RARE DISEASE
Congenital factor II deficiency
Congenital factor II deficiency
Congenital factor II deficiency
Synonyms: Dysprothrombinemia, Hypoprothrombinemia, Prothrombin deficiency
Synonyms: Dysprothrombinemia, Hypoprothrombinemia, Prothrombin deficiency
Synonyms: Dysprothrombinemia, Hypoprothrombinemia, Prothrombin deficiency
Drug discovery
2
drugs
With orphan designations
Overview
Congenital Factor II Deficiency is a rare autosomal recessive bleeding disorder caused by mutations in the F2 gene, leading to reduced prothrombin activity. It manifests with mucocutaneous bleeding (epistaxis, menorrhagia), soft tissue hemorrhage, and rare intracranial bleeding. Severity correlates with Factor II levels (<10% in severe cases). Diagnosis involves prolonged PT/aPTT and Factor II activity assays [1][7][12].
Population
Prevalence: ~1 in 2 million globally; true deficiency (activity <10%) is extremely rare [1][7][12].
Genetic: Autosomal recessive inheritance; >40 F2 mutations identified (primarily missense) [9][11].
Presentation: Symptoms range from asymptomatic (heterozygotes) to life-threatening hemorrhage (homozygotes/compound heterozygotes) [1][19].
Burden
Clinical: Risk of intracranial hemorrhage, postpartum bleeding, and arthropathy (from recurrent hemarthrosis) [1][9][19].
Management: Lifelong hematologist-led care; challenges in resource-limited settings due to PCC availability [11][16].
Psychosocial: Impacts quality of life due to bleeding risk during routine activities/surgeries [6][19].
Categories: rare genetic diseases, rare hematological diseases
Research Papers
229 drug discovery papers about Congenital factor II deficiency, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
229 drug discovery papers about Congenital factor II deficiency, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2025-12-08 | REPRODUCTIVE LOSSES OF THE FETUS IN MODERN OBSTETRICS-GYNECOLOGY AND REPRODUCTOLOGY
The issue of reproductive losses remains a firmly established and pressing concern in modern obstetrics–gynecology and reproductive medicine. Among obstetric pathologies, one of the least studied yet most significant due to the severity of its consequences is fetal antenatal loss, caused by genetic, endocrine, anatomical abnormalities, and infection-related changes. To this list have been added pathologic conditions associated with coagulation disorders, including congenital and acquired thrombophilia and the complications arising from it: recurrent pregnancy loss, gestosis, preeclampsia/eclampsia, premature detachment of a normally implanted placenta, Intrauterine Growth Restriction (IUGR), HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), and Disseminated Intravascular Coagulation (DIC). Since hereditary thrombophilia represents a group of genetic disorders that promote thrombosis and contribute to a hypercoagulable state, and despite the fact that hereditary thrombophilia accounts for 20–30% of venous thromboembolism cases, universal screening does not exist; however, testing is essential in individuals with high-risk profiles (burdened family history of thrombosis, recurrent venous thromboembolism, pregnancy, or planned surgical intervention). Furthermore: Factor V Leiden mutation (resistance to activated protein C) is the most common form of hereditary thrombophilia (5–7% in Caucasians). A mutation in the F5 gene renders coagulation factors resistant to protein C. Prothrombin gene mutation (G20210A) has a prevalence of 2–3% in Caucasians. The F2 gene mutation increases prothrombin levels and the risk of hypercoagulation. Protein C deficiency is a rare form of hereditary thrombophilia (0.2–0.5%). Protein C inactivates factors Va and VIIIa; deficiency leads to excessive activity of clotting factors and thrombus formation. Protein S deficiency is also rare (0.1–0.7%). Protein S functions as a cofactor for protein C; its deficiency increases the risk of thrombosis. Antithrombin deficiency is another rare inherited thrombophilia (0.02–0.2%). Antithrombin inhibits thrombin and factors Xa, IXa, and XIa; deficiency leads to excessive activity of these factors and development of hypercoagulation. Rare forms include dysfibrinogenemia and hyperhomocysteinemia. Clinical manifestations involve venous thromboembolism (pulmonary embolism, deep vein thrombosis). Thrombosis may also develop in unusual sites—cerebral veins, or veins of internal organs. Thrombophilia is frequently associated with recurrent pregnancy losses at various gestational ages. It is noteworthy that hereditary thrombophilia tends to manifest at a younger age compared with acquired forms. Our aim was to discuss this issue: 1. By reviewing our own retrospective cases (women treated in our clinic during 2023–2025); 2.By summarizing the positive outcomes in the management of relatively complex cases and assessing treatment effectiveness: a. Based on the obtained results, abnormalities of the coagulation–vascular and fibrinolytic systems were identified, requiring treatment both during preconception planning and b. Throughout pregnancy, childbirth, and the postpartum period, with dynamic monitoring of hemostasis markers until full correction; 3. Mathematical modeling of the data was performed using the three-component inclusion–exclusion principle known in combinatorial analysis.
