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Antithrombin (AT), a glycoprotein, plays a key role in anticoagulation by inhibiting coagulation proteases. It is also the primary mediator of heparin's anticoagulant effect, with heparin binding amplifying AT activity up to 1000-fold. Deficiency in AT contributes to a hypercoagulable state associated with adverse clinical outcomes, including morbidity and mortality. Hereditary AT deficiency (hATD) is a rare autosomal dominant disorder caused by mutations in the gene encoding AT ( SERPINC1 ), resulting in decreased AT levels or activity. As the most thrombogenic inherited thrombophilia, hATD confers a lifetime venous thromboembolism (VTE) risk of up to 85%, with similar annual VTE incidence in both pediatric and adult patients. Management of hATD often includes AT concentrate (ATc) therapy in high-risk clinical settings. Although ATc has a long history of use in adults, pediatric use has been largely off-label and guided by extrapolation from adult data. In August 2025, the U.S. Food and Drug Administration (FDA) approved an expanded indication for antithrombin III concentrate (human) to include pediatric patients with hATD, representing the first product specifically approved for this population. In light of this recent shift in the treatment landscape, this review provides a timely synthesis of the current clinical understanding and evidence-informed strategies to optimize AT therapy in the management of pediatric hATD.

Hereditary thrombophilia (HT) is a genetic predisposition to thrombosis. Asian mutation spectrum of HT is different from Western ones. We investigated the incidence and clinical characteristics of HT in Korean patients with unprovoked venous thromboembolism (VTE). Among 369 consecutive patients with thromboembolic event who underwent thrombophilia tests, we enrolled 222 patients diagnosed with unprovoked VTE. The presence of HT was confirmed by DNA sequencing of the genes that cause deficits in natural anticoagulants (NAs). Median follow-up duration was 40±38 months. Among the 222 patients with unprovoked VTE, 66 (29.7%) demonstrated decreased NA level, and 33 (14.9%) were finally confirmed to have HT in a genetic molecular test. Antithrombin III deficiency (6.3%) was most frequently detected, followed by protein C deficiency (5.4%), protein S deficiency (1.8%), and dysplasminogenemia (1.4%). The HT group was significantly younger (37 [32-50] vs. 52 [43-65] years; P < 0.001) and had a higher proportion of male (69.7% vs. 47%; P = 0.013), more previous VTE events (57.6% vs. 31.7%; P = 0.004), and a greater family history of VTE (43.8% vs. 1.9%; P < 0.001) than the non-HT group. Age <45 years and a family history of VTE were independent predictors for unprovoked VTE with HT (odds ratio, 9.435 [2.45-36.35]; P = 0.001 and 92.667 [14.95-574.29]; P < 0.001). About 15% of patients with unprovoked VTE had HT. A positive family history of VTE and age <45 years were independent predictors for unprovoked VTE caused by HT.

Background: The early diagnosis of inherited thrombophilia in children is challenging because of the rarity and hemostatic maturation. Methods: We explored protein C (PC), protein S (PS), and antithrombin (AT) deficiencies in 306 thromboembolic patients aged ≤20 y using the screening of plasma activity and genetic analysis. Results: Reduced activities were determined in 122 patients (40%). Low PC patients were most frequently found in the lowest age group (0–2 y, 45%), while low PS or low AT patients were found in the highest age group (16–20 y; PS: 30% and AT: 20%). Genetic study was completed in 62 patients having no other causes of thromboembolism. Mutations were determined in 18 patients (8 PC, 8 PS, and 2 AT genes). Six of eight patients with PC gene mutation were found in age 0–2 y (75%), while six of eight patients with PS gene mutation were in 7–20 y. Two AT gene–mutated patients were older than 4 y. Four PC-deficient and two PS-deficient patients carried compound heterozygous mutations. All but one PC gene–mutated patient suffered from intracranial thromboembolism, while PS/AT gene–mutated patients mostly developed extracranial venous thromboembolism. Conclusion: Stroke in low PC infants and deep vein thrombosis in low PS/AT school age children could be targeted for genetic screening of pediatric thrombophilias.

Stratification for risk of recurrence after a first episode of venous thromboembolism (VTE) would affect the duration of anticoagulant therapy. We aimed to determine the incidence of recurrence of VTE in relation to clinical risk factors and standard laboratory testing for heritable thrombophilic defects. We established a database to prospectively follow-up a cohort of unselected patients who had had a first episode of objectively proven VTE. We excluded patients with malignant disease and antiphospholipid syndrome. All patients were offered testing for heritable thrombophilia. At 2 years, the cumulative recurrence rate in 570 patients was 11%. Incidence was lowest after surgery-related VTE (0%) and highest after unprecipitated VTE (19·4%) (p<0·001). 85% of patients were tested for heritable thrombophilic defects. Recurrence rates were not related to presence or absence of laboratory evidence of heritable thrombophilia (hazard ratio 1·50 [95% CI 0·82–2·77]; p=0·187). In patients with a first event that was unprecipitated or was associated with a non-surgical trigger, recurrence rates did not differ in patients with or without thrombophilia (1·34 [0·73–2·46]; p=0·351). In unselected patients who have had a first episode of VTE, testing for heritable thrombophilia does not allow prediction of recurrent VTE in the first 2 years after anticoagulant therapy is stopped. However, assessment of clinical risk factors associated with the first episode of VTE does predict risk of recurrence. Patients with postoperative VTE have a very low rate of recurrence.

Antithrombin is a progressive inhibitor of active factor X (FXa) and thrombin (FIIa). Its effect is 500- to 1,000-fold accelerated by heparin or heparan sulfate. Heterozygous type I (quantitative) and most type II (qualitative) antithrombin deficiencies highly increase the risk of venous thromboembolism (VTE), while homozygous mutations are lethal. The functional defect affecting the heparin-binding site confers moderate risk of VTE to heterozygous and high risk of VTE to homozygous individuals. Antithrombin activity assays based on the inhibition of FIIa and FXa were compared for their efficiency in detecting heparin-binding site defects. With a single exception, in heterozygotes for heparin-binding site defects (n = 20), anti-FIIa activities remained in the reference interval, while anti-FXa activities were uniformly decreased. In individuals who were homozygous for heparin-binding site mutations (n = 9), anti-FIIa activities were in the range of 48% to 80%; the range of anti-FXa activities was 9% to 25%. Anti-FIIa and anti-FXa activities in type I deficiencies and type II pleiotropic deficiency did not differ significantly. Anti-FXa antithrombin assay is recommended as a first-line test to detect type II heparin-binding site antithrombin deficiency.

We present the case of a man in his 50s with a history of recurrent unprovoked venous thromboembolism who developed haemorrhagic shock due to venous intestinal ischaemia. Despite anticoagulation and monitoring of anti-Xa levels, the thrombosis progressed, leading to complete necrosis and perforation of the small bowel wall, persistent septic shock and ultimately death. The clinical course and family history raised suspicion for hereditary antithrombin deficiency, a rare but potentially catastrophic thrombophilia. This case highlights the importance of considering inherited thrombophilia in critically ill patients with progressive thrombosis despite adequate anticoagulation, and the challenges of managing these conditions in the intensive care unit.

Antithrombin (AT) is a major physiological inhibitor of hemostasis. We report 22 novel antithrombin gene (SERPINC1) mutations associated with antithrombin deficiency in 17 French and five German families. They were all present at the heterozygous state. Nine missense mutations accounted for type I deficiency, defined by equally low antithrombin activity and antigen level. Most of them (7/9) affected highly conserved serpin residues and were associated with venous thrombosis occuring at a young age (before age 32). One splice site, one nonsense mutation, three small deletions and one insertion were also identified as a cause for type I antithrombin deficiency. Seven other missense mutations were identified in type II or unclassified AT deficiency; g.5270C>T (p.T147I, T115I) and g.5281A>T (p.I151F, I119F) change residues in the heparin binding region, g.13267C>G (p.P439A, P407A) and g.13271T>C (p.F440S, F408S) affect amino acids in the pleiotropic region, g.2372G>A (p.G25D, G‐8D) changes a signal peptide amino acid, g.2456G>C (p.C53S, C21S) affects one of the three disulfide bonds of the protein, and g.7585A>T (p.M347K, M315K) changes a nonconserved residue on strand 2C. © 2006 Wiley‐Liss, Inc.

We presented an unique case of portal vein thrombosis (PVT) after aortic valve replacement due to antithrombin III (ATIII) deficiency. PVT after aortic valve replacement (AVR) is a serious complication, which has not previously been reported.

Acquired angioedema (AAE) due to the functional deficiency of the C1 inhibitor (C1-INH) is a rare disease characterized by recurrent bouts of edema that involve subcutaneous tissues, the larynx or the gastrointestinal tract. In the present paper, we report the case of a male patient with symptoms of AAE and recurrent deep venous and arterial thrombosis. As a trigger of AAE in the present patient, we revealed primary antiphospholipid syndrome accompanied by antithrombin III deficiency, along with malignancy in the history, and angiotensin-converting enzyme inhibitor therapy. Although anti-C1-INH titers (type I AAE) were normal initially, we observed a sharp increase in anti-C1-INH titers (suggestive of type II AAE) during follow-up. It seems that thrombosis might worsen angioedematous attacks in functional C1-INH deficiency. Thrombophilia should be considered a provoking factor of AAE and should be carefully sought for in these patients, as the key to successful management of AAE is the effective treatment of the underlying disease.