Background: Unfractionated heparin (UFH) is the standard anticoagulant during cardiopulmonary bypass (CPB). A clinically relevant subset develops heparin resistance (HR)—failure to reach adequate anticoagulation with usual UFH—raising thrombotic risk and complicating perioperative care. Objectives: To synthesize contemporary evidence on the mechanisms, clinical implications, and perioperative management of HR in adult cardiac surgery with CPB. Methods: This narrative review synthesizes contemporary evidence on the epidemiology, mechanisms, recognition, and management of HR in adult cardiac surgery with CPB, emphasizing clinically actionable points. Results: Incidence varies across centers and definitions. Mechanisms include antithrombin (AT) deficiency or consumption and AT-independent drivers such as systemic inflammation or sepsis, protein-loss states, thrombocytosis, hyperfibrinogenemia, obesity, prior heparin exposure, and drug interactions. Sole reliance on activated clotting time (ACT) may misestimate anticoagulant effect; anti–factor Xa (anti-Xa) assays or heparin titration systems improve assessment when available. Management is stepwise: UFH dose escalation; targeted AT supplementation (or fresh frozen plasma where concentrates are unavailable); and transition to direct thrombin inhibitors when HR persists or UFH is contraindicated. Protocolized pathways and multidisciplinary coordination reduce delays and adverse events. Conclusions: HR is a multifactorial, common challenge in CPB. Pre-bypass risk assessment, multimodal monitoring, and an algorithm prioritizing UFH optimization, AT repletion, and timely use of direct thrombin inhibitors provide a pragmatic framework to limit thrombosis and bleeding. Harmonized definitions and comparative trials remain priorities.

BackgroundHereditary antithrombin deficiency (HATD) is a rare disease caused by mutations in the SERPINC1 gene characterized with venous thromboembolism and/or arterial thrombotic events. We identified a proband with recurrent arterial and venous thrombosis at multiple anatomical sites and subsequently performed comprehensive thrombophilia screening and genetic analysis within the kindred.MethodsMutation screening of the SERPINC1 gene in the proband and family members was conducted using Sanger sequencing. Wild-type and mutant (c.473T > A; p.Leu158Gln) SERPINC1 expression plasmids were constructed and transiently transfected into HEK293T cells. Functional consequences of the variant were assessed through immunoblotting, immunofluorescence, enzyme-linked immunosorbent assay (ELISA), and computational structural analysis.ResultsThrombophilia evaluation revealed significantly reduced antithrombin activity (46.2%) in the proband. Sanger sequencing identified an unreported heterozygous missense variant (c.473T > A; p.Leu158Gln) in SERPINC1. Cellular studies demonstrated that this mutation reduced both the quantity and functional activity of secreted antithrombin. Immunoblot analysis indicated a slightly faster migration of the mutant protein compared to wild-type, while immunofluorescence revealed abnormal cytoplasmic aggregation. Bioinformatics analysis confirmed substitution of leucine-158 by glutamine without disruption of conserved disulfide bonds (Cys40-Cys160, Cys128-Cys182, Cys247-Cys430) or N-glycosylation sites (Asn128, Asn167, Asn187, Asn224).ConclusionWe establish the c.473T > A (p.Leu158Gln) variant in SERPINC1 as a pathogenic mutation underlying type I HATD, characterized by impaired secretion, cytoplasmic retention, and reduced functional activity of the mutant protein.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12959-025-00801-0.

Survey on current practice in thrombophilia testing: from phenotype to genotype. Communication from the SSC of the ISTH.

Abstract The Dilute Russel Viper Venom Time (DRVVT) is considered one of the most sensitive and specific tests for detecting a lupus anticoagulant (LA). A prolonged DRVVT (greater than 99% of the normal population), is indicative of a positive screening LA result. However, occasionally we observed unexpected shorter-than-reference range results in the DRVVT screen instead of prolonged results. Unlike the Activated Partial Thromboplastin Time, the other common LA screening test, which can be short due to elevated levels of the acute phase reactant factor VIII, the DRVVT is unaffected by intrinsic factor levels or other acute phase reactants. Thus, we hypothesize that a short DRVVT may reflect impaired inactivation of coagulation factors in the common pathway, rather than increased levels of common pathway coagulation factors. We aimed to investigate a possible association of a short DRVVT with thrombophilias. We studied all the cases in which a hypercoagulable panel and DRVVT were performed within the same collection from January 2018 to February 2022 at our institute (n = 1385). We sorted the data into 3 cohorts based on our reference range: short (<32 seconds), normal (32- 45.7 seconds), and prolonged DRVVT (>45.7 seconds, with the prolonged cohort excluded to avoid interference by lupus anticoagulants, drugs, or factor deficiencies). We calculated the odds ratios (OR) of thrombophilias in the short and normal DRVVT cohorts, excluding cases with liver disease, multiple anticoagulation deficiencies, elevated factor VIII, and prolonged PT. Our results show that the prevalence of thombophilias was 42.5% in the short DRVVT cohort (20 known thrombophilias within 47 short DRVVT cases; 20/47) vs. 18.0% in the normal DRVVT cohort (84 /466) (OR of 3.37; 95% CI 1.8-6.29, p = 0.0001). Isolated protein S deficiency was the most common thrombophilia within these cohorts, with a higher prevalence in the short DRVVT cohort (10 cases) compared to the normal DRVVT cohort (28 cases) (OR 4.23, 95% CI 1.90-9.37, p = 0.0004). The other thrombophilias did not show significant individual ORs (22 Factor V Leiden heterozygous, 4 in short DRVVT; 19 Prothrombin gene heterozygous, 5 in short DRVVT; 9 isolated protein C deficiency, 1 in short DRVVT; 16 isolated antithrombin deficiencies, none in short DRVVT). To conclude, there seems to be an association of increased thrombophilias in cases with short DRVVT. The association is stronger with protein S deficiency, however, an association with all other thrombophilias was limited due to the low incidence of inherited thrombophilias and the small sample size. In summary, a short DRVVT should not always be deemed normal. Recommendation of thrombophilia testing in patients with a short DRVVT within an LA panel may be warranted in cases with high pretest probability (young adult patients with unprovoked venous thromboembolism and/or recurrent miscarriage).

Background: Hemostasis is governed by a dynamic balance between procoagulant and anticoagulant forces. While inherited bleeding and thrombotic disorders are typically studied as discrete entities, rare cases of co-inheritance may produce unique clinical phenotypes due to compensatory interactions. Among these, hemophilia A and antithrombin (AT) deficiency represent prototypical yet contrasting conditions: patients with severe hemophilia A often experience spontaneous joint and muscle bleeding, requiring lifelong prophylaxis or on-demand therapy with FVIII concentrates, whereas AT deficiency is associated with a markedly increased risk of venous thromboembolism (VTE), particularly in high-risk situations such as surgery, trauma, or prolonged immobilization. Understanding how opposing defects interact within the same individual may inform individualized management and therapeutic innovation. Case Report: We describe the case of a 19-year-old male with severe hemophilia A (FVIII <1%, no inhibitors), carrying a mutation in exon 3 of the F8 gene (NM_000132.4:c.296A>G, resulting in p.His99Arg), co-inherited with congenital AT deficiency (~50% activity). At birth, neonatal screening was prompted by a maternal family history of hemophilia A and a paternal history of thrombophilia. The patient’s father had been diagnosed with AT deficiency following a life-threatening episode of VTE involving extensive ilio-caval thrombosis and pulmonary embolism. Despite the severe FVIII deficiency, the patient has remained asymptomatic, with an annual bleeding rate (ABR) of zero and no history of spontaneous hemorrhage. He has only received perioperative FVIII prophylaxis and has remained free of thrombotic complications. Thrombin generation assay (TGA) showed delayed initiation and propagation, reduced peak and velocity index, but preserved endogenous thrombin potential (ETP), suggesting a compensatory procoagulant effect from AT deficiency (Figure 1). Although the patient demonstrated impaired thrombin amplification – consistent with FVIII deficiency – the preserved ETP suggests that decreased anticoagulant activity due to AT deficiency provides sufficient compensatory procoagulant effect to maintain clinical hemostasis. This dynamic interplay reflects a finely tuned compensatory mechanism that may alter the clinical expression of inherited bleeding disorders. Conclusions: This case exemplifies a naturally rebalanced hemostatic state resulting from the dual inheritance of opposing coagulation traits, and aligns with previously reported cases. The preserved ETP despite FVIII deficiency supports the concept of compensatory interplay and provides a rationale for rebalancing therapies such as Fitusiran, a small interfering RNA (siRNA) agent that suppresses hepatic AT production. By mimicking this compensatory mechanism, Fitusiran enhances thrombin generation and may improve coagulation in hemophilia patients, including those with inhibitors. Recognition of such rare but informative genetic constellations not only improves diagnostic accuracy, but also has significant implications for therapeutic decision-making. Comprehensive coagulation profiling, including genetic and functional assays, is essential for characterizing atypical presentations and guiding personalized treatment strategies.

Clinical utility of thrombin generation using ST-Genesia® in patients with hereditary and acquired thrombophilia: A cross-sectional study.

Analysis of Risk Factors for Heparin Resistance During Cardiac Surgery: Does Antithrombin Deficiency Cause Heparin Resistance?

Development of Experimental Models of Antithrombin-independent Heparin Resistance Using Platelet Factor 4 and the Effect of Antithrombin in These Models.

Stratifying and managing the risk of antithrombin deficiency in pregnancy.

Venous thromboembolism (VTE) is notably more common in pregnancy, with at least a 5‑foldhigher risk than in nonpregnant women, and an even greater surge postpartum. Pregnancy induces a hypercoagulable state with venous stasis and vascular changes, making VTE a leading cause of maternal morbidity and mortality, particularly in the postpartum period. Clinical presentation is often subtle or nonspecific, highlighting the need for objective diagnostic strategies adapted to pregnancy. Emerging diagnostic algorithms, including D‑dimer-guided approaches and pregnancy‑specific rules, such as the pregnancy‑adapted YEARS criteria, are improving diagnostic accuracy while limiting unnecessary imaging. Prevention and treatment regimens are tailored to pregnant patients, with low‑molecular‑weight heparin remaining the cornerstone of therapy. Ongoing research is exploring individualized prophylaxis based on personal risk profiles, biomarker‑driven risk stratification, and optimized postpartum management protocols. Under‑recognized issues, such as superficial vein thrombosis and rare but high‑risk thrombophilias (eg, antithrombin deficiency) are also garnering attention for their contribution to pregnancy‑associated VTE risk. This review provides a comprehensive update on pregnancy‑related VTE, highlighting evolving concepts in epidemiology, diagnosis, prevention, and management of deep and superficial venous thromboses and pulmonary embolism from pregnancy through the postpartum period.

A comprehensive study of antithrombin deficiency in a large cohort of Chinese thrombophilia pedigrees: uncovering 4 SERPINC1 pathogenic variants merely impaired progressive activities.

Anti-Xa directed low-molecular-weight heparin dosing to reduce the risk of venous thromboembolism in pregnant women with inherited antithrombin deficiency.

Inherited antithrombin deficiency (ATD) is associated with a high risk of venous thromboembolic complications. Association of ATD with other conditions such as pregnancy obviously increases thromboembolic risk and may require anticoagulant therapy for prevention. Although there are several/heterogenous international guidelines regarding thromboprophylaxis in pregnant patients with ATD, data on anticoagulant prophylaxis in this context are scarce in the literature. Thus, this situation remains a challenge both in the antepartum period and during delivery. Physicians from the French Society of Thrombosis and Haemostasis (SFTH) performed a review of the literature to suggest propositions regarding the management of thrombosis prevention based on anticoagulation and antithrombin substitution in ATD pregnant women. In this review, after reporting the thrombotic risk associated with ATD, the indication of anticoagulant therapy, its dosing regimen and monitoring, and the indication of antithrombin concentrates during pregnancy and the postpartum period are discussed as well as peripartum management. Finally, this work confirms the complex management of thrombotic prevention in pregnant patients with ATD. Indeed, it requires to take into account a multiplicity of features cited in our propositions that will hopefully provide some help in this field. This work also highlights the importance of multidisciplinary discussions for pregnant women with ATD who should be counseled in an expert center including hematologist, obstetrician, and anesthetist to optimize their management.

Thrombophilia Testing in Venous Thromboembolism.

Hereditary antithrombin (AT) deficiency is a rare autosomal dominant disorder that predisposes to the development of recurrent venous thromboembolism (VTE). Diagnosis is based on the measurement of reduced AT activity in plasma. However, not all commercial AT activity assays are equally suited for diagnosis since they differ in sensitivity toward different AT mutations.The aim of this study was to compare the ability of commonly used AT activity assays to diagnose inherited antithrombin deficiency, with a focus on type II AT deficiencies. We used samples from genetically confirmed AT deficient subjects (n = 76) and from patients with request for AT activity measurement for diagnostic purposes (n = 152). AT activity was measured with five commercial assays on three analyzers.All reagent/analyzer combinations showed specificities varying from 87 to 100%, except for 1 assay (56.5% specificity). Diagnostic sensitivity varied widely between assays, from 36.8% to 100%. All reagent-analyzer combinations correctly identified variants causing type I AT deficiencies but only one variant responsible for type II heparin binding site (HBS) deficiency: p.Arg79Cys. For one of the assays, we observed a large difference in sensitivity (82.9 versus 55.3%) toward antithrombin type II HBS variants depending on the coagulation analyzer on which it is performed, suggesting that incubation time of sample and substrate could be a crucial driver of the sensitivity toward variants causing type II antithrombin deficiency. Our results suggest that inherited antithrombin deficiency is probably underestimated and improved diagnostic strategies are mandatory.

Multigene panel for thrombophilia testing in venous thromboembolism.

Antithrombin supplementation to prevent venous thromboembolism: A case of hereditary antithrombin deficiency with increased antithrombin clearance during pregnancy and peripartum

Severe type I antithrombin (AT) deficiency is considered to cause embryonic lethality. Although several pathological analyses using mice or zebrafish have been attempted, the previous studies did not unveil the detailed mechanism leading to lethality in the early developmental stage. In order to solve this problem, we established type I AT deficient zebrafish by the CRISPR/Cas9 system into Tg(gata1:dsRed) and Tg(fli1a:GFP) lines, so that we could conduct real-time imaging of thrombosis and angiogenesis using fluorescence stereo zoom microscopy. The established zebrafish AT (zAT) mutants harbored frameshift mutations which resulted to be type I AT deficient, unable to secrete zAT protein into blood. Both heterozygous (zAT+/−) and homozygous (zAT−/−) mutants showed reduced survival rate and diverse thrombosis up to 9 days post fertilization. In addition, blood vessel formation was delayed at 30 hpf in zAT−/−, which was recovered normally by 5 dpf and had little effect on survival. Notably, we analyzed the differences in gene expression profiles under AT-depleted conditions by real-time quantitative PCR, and zAT−/− juvenile zebrafish showed increased PLG gene expression and decreased F2 gene expression. Our in vivo study revealed the effects of AT deficiency on embryos during development from the aspects of coagulation and vascular formation.

Investigation of the impact of antithrombin deficiency on the inflammatory response: Results from a single centre cohort study.

How we treat severe inherited antithrombin deficiency: lessons from cases homozygous for the Budapest 3 variant.