multinational, phase 1-2, prospective, open-label, single-arm, uncontrolled clinical study received a single infusion of FIB Grifols, 70 mg/kg bw. Fibrinogen pharmacokinetics (fibrinogen activity: Clauss method; antigen plasma concentrations: ELISA) and efficacy parameters were determined over 14 days after infusion. Efficacy endpoints were the mean change on plasma maximum clot firmness (MCF) on viscoelastic testing and coagulation tests 1-hour post-infusion, and correlation with fibrinogen levels throughout. Safety parameters were also assessed. RESULTS: For the Clauss method, (mean [standard deviation]) baseline adjusted Cmax was 1.99 (0.40) g/L, reached 1.76 (1.00) h after infusion, and half-life was 76.94 (20.21) h. Using ELISA, Cmax after FIB Grifols infusion was 2.88 (0.86) mg/mL, with a tmax of 3.06 (2.24) h. Fibrinogen activity and antigen concentrations showed statistically significant correlation of 0.9120 (P < 0.001). Surrogate efficacy was demonstrated by a significant increase of 12.35 (3.85) mm in MCF. Prothrombin time, activated partial thromboplastin time and thrombin time, returned to normal ranges over time, indicating restoration of functionally active fibrinogen. There were no treatment-related adverse events, allergic reactions, serious adverse events, or discontinuations. CONCLUSIONS: The pharmacokinetic profile of functionally active FIB Grifols was established, hemostasis was restored, and FIB Grifols was safe and well tolerated in fibrinogen-deficient patients.

Glanzmann Thrombasthenia in Children: Experience From a Tertiary Care Center in Southern India.

BACKGROUND: Glanzmann thrombasthenia (GT) is a globally rare inherited disorder of hemostasis. OBJECTIVES: To describe the clinical profile of GT in a tertiary care center in Southern India. METHODS: A retrospective chart review of all children with GT was performed between January 2005 and August 2017 in the Department of Paediatrics. RESULTS: A total of 48 patients (representing 43 families) were included. Median age at diagnosis was 2.75 years (interquartile range: 1.5 to 6.75). Two thirds had an onset of bleeding within the first 2 years of life. Sixty-seven percent were born out of consanguineous marriage. The common symptoms were epistaxis, gingival bleeding, and ecchymoses. Neonatal onset of bleeding manifested as purpura, epistaxis, and intracranial hemorrhage. Postsurgical bleeding and menorrhagia were unique presentations in adolescence. About 25% had life-threatening hemorrhage while 50% had growth retardation due to chronic anemia. CONCLUSIONS: GT is relatively more common in areas of Southern India due to the higher prevalence of consanguinity. Chronic anemia can contribute to growth stunting in these patients.

Management of acquired haemophilia bleed in the backdrop of multiple myeloma.

Acquired haemophilia A is an uncommon, potentially life-threatening disorder caused by onset of auto-antibodies against coagulation factor VIII. The association of acquired haemophilia and multiple myeloma is extremely rare. Prompt diagnosis of this acquired bleeding disorder is essential for management, aimed at haemorrhage control and inhibitor suppression. We describe a case of acquired haemophilia in a patient with multiple myeloma.

Left ventricular lateral annulus and left atrial free-wall velocity time integral indicate thromboembolism in patients with rheumatic atrial fibrillation.

BACKGROUND: Low wall motion and stasis increase the likelihood of clot formation. We hypothesized that tissue Doppler indices of left atrial (LA) motion are reduced in the presence of LA thrombi and may be predictive for clot formation in patients with atrial fibrillation (AF). METHODS: We did an observational study for 3 years in 118 patients with rheumatic mitral valve disease in chronic AF who had not received anticoagulation, with (Group 1, n = 36) and without (Group 2, n = 82) thromboembolism. Pulsed tissue Doppler systolic velocities and velocity time integrals (VTIs) were measured in all four chambers. A mean LA VTI was calculated. LA strain during ventricular systole was calculated using VTI and distance between two LA locations. RESULTS: Logistic regression analysis showed that, after adjusting for age, gender, diabetes, hypertension, LA size, and left ventricular (LV) ejection fraction, mean LA VTI [Odds ratio (OR) 0.69, 95%CI (0.56-0.86, P = 0.03)] and lateral mitral annulus VTI [OR 0.15 (0.04-0.56, P = 0.03)] were associated with clot formation. The addition of these two parameters to the conventional risk factors increased the ability to predict thromboembolism (Nagelkerke R² = 0.32-0.50, P = 0.01; area under the curve 0.83 by receiver operating characteristic analysis, P = 0.01). LA strain also had potential to indicate clot formation (0.9 ± 13.8 vs. -8.2 ± 15.1%, group 1 vs. 2, respectively, P = 0.01). CONCLUSION: Patients with chronic AF and thromboembolism have reduced LA and LV motion independently of LA size and LV ejection fraction. Tissue Doppler parameters may have potential to predict clot formation in these patients.