2025-10-01 | The Impact of Prothrombin Complex Concentrate Versus Fresh Frozen Plasma for Hemorrhage Management in Cardiac Surgery: A Systematic Review and Meta-analysis of Randomized Clinical Trials.
To clarify the efficacy and safety endpoints, comparing prothrombin complex concentrate (PCC) versus fresh frozen plasma (FFP) for hemorrhage management in cardiac surgery. Systematic review and meta-analysis of randomized clinical trials (RCTs). Tertiary care. Adult patients who developed hemorrhage related to coagulation factor deficiency during cardiac surgery. PCC or FFP for hemorrhage management in cardiac surgery. A systematic search was conducted in PubMed, Embase, and Cochrane Library and identified RCTs comparing PCC with FFP for hemorrhage management in cardiac surgery. The primary outcome was postintervention hemoglobin levels. Secondary outcomes included 30-day mortality, transfusion requirements, adverse events, postintervention international normalized ratio, and reoperation rates. Categorical values were analyzed using risk ratios with 95% confidence intervals (CIs), whereas continuous values were compared using the mean difference and standardized mean difference with 95% CIs. Statistical analyses were conducted using R software, version 4.4.2. Four RCTs (671 patients) were included, with 343 (51.1%) patients receiving PCC. PCC was associated with higher postintervention hemoglobin levels (mean difference 1.17 g/dL, 95% CI 0.93-1.41, p < 0.01). Compared with FFP, the PCC group required fewer red blood cell transfusions at 24 hours, had reduced use of recombinant factor VII, and demonstrated improved postintervention international normalized ratio. In patients undergoing cardiac surgery with significant bleeding, PCC was associated with higher postintervention hemoglobin levels and reduced transfusion needs compared with FFP, without an increase in adverse events.
2025-04-07 | Twenty years of the four-factor prothrombin complex concentrate Octaplex/Balfaxar: A narrative review.
Prothrombin complex concentrate (PCC) is used to boost thrombin potential, support clot formation, and aid in the treatment and prophylaxis of bleeding. The two main forms of PCC are three-factor (3 F-PCC; comprising coagulation factors II, IX, and X) and four-factor (4F-PCC; factors II, VII, IX, X), which contain 25 times the clotting factors found in human plasma. This narrative review summarizes published efficacy and safety data on one 4F-PCC (Octaplex/Balfaxar, Octapharma) within its recognized uses and explores potential applications across different clinical contexts. Clinically available for > 20 years, Octaplex/Balfaxar is supplied as a freeze-dried powder for reconstitution and intravenous infusion. This 4F-PCC contains non-activated forms of coagulation factors as well as anticoagulant proteins C and S, potentially affording a balanced hemostatic effect and mitigating thrombosis risk. Production involves two virus inactivation/removal steps: solvent/detergent treatment and nanofiltration. 4F-PCC is approved for acquired deficiency of vitamin K-dependent clotting factors, such as those induced by vitamin K antagonists (VKAs, e.g., warfarin), and for congenital deficiency of factors II and X. Five published trials in 444 adult patients demonstrated the efficacy of 4F-PCC in VKA reversal, reducing the international normalized ratio (INR) with only two potentially treatment-related thrombotic events reported. While 4F-PCC dosing is currently indicated to be INR-guided, emerging evidence supports fixed dosing as an alternative to conventional weight-based dosing for VKA reversal. Recent guidelines support 4F-PCC use for direct oral anticoagulant-associated bleeding, cardiac surgery and trauma/emergencies. Ongoing studies will further clarify the efficacy and safety of 4F-PCC beyond its approved indications.
2025-03-30 | Prothrombin Complex Concentrate vs Frozen Plasma for Coagulopathic Bleeding in Cardiac Surgery: The FARES-II Multicenter Randomized Clinical Trial.
Excessive bleeding is a common and prognostically important complication of cardiac surgery. For bleeding related to coagulation factor deficiency, frozen plasma is the most used therapy. Preliminary trials indicate that 4-factor prothrombin complex concentrate (PCC) may be a suitable alternative. To compare the efficacy and safety of PCC with frozen plasma in patients undergoing cardiac surgery with coagulopathic bleeding. Unblinded randomized noninferiority controlled clinical trial at 12 hospitals in Canada and the US involving adults (≥18 years) who had developed bleeding related to coagulation factor deficiency after termination of cardiopulmonary bypass during surgery (November 30, 2022, to May 28, 2024). Final 30-day follow-up visit was completed on June 28, 2024. A total of 265 patients were randomized to receive PCC (1500 IU ≤60 kg; 2000 IU >60 kg) and 263, frozen plasma (3 U ≤60 kg; 4 U >60 kg) in the operating room. A second dose was allowed over the next 24 hours if indicated; thereafter, only frozen plasma could be used. The primary outcome was hemostatic response (effective if no hemostatic interventions occurred from 60 minutes to 24 hours after treatment initiation). The noninferiority of PCC vs frozen plasma was assessed using a 10% margin and a 1-sided α of .025, with subsequent testing for superiority if noninferiority was demonstrated. Secondary outcomes included allogeneic blood transfusions and adverse events. Patients were followed up until postoperative day 30. Of 538 enrolled patients, 420 patients (median age, 66 years [IQR, 57-73 years]; 74%, male; 10%, Asian; 1%, Black; and 65%, White) were included in the primary analysis; of those, 296 (70%) underwent complex surgeries. Compared with the 207 patients in the frozen plasma group, the 213 patients in the PCC group had higher hemostatic effectiveness (166 [77.9%] vs 125 [60.4%]; difference, 17.6%; 95% CI, 8.7%-26.4%; P < .001 for noninferiority and superiority) and had received fewer transfusions including red blood cells, platelets, and noninvestigational frozen plasma units (mean, 6.6 units; 95% CI, 5.7-7.7 vs 9.3 units; 95% CI, 8.0-10.8; difference, 2.7; 95% CI, 1.0-4.4; P = .002). Seventy-seven patients (36.2%) in the PCC group vs 98 (47.3%) in the frozen plasma group experienced serious adverse events (relative risk [RR], 0.76; 95% CI, 0.61-0.96; P = .02). Twenty-two patients (10.3%) in the PCC group and 39 (18.8%) in the frozen plasma group had acute kidney injury (RR, 0.55; 95% CI, 0.34-0.89; P = .02). In this unblinded randomized clinical trial, PCC had superior hemostatic efficacy and safety advantages to frozen plasma among patients requiring coagulation factor replacement for bleeding during cardiac surgery. ClinicalTrials.gov Identifier: NCT05523297.
2024-11-05 | Tetraspanin CD37 Regulates Platelet Hyperreactivity and Thrombosis
Psychosocial stress increases the risk of a myocardial infarction 2-fold and is associated with a 40% higher risk of death following an acute thrombotic event. With approximately a third of US adults reporting overwhelming stress levels most days, defining the mechanisms by which stress contributes to adverse thrombosis is paramount. Platelets are key contributors to thrombotic cardiovascular events, with platelet hyperreactivity associated with thrombosis and psychosocial stress. In humans and mouse models, psychosocial stress induces a hyperreactive platelet phenotype and increases the risk of thrombosis. To investigate how stress contributes to platelet hyperreactivity, platelets were isolated from 1) mice that experienced chronic variable stress and stress-free controls (n=8/group) and 2) human subjects with self-reported high and no stress levels (n=18/group) and RNA-sequencing performed. By comparison of mutually expressed transcripts, we identified a subset of genes differentially expressed following psychosocial stress in both human and mouse platelets. To assess the contribution of the identified transcripts to platelet functional responses that underlie thrombosis, the association of identified genes with platelet aggregation to epinephrine (0.4 μM) was assessed. Amongst screened candidates, the tetraspanin CD37 was significantly associated with platelet aggregation in a cohort of participants whose platelet aggregation and platelet transcriptome were measured simultaneously (R=0.30, p=0.0002, n=145). Following confirmation of CD37 expression in platelets at the transcriptomic and protein level in humans and mice, we assessed the functional outcome of platelet CD37 deficiency. Cd37-/- platelets spread significantly less relative to wild-type platelets on both poly-D-lysine and fibrinogen (p<0.01 and p<0.005, respectively) and underwent a minimal change in morphology following fibrinogen adhesion. Platelet solidity, a proxy measure inversely proportional to efficient maximal spreading mediated by filopodial-to-lamellipodial transitions, was significantly decreased in wild-type platelets relative to Cd37-/- (p<0.0001), indicative of a spreading dysfunction in CD37 deficient platelets. In whole blood flood cytometry, platelet expression of activated integrin αIIbβ3 (JON/A) and CD63 is significantly attenuated on Cd37-/- platelets relative to wild-type following stimulation with PAR4-AP (p<0.0001, p<0.05, respectively). However, JON/A and CD63 expression is unaltered under resting conditions between Cd37-/- and wild-type platelets. Consistent with a role for CD37 in regulating thrombosis-relevant platelet activation responses, chimeric mice that received Cd37-/- bone marrow experienced a significantly increased time to vessel occlusion (p<0.05) in the carotid artery FeCl3 model, relative to mice reconstituted with wild-type bone marrow. CD37 deficiency does not alter hemostasis, as platelet count, coagulation metrics, prothrombin time, and partial thromboplastin time do not differ in Cd37-/- mice relative to wild-type mice. Consistent with this, bleeding time does not differ between wild-type and Cd37-/- mice following tail tip transection. In humans and mice, platelet CD37 positively associates with platelet aggregation and phenotypic responses that underlie thrombosis. Cd37-deficient platelets exhibit impaired integrin αIIbβ3 signaling, characterized by reduced platelet fibrinogen spreading and decreased agonist-induced αIIbβ3 activation. Notably, CD37 deficiency significantly reduces thrombotic risk without altering hemostasis or bleeding susceptibility. This study provides new insight into a platelet-associated stress-induced mechanism contributing to accelerated thrombotic risk and provides the first direct evidence for CD37 as a regulator of platelet activation responses and thrombosis.
antibodies
2024-12-18 | Deficiency of neutrophil gelatinase-associated lipocalin elicits a hemophilia-like bleeding and clotting disorder in mice.
Coagulation is related to inflammation, but the key pathway, especially innate immune system and coagulation regulation, is not well understood and need to be further explored. Here, we demonstrated that neutrophil gelatinase-associated lipocalin (NGAL), an innate immune inflammatory mediator, is upregulated in patients with thrombosis. Furthermore, it contributes to the initiation and amplification of coagulation, hemostasis, and thrombosis. This occurs by enhancing tissue factor expression on the cell surface, potentiating various clotting factors such as thrombin, kallikrein, factor XIa (FXIa), and FVIIa, promoting thrombin-induced platelet aggregation, and inhibiting antithrombin. NGAL knockout led to strikingly prolonged clot reaction time and kinetic time in thromboelastography analysis, along with reduced thrombus generation angle and lower thrombus maximum amplitude, which were in line with remarkably prolonged activated partial thromboplastin time and prothrombin time. In several mouse hemostasis and thrombosis models, NGAL overexpression or IV administration promoted coagulation and hemostasis and aggravated thrombosis, whereas NGAL knockout or treatment with anti-NGAL monoclonal antibody significantly prolonged bleeding time and alleviated thrombus formation. Notably, NGAL knockout prolonged mouse tail bleeding time or artery occlusion time to over 40 or 60 minutes, respectively, resembling uncontrollable bleeding and clotting disorder seen in hemophilic mice. Furthermore, anti-NGAL monoclonal antibody treatment markedly reduced the formation of blood clots in inflammation-induced thrombosis models. Collectively, these findings unveil a previously unidentified role of NGAL in the processes of coagulation, hemostasis, and thrombosis, as well as the cross talk between innate immunity, inflammation, and coagulation. Thus, modulating NGAL levels could potentially help balance thrombotic and hemorrhagic risks.
2016-12-02 | Treatment of rare factor deficiencies in 2016
Rare bleeding disorders (RBDs) are a heterogeneous group of coagulation disorders characterized by fibrinogen, prothrombin, factors V, VII, X, XI, or XIII (FV, FVII, FX, FXI, or FXIII, respectively), and the combined factor V + VIII and vitamin K-dependent proteins deficiencies, representing roughly 5% of all bleeding disorders. They are usually transmitted as autosomal, recessive disorders, and the prevalence of the severe forms could range from 1 case in 500 000 for FVII up to 1 in 2-3 million for FXIII in the general population. Patients affected with RBDs may present a wide range of clinical symptoms, varying from mucocutaneous bleeding, common to all types of RBDs to the most life-threatening symptoms such as central nervous system and gastrointestinal bleeding. Treatment of these disorders is mainly based on the replacement of the deficient factor, using specific plasma-derived or recombinant products. In countries where these facilities are not available, bleedings could be managed using cryoprecipitate, fresh frozen plasma (FFP), or virus-inactivated plasma. Minor bleedings could be managed using antifibrinolytic agents. Recently, 2 novel drugs, recombinant FXIIIA and a plasma-derived FX, have been added to the list of available specific hemostatic factors; only prothrombin and FV deficiencies still remain without a specific product. Novel no-replacement therapies, such as monoclonal antibody anti-tissue factor pathway inhibitor, RNA interference, and a bispecific antibody that is an FVIIIa mimetic, enhancing thrombin generation through different mechanisms, were developed for patients with hemophilia and may in the future be a good therapeutic option also in RBDs.
1940-04-01 | Experimental Hypoprothrombinemia with Anti-Prothrombin Serum
An antiprothrombin serum may be prepared in the guinea pig by injecting it with fibrinogen-free prothrombin isolated from rabbit plasma. Intravenous injections of this antiserum in fasting rabbits produce a hypoprothrombinemia of a transient and moderate character.
proteins
2026-05-24 | Molecular Modeling of Protein-Peptide Complexes Mimicking Factor Xa-Prothrombin Using AlphaFold-Multimer and Molecular Dynamics Simulations for Functional Prediction.
Accurately predicting how point mutations influence protease activity is a major challenge in protein engineering and in the study of coagulation disorders. Factor Xa (FXa) catalyzes the proteolytic activation of prothrombin, a critical step in thrombin generation, yet the molecular details of direct enzyme-substrate recognition and the impact of pathogenic variants remain incompletely defined. Here, we combined AlphaFold-Multimer modeling with explicit-solvent molecular dynamics (MD) simulations to investigate simplified FXa-substrate interactions using prothrombin-derived peptides encompassing the Arg271 and Arg320 cleavage sites in the absence of the full prothrombinase complex. AlphaFold predictions identified catalytically competent peptide orientations, while subsequent MD simulations and free energy analyses identified key contributions of the P1 and P4 cleavage site residues to FXa binding. Distinct stability and affinity differences between the two cleavage sites were highlighted. Active site variants associated with factor X deficiency demonstrated variant-specific disruptions in peptide engagement, implicating key residues within the FXa active site as critical determinants of catalytic activity. Experimental validation with recombinant FXa variants was consistent with the computational predictions, indicating comparable inhibition by the prothrombin peptides. Together, these findings establish an integrative computational-experimental framework for probing local protease-substrate recognition, rationalizing the effects of disease-causing mutations, and guiding the design of therapeutic protease variants.
2026-03-02 | Factor II and Factor V Deficiencies: Current Management, Care Gaps and Call to Action for Therapeutic Advances.
Among rare inherited coagulation disorders (RICDs), prothrombin (factor II) and factor V (FV) deficiency are still orphans of treatments, lacking availability of single-factor replacement products. This clinical care gap is hampering the implementation of prophylactic and episodic treatment regimens in patients. We chose to produce a narrative review to evaluate to which degree bleeding prophylaxis, that is the standard of care for inherited coagulation disorders, has been implemented in these RICDs with the currently available therapeutics, that is fresh frozen plasma and prothrombin complex concentrates. The outcome of the episodic treatment of acute bleeding episodes and invasive procedures was also reviewed. Perusal of the published case reports shows a paucity of prophylaxis implementation even after life-threatening bleeding episodes such as intracerebral hemorrhage and ovulation-associated hemoperitoneum: only seven cases for prothrombin and three for FV deficiency. By the same token, there are relatively few reports on the acute treatment of bleeding episodes (particularly for prothrombin deficiency), as well as on the episodic treatment at the time of surgery or invasive procedures. Our review indicates that currently available therapeutics are largely suboptimal and justify a call to action in order to streamline regulatory pathways for single-factor concentrate development, as well as for the potential evaluation of prophylaxis of coagulation-rebalancing, non-replacement products.
2026-01-31 | CONSTITUTIONAL PROTHROMBIN DEFICIENCY REVEALED BY A FAMILY INVESTIGATION
Congenital prothrombin (factor II) deficiency is an extremely rare inherited coagulation disorder transmitted in an autosomal recessive manner and characterized by wide clinical variability, ranging from mild bleeding manifestations to life threatening hemorrhage. We report a familial case of severe congenital factor II deficiency diagnosed in the hematology laboratory of the Mohammed V Military Teaching Hospital in Rabat. The index case was a 6 year old girl born to a second degree consanguineous marriage, referred for cutaneous bleeding manifestations associated with recurrent knee pain, in a context of prolonged activated partial thromboplastin time and reduced prothrombin time. Coagulation studies revealed an isolated and severe reduction in factor II activity to 3%, with normal levels of the other coagulation factors.Family investigation identified a similar severe deficiency in both brothers, with variable hemorrhagic manifestations, whereas the parents were asymptomatic and exhibited moderately reduced factor II activity, consistent with a heterozygous carrier state.The combination of clinical and biological findings supported the diagnosis of severe constitutional factor II deficiency, most likely type I. This case highlights the importance of family investigation and consideration of consanguinity in the diagnosis of rare bleeding disorders, and underscores the central role of the laboratory in early identification, patient management, and genetic counseling.
2026-01-10 | Use of Plasma-Derived FVII Concentrate in Surgical Patients with Factor VII Deficiency: A Case Series.
Congenital factor VII (FVII) deficiency is the most common rare hemorrhagic disorder. Acquired FVII deficiency can be isolated or associated with other low coagulation factor levels. FVII levels do not accurately predict a patient's bleeding risk. In the case of surgery, the perioperative management needs to be evaluated on a case-by-case basis, considering the patient's bleeding history and the type of surgery. We present 12 patients with congenital or acquired FVII deficiency and describe the perioperative management with plasma-derived nonactivated FVII (pd-FVII) concentrate. Patients with factor VII deficiency treated with pd-FVII for perioperative hemostasis, between April 2022 and May 2025. We report thirteen procedures in 12 patients (11 males and 1 female; age range: 15-78 years). Two patients were affected by acquired deficiency, and 10 patients presented congenital deficiency. Perioperative prophylaxis with pd-FVII was performed at doses ranging from 20 to 40 IU/kg/dose. Total pd-FVII consumption ranged between 20 and 320 IU/kg. During and after surgery, there were no major bleeding or thrombotic events. In the postoperative period, only one patient presented with hematuria.
2025-08-05 | CO35 | Bleeding phenotype characterization in patients with congenital bleeding disorders: a multigenic approach using next generation sequencing to identify coagulation-modulating variants
Background and Aims: Congenital bleeding disorders, including hemophilia A (HA), hemophilia B (HB), and rare bleeding disorders (RBDs), often display variable clinical phenotypes not fully explained by a single pathogenic variant. Additional genetic variants modulating the coagulation cascade may influence bleeding severity. This study aimed to investigate such variants using a multigenic sequencing approach. Methods: Eighteen patients with a previously confirmed diagnosis of congenital bleeding disorder were selected for analysis. The cohort included individuals with HA, HB, FV deficiency, FXI deficiency, and plasminogen deficiency, all followed at the Hemophilia Center of Padua University Hospital. Genetic analysis was performed using a custom Next-Generation Sequencing (NGS) panel (xGen™ Hyb Panel, Integrated DNA Technologies) targeting 33 coagulation-related genes: A2M, CPB2, F2, F3, F5, F7, F8, F9, F10, F11, F12, F13A1, F13B, FGA, FGB, FGG, KLKB1, KNG1, PLAT, PLG, PROC, PROCR, PROS1, PROZ, SERPINA5, SERPINA10, SERPINC1, SERPIND1, SERPINE1, SERPINF2, TFPI, THBD, VWF. Sequencing was performed on the Illumina NextSeq550 platform. Variants with a minor allele frequency <0.1% were classified according to ACMG criteria. Results: The study population consisted of 10 patients with HA (1 mild, 1 moderate, 8 severe), 2 with HB (1 mild, 1 severe), 1 with FV deficiency, 1 with FXI deficiency, and 4 with plasminogen deficiency. On average, 150 variants per patient were observed. NGS identified class 5 pathogenic variants in 8 patients with HA (F8, including intron 22 inversion) and in 2 with HB (F9), and class 4 likely pathogenic variants in 3 patients (F8 [n=2] and, F11 [n=1]). Although only class 3 variants were identified in patients with plasminogen deficiency (n=4) and FV deficiency (n=1), these were located in the gene associated with the clinical phenotype (PLG and F5, respectively). Moreover, two plasminogen-deficient patients harboured two distinct variants in PLG. Beyond the causative mutations, 11 out of 18 patients (61%) harboured at least one variant of class 3 or 4 with potential modulatory effect. These were found in F2, F5, F10, F13A1, KNG1, VWF, SERPINA5, SERPINC1, PROS1, and PLG and included well-characterized variants such as FV Leiden, the prothrombin G20210A mutation (prothrombotic), and the Friuli FX variant (bleeding phenotype). Moreover, two predisposing variants were identified in F13A1 (n=2, pro-hemorrhagic) and F2 (n=1, prothrombotic). The distribution of class 3, 4, and 5 variants and predisposing variants is illustrated in Figure 1. Conclusions: NGS identified the putative causative mutation in all patients and revealed additional coagulation-related variants in the majority of the cohort. These results support a multigenic model influencing the bleeding phenotype in congenital bleeding disorders. Functional and segregation studies are warranted to clarify the role and clinical impact of the predisposing variants identified.
gene therapies
2025-08-01 | Molecular Aspects of Rare Coagulation Factor Deficiencies.
Rare coagulation factor deficiencies are inherited disorders affecting factors I, II, V, VII, X, XI, XIII, and combined forms. They mainly present with bleeding symptoms of variable severity. These deficiencies show significant clinical heterogeneity, with no consistent correlation between factor levels and bleeding intensity. Prevalence is higher in populations with high consanguinity rates. Understanding relies on the study of genetic and molecular mechanisms. Diagnosis is based on hemostasis testing, including prothrombin time (PT), activated partial thromboplastin time (aPTT), and factor activity assays. In case of abnormalities, Molecular analysis is undertaken using genomic DNA extracted from peripheral blood samples. Depending on the clinical context and the level of detail required, sequencing is performed using either Sanger sequencing or next-generation sequencing (NGS) platforms, enabling the identification of pathogenic variants responsible for the coagulation disorder. Variant interpretation follows American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) guidelines. Large deletions or duplications are assessed via Multiplex Ligation-dependent Probe Amplification (MLPA) or Copy number variations (CNV) analysis. Molecular analysis revealed a wide range of mutations depending on the deficient factor. Missense mutations are the most common, followed by nonsense, splicing, and insertion/deletion mutations. Some mutations prevent factor production, while others alter its structure or secretion. Each mutation type has a distinct impact on the bleeding phenotype. Genetic characterization improves diagnostic accuracy and guides clinical management. Modern molecular tools have enhanced the understanding of these disorders' pathophysiology. A multidisciplinary approach is essential for optimal patient care. Ongoing research is key to developing targeted therapies.
small molecules
2025-12-08 | REPRODUCTIVE LOSSES OF THE FETUS IN MODERN OBSTETRICS-GYNECOLOGY AND REPRODUCTOLOGY
The issue of reproductive losses remains a firmly established and pressing concern in modern obstetrics–gynecology and reproductive medicine. Among obstetric pathologies, one of the least studied yet most significant due to the severity of its consequences is fetal antenatal loss, caused by genetic, endocrine, