High Risk of Venous Thrombosis Recurrence in Fully Anticoagulated Patient with Antithrombin Deficiency during COVID-19: A Case Report

Coagulation dysfunction is a serious issue in patients with Coronavirus disease-19 (COVID-19). With regard to recently published studies, a high number of patients with acute respiratory distress syndrome (ARDS) secondary to COVID-19 developed life-threatening thrombotic complications despite anticoagulation. We report a case of young woman with the type-II heparin-binding site (HBS) antithrombin (AT) deficiency (Budapest 3-homozygous), who developed acute deep vein thrombosis on two occasions due to COVID-19 infection in the course of stable anticoagulation with vitamin K antagonist. The first thrombotic event was observed during mild COVID-19 infection, while the second thrombotic event she developed 2 months after she was negative for severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2). Our case highlights the complexity of the treatment in this particular type of thrombophilia and the need for precaution even in mild forms of viral infection. In the treatment of acute thrombosis, AT-deficient patients may benefit from the use of AT concentrate along with low-molecular weight heparin (LMWH), while in cases of type II-HBS, AT supplementation is mandatory.

Coexistence of antithrombin deficiency and suspected inferior vena cava atresia in an adolescent and his mother – case report and clinical implications

Background Antithrombin deficiency (ATD) is an autosomal dominant thrombophilia presenting with varying phenotypes. In pediatric patients with ATD, thrombosis typically develops during the neonatal period or adolescence. However, to date there are no consistent recommendations on the therapeutic management of children with ATD. Inferior vena cava atresia (IVCA) belongs to a range of congenital or acquired vena cava malformations and is described as an independent risk factor for thrombosis. The present case report explores two cases of combined ATD and IVCA in an adolescent and his mother. Case presentation A 14-year-old male presented with extensive deep venous thromboses (DVTs) of both lower extremities as well as an IVCA. The patient had previously been diagnosed with an asymptomatic ATD without therapeutic consequences at that time. His mother was suffering from an ATD and had herself just been diagnosed with IVCA, too. The DVTs in the adolescent were treated by systemic anticoagulation and catheter-directed local thrombolysis causing favourable results. Yet, despite adequate oral anticoagulation the DVTs in both lower extremities reoccurred within 1 week after the patient was discharged from hospital. This time, thrombolysis could not be fully achieved. Surprisingly, probing and stenting of the IVCA was achieved, indicating an acquired IVCA which could have occurred after undetected thrombosis in early childhood. Genetic analyses showed the same mutation causing ATD in both son and mother: heterozygote missense mutation c.248 T > C, p.(Leu83Pro), within the heparin binding domain of antithrombin. This mutation was never reported in mutation databases before. Conclusions To our knowledge this is the first case report discussing combined ATD and IVCA in two family members. Since ATDs present with clinical heterogeneity, taking a thorough family history is crucial for the anticipation of possible complications in affected children and decisions on targeted diagnostics and therapeutic interventions. Affected families must be educated on risk factors and clinical signs of thrombosis and need an immediate diagnostic workup in case of clinical symptoms. IVCA in patients with ATD could occur due to thrombotic occlusion at a very early age. Therefore, in case of family members with IVCA and ATD ultrasound screening in newborns should be considered.

Unfavorable Outcomes Associated with Antithrombin Deficiency in Patients Required Mechanical Ventilation: A Nationwide Database Study

Background: Mechanical ventilation (MV) is associated with increased risk of venous thromboembolism (VTE). Together with other thrombosis risk factors such as hereditary thrombophilia (HT), VTE can lead to unfavorable outcomes. We aim to investigate the outcomes in various types of HT patients required mechanical ventilation (MV), which is relatively unknown. Methods: This was a retrospective study using National Inpatient Sample from the year 2016 to 2018. International Classification of Diseases 10 th Revision was used to identify various types of HT (antithrombin III deficiency [ATIII deficiency), Factor V Leiden, congenital protein C or S deficiency, prothrombin gene mutation, other congenital hyper-coagulopathy), VTE, MV, and other conditions or procedures. The cohort of interest was MV-associated adults (age at least 18-year-old). Primary outcome was mortality. Comorbidities were evaluated with Charlson Comorbidity Index (CCI). Continuous variables were compared using Welch two sample T-test. Categorical variables were analyzed with Pearson's Chi-squared test. The possible associated variables and confounders were adjusted with the generalized linear model. Results: Among 616,717 adult MV hospitalizations, 5,024 cases had at least one HT diagnosis. In HT subgroup, the patients were significantly younger (mean age 59.4 vs 61.7, p value <0.0001). The portion of female and Caucasian were higher in the HT subgroup (46.7% vs 44.5%, p value <0.002; 66.0% vs 63.3%, p value <0.0001). CCI was slightly higher in HT group (5.09 vs 4.94, p value <0.005). HT was independently associated with higher mortality (adjusted odds ratio [aOR]: 1.16; p value<0.000005) even after adjusted for VTE, myocardial infarction, ischemic stroke, and other comorbidities. HT patients had significantly higher risk of developing pulmonary embolism (PE) and deep vein thrombosis (DVT) (aOR: 2.86 and 2.09 respectively; both p value <0.0001). Among various types of HT, subgroup analysis revealed that only ATIII deficiency was associated with significantly higher mortality (aOR: 1.67, p value <0.0001). The odd of mortality in ATIII deficiency was higher in young adults and less prominent among older population (<40-year-old aOR: 2.81, p value <0.0001; >=65-year-old aOR: 1.53, p value <0.0001). ATIII deficiency patients also had higher risk of developing severe sepsis (aOR: 1.52, p value <0.0001). Conclusion: Among HT, only ATIII deficiency significantly increased the risk of mortality. The mortality odd was higher especially among young adults with ATIII deficiency. ATIII deficiency group also had higher odd of developing severe sepsis and VTE. Even though the other types of HT also had increased risk of VTE, they were not found to be associated with mortality in MV. It was unclear why only ATIII deficiency was associated with poor prognosis. Additional research needs to be done to fully investigate the underlying mechanism. Disclosures No relevant conflicts of interest to declare.

Molecular and Biological Characterization of Transient Antithrombin Deficiency: A New Concept in Congenital Thrombophilia

Antithrombin deficiency, mainly but not exclusively due to SERPINC1 gene variants, is a major thrombophilia that is significantly associated to early-onset venous thromboembolism. The diagnostic algorithm of antithrombin deficiency relies on the classical biochemical-molecular sequence, adopted for all thrombophilic states. Therefore, genetic analysis of SERPINC1 is restricted to cases with confirmed antithrombin deficiency, that is, cases with at least two positive findings by using functional assays or with other relatives carrying this disorder. This strategy has enabled the identification of gene variants in up to 80% of cases with antithrombin deficiency and rendered plenty of both biochemical and genetic knowledge about antithrombin. Furthermore, defects of N-glycosylation underlie a proportion of cases with antithrombin deficiency that is not explained by SERPINC1 variants. Nevertheless, diagnosis of antithrombin deficiency still encloses some uncertain puzzling questions. Although the prevalence of antithrombin deficiency is tremendously low, the use of high-throughput nucleotide sequencing for genetic analysis of SERPINC1 in consecutive patients with thromboembolic events suggests that antithrombin deficiency might be and underestimated disorder that surreptitiously increases thrombotic risk. Additionally, false negative results by using functional methods for antithrombin deficiency screening have been reported, all involving type II deficiencies. The present study aimed to identify gene defects and mechanisms involved in a specific type of antithrombin deficiency that might be elusive to an easy diagnosis to the classic diagnostic strategy. We addressed this aim with an original approach, the selection of cases with at least a positive finding by functional methods that however was not confirmed by a second analysis in other laboratory or in other sample from the same patient: what we have called transient antithrombin deficiency. This work included a total of 444 consecutive unrelated subjects, referred to our centre from more than 20 European hospitals during 23 years (1998-2021), with potential antithrombin deficiency, based on at least one positive functional assay performed at the hospital of origin. At least a new sample from all patients was delivered to our centre, so a new functional assay (a uniform anti-FXa assay for all recruited samples) was carried out for validation. By performing a full clinical, biological and characterization, a genetic defect was observed in 84.6% of 305 cases with constitutive deficiency, those with consistent deficiency in all tested samples: 248 in SERPINC1 and 10 had N-glycosylation defects. These results are fully compatible with those obtained from other large cohorts, supporting the high success rate of identification of a SERPINC1 genetic variant in these patients, and confirmed the relevance of disorders of glycosylation among cases with not SERPINC1 defect. But more interestingly, our study identified a molecular basis explaining antithrombin deficiency in 43.9% of 139 cases who had normal antithrombin activity in at least one sample, what we called transient antithrombin deficiency. These 61 cases, all with thrombosis, had missense SERPINC1 mutations (N=48), with two recurrent mutations (p.Ala416Ser, antithrombin Cambridge II, N=15 and p.Val30Glu, antithrombin Dublin, N=12) or N-glycosylation defects (N=13). Two mechanisms explained transient deficiency: the limitation of current functional methods to detect some variants, and the influence of external factors (conformational stress, generation of thrombin, alcohol intake) on the pathogenic consequences of these mutations. Our study supports that antithrombin deficiency is underestimated and cases with moderate risk of thrombosis may be missed if only functional methods and classical diagnostic algorithms are used. Furthermore, although we must take into consideration that most cases with transient deficiency are explained by acquired deficiency and laboratory mistakes, this work shows new evidences supporting that the pathogenic effect of a gene defect may be modulated by external factors, changing the paradigm of congenital thrombophilia and making it also a transient disorder. Disclosures No relevant conflicts of interest to declare.

Management of heparin resistance due to antithrombin deficiency in a Chinese pregnant woman: a case report

Untreated individuals with antithrombin (AT) deficiency are at higher risk of thrombosis and adverse pregnancy outcomes. The present recommendations are mostly empirical for treating patients with AT deficiency during pregnancy because of the absence of guidelines. We report a rare case of heparin resistance due to AT deficiency in a pregnant 32-year-old Chinese woman. We also reviewed the English medical literature for AT deficiency and its association with thromboembolism and treatment. This patient suffered two early miscarriages because of thrombosis due to AT deficiency. The patient was administered the combination of adequate low molecular weight heparin with fresh frozen plasma and warfarin because of her heparin resistance. She delivered a healthy female newborn without any adverse effects of the anticoagulation therapy. Our findings suggest that the combination of adequate low molecular weight heparin with fresh frozen plasma and warfarin is effective for preventing thrombus during pregnancy.