The rs867186 single-nucleotide polymorphism in the
gene (g.6936A > G, c.4600A > G) results in a serine-to-glycine substitution at codon 219 of endothelial protein C receptor (EPCR). We performed a ...case-control study followed by an updated meta-analysis of the association between this polymorphism and the risk of venous thromboembolism (VTE).
We enrolled 263 VTE patients and 320 unrelated healthy controls for the case-control study. The total number of cases and controls for the meta-analysis were 5,768 and 30,017, respectively. A new online MetaGenyo Statistical Analysis System software was used to perform the current meta-analysis. Furthermore, a reproducibility study was conducted to validate our results.
Among well-defined thrombosis risk factors, Factor V Leiden was more frequent in the VTE group (
< 0.001), while there was no difference in mutation frequency of prothrombin 20210G>A polymorphism between the two groups. There was no difference in the mutation frequency of Factor V Leiden and prothrombin 20210G>A between cases with and without provoking factors and cases with and without VTE recurrence. The rs867186 "G" carriership did not influence the risk of VTE odds ratio (OR) 1.339; 95% confidence interval (CI): 0.904-1.984 in our study. No significant differences could be demonstrated among the rs867186 genotype frequencies between VTE cases with and without provoking factors (
= 0.430).
rs867186 was associated with an OR of 1.72 (95% CI: 0.95-3.13,
= 0.075) in terms of VTE recurrence. In the meta-analysis, a significant association was found between EPCR Ser219Gly polymorphism and VTE under the dominant model (OR = 1.27, 95% CI: 1.11-1.46,
= 0.0006), the recessive model (OR = 1.60, 95% CI: 1.26-2.04,
= 0.0001), the GG vs. AA contrast model (OR = 1.64, 95% CI: 1.28-2.09,
= 0.0001), and the GA vs. AA contrast model (OR = 1.24, 95% CI: 1.08-1.43,
= 0.002).
The rs867186 was not associated with the first VTE risk in our case-control study; however, a tendency to VTE recurrence was observed. Based on the results of our reproducibility study, MetaGenyo is acceptable for meta-analysis in case of genetic epidemiology studies. Although the risk conferred by the rs867186 is mild in all meta-analyses, including ours, identifying patients carrying the minor allele might have an impact on personalized VTE risk assessment, risk-score calculation, and patient management.
Acquired factor XIII (FXIII) deficiency due to autoantibody against FXIII is a very rare severe hemorrhagic diathesis. Antibodies directed against the A subunit of FXIII, which interfere with ...different functions of FXIII, have been described. Here, for the first time, we report an autoantibody against the B subunit of FXIII (FXIII-B) that caused life-threatening bleeding in a patient with systemic lupus erythematosus. FXIII activity, FXIII-A2B2 complex, and individual FXIII subunits were undetectable in the plasma, whereas platelet FXIII activity and antigen were normal. Neither FXIII activation nor its activity was inhibited by the antibody, which bound to structural epitope(s) on both free and complexed FXIII-B. The autoantibody highly accelerated the elimination of FXIII from the circulation. FXIII supplementation combined with immunosuppressive therapy, plasmapheresis, immunoglobulin, and anti-CD20 treatment resulted in the patient's recovery. FXIII levels returned to around 20% at discharge and after gradual increase the levels stabilized above 50%.
Diagnosis of rare bleeding disorders is challenging and there are several differential diagnostics issues. Next-generation sequencing (NGS) is a useful tool to overcome these problems. The aim of ...this study was to demonstrate the usefulness of molecular genetic investigations by summarizing the diagnostic work on cases with certain bleeding disorders. Here we report only those, in whom NGS was indicated due to uncertainty of diagnosis or if genetic confirmation of initial diagnosis was required. Based on clinical and/or laboratory suspicion of von Willebrand disease (vWD,
= 63), hypo-or dysfibrinogenemia (
= 27), hereditary hemorrhagic telangiectasia (HHT,
= 10) and unexplained activated partial thromboplastin time (APTT) prolongation (
= 1), NGS using Illumina platform was performed. Gene panel covered 14 genes (
,
,
,
,
,
,
,
,
,
,
,
,
and
) selected on the basis of laboratory results. We identified forty-seven mutations,
= 29 (6 novel) in vWD,
= 4 mutations leading to hemophilia A,
= 10 (2 novel) in fibrinogen disorders,
= 2 novel mutations in HHT phenotype and two mutations (1 novel) leading to prekallikrein deficiency. By reporting well-characterized cases using standardized, advanced laboratory methods we add new pieces of data to the continuously developing "bleeding disorders databases", which are excellent supports for clinical patient management.
A vénás thromboembolia a fiatal betegeket is gyakran érinti, és bizonyos esetekben tartós antikoaguláns kezelést indokol. Fiatal nőkben a véralvadásgátló terápia speciális kérdéseket vet fel. Ezek ...közül a leggyakoribb probléma az antikoaguláns terápia mellett fokozódó nőgyógyászati vérzés, mely sokszor jelentős mértékű és anaemiához vezethet. Valamennyi véralvadásgátló gyógyszer szedése okozhat menorrhagiát, amely a jelenleg rendelkezésre álló adatok szerint leggyakrabban az aktivált X-es faktort gátlók szedéséhez társul. Megoldása a nőgyógyász és hematológus együttműködését igényli.
Acquired von Willebrand syndrome (AVWS) is a rare, frequently underdiagnosed and underestimated bleeding disorder. Careful personal and family history and late-onset mucocutaneous bleeding could help ...clarify the etiology of bleeding deficiency.
An 82-year-old male patient was admitted to our clinic with a severe nosebleed on 30.05.2018. Laboratory results revealed thrombocytosis, elevated white blood cell count and high LDH. Basic coagulation parameters were normal. He was referred to our clinic, where a bone marrow biopsy was taken. His personal and family history had no mention of bleeding disorders, nor was he on anticoagulant therapy. We detected elevated VWF antigen and decreased VWF ristocetin cofactor activity. Loss of high molecular weight multimers was detected by using agarose gel electrophoresis. These laboratory results were indicative of AVWS. Hydroxyurea treatment was initiated, leading to a gradual decrease in platelet count. The histological examination revealed essential thrombocytosist while mutation analysis was JAK2/CALR/MPL negative. However, due to severe nosebleeds, the patient was hospitalized and needed blood transfusion. A cardiological check-up revealed the progression of aortic valve stenosis. After, balloon-dilation a transcatheter aortic valve implantation was performed. As a result, VWF activity and activity to antigen ratio returned to normal as did multimeric structure. In July 2019, the follow-up examination showed that the patient was in a satisfactory condition, with normal hematological parameters, and no new nosebleed episode occurred.
The patient complained of recurring nosebleeds, which stopped completely after the resolution of both underlying conditions successful cytoreductive treatment of triple-negative ET and transcatheteric aortic valve replacement.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
In acquired haemophilia A (AHA), risk for recurrent bleeding exists until the inhibitor is detectable. Thus, patients with persisting inhibitor may benefit from prophylaxis with activated prothrombin ...complex concentrate (aPCC). Potential thromboembolic complications and cost are also factors to consider. Today, no high level evidence or clear recommendations are available on aPCC prophylaxis in AHA. Recently, a small prospective study demonstrated a favourable outcome with short-term, daily administered aPCC infusion. Here we report a retrospective case series of 19 patients with AHA to demonstrate our practice on aPCC prophylaxis. In our practice, clinical bleeding tendency guided our decision on the initiation of aPCC prophylaxis. In patients with serious bleeding tendency, aPCC infusion was prolonged beyond bleeding resolution in a twice-weekly or thrice-weekly regimen. Serious bleeding phenotype included a single episode of life-threatening bleeding or recurrent, severe haemorrhages. Patients who did not present such events were treated on-demand. The preventive dose of aPCC was equal with the lowest effective therapeutic dose. Prophylaxis was continued until the inhibitor disappeared. Eleven patients received aPCC prophylaxis. In nine cases, prophylaxis lasted beyond two months. No severe bleeding developed spontaneously and no thromboembolic complication occurred in the median 16 weeks (interquartile range 9–34) duration of prophylaxis. Eight patients of the nonprophylaxis group did not present any severe haemorrhage. According to our experience, we consider prophylaxis with aPCC effective and well tolerated for patients with AHA and serious bleeding tendency, until the acquired inhibitor persists.
Atresia of inferior vena cava (IVC) is a rare congenital malformation associated with high risk of venous thrombosis that still has unknown etiology, although intrauterine IVC thrombosis has been ...suggested to be involved. The identification of IVC atresia in a case with early idiopathic venous thrombosis and antithrombin deficiency caused by the homozygous SERPINC1 c.391C > T variant (p.Leu131Phe; antithrombin Budapest 3) encouraged us to evaluate the role of this severe thrombophilia in this vascular abnormality. We have done a cross‐sectional study in previously identified cohorts of patients homozygous for the Budapest 3 variant (N = 61) selected from 1118 patients with congenital antithrombin deficiency identified in two different populations: Spain (N = 692) and Hungary (N = 426). Image analysis included computed tomography and phlebography. Atresia of the IVC system was observed in 17/24 cases (70.8%, 95% confidence interval CI: 48.9%–87.3%) homozygous for antithrombin Budapest 3 with available computed tomography (5/8 and 12/16 in the Spanish and Hungarian cohorts, respectively), 16 had an absence of infrarenal IVC and one had atresia of the left common iliac vein. All cases with vascular defects had compensatory mechanisms, azygos‐hemiazygos continuation or double IVC, and seven also had other congenital anomalies. Short tandem repeat analysis supported the specific association of the IVC system atresia with SERPINC1. We show the first evidence of the association of a severe thrombophilia with IVC system atresia, supporting the possibility that a thrombosis in the developing fetal vessels is the reason for this anomaly. Our hypothesis‐generating results encourage further studies to investigate severe thrombophilic states in patients with atresia of IVC.
Inherited antithrombin (AT) deficiency is a heterogeneous disease. Due to low prevalence, only a few studies are available concerning genotype-phenotype associations. The aim was to describe the ...clinical, laboratory and genetic characteristics of AT deficiency in a large cohort including children and to add further laboratory data on the different sensitivity of functional AT assays.
Non-related AT deficient patients (n=156) and their family members (total n=246) were recruited. Clinical and laboratory data were collected, the mutation spectrum of SERPINC1 was described. Three different AT functional assays were explored.
Thirty-one SERPINC1 mutations including 11 novel ones and high mutation detection rate (98%) were detected. Heparin binding site deficiency (type IIHBS) was the most frequent (75.6%) including AT Budapest3 (ATBp3), AT Padua I and AT Basel (86%, 9% and 4% of type IIHBS, respectively). Clinical and laboratory phenotypes of IIHBS were heterogeneous and dependent on the specific mutation. Arterial thrombosis and pregnancy complications were the most frequent in AT Basel and AT Padua I, respectively. Median age at the time of thrombosis was the lowest in ATBp3 homozygotes. The functional assay with high heparin concentration and pH7.4 as assay conditions had low (44%) sensitivity for ATBp3 and it was insensitive for AT Basel and Padua I.
Type IIHBS deficiencies behave differently in clinical and laboratory phenotypes from each other and from other AT deficiencies. Heparin concentration and pH seem to be the key factors influencing the sensitivity of AT functional assays to IIHBS.
•11 novel and 20 known mutations are described in AT deficiency in a large cohort.•Type IIHBS is a heterogeneous clinical group.•It is useful to investigate for AT deficiency in children with unprovoked thrombosis.•ATBp3 behaves differently in certain assay conditions than AT Padua I and AT Basel.•Heparin concentration and pH seem to be crucial in functional assay sensitivity.
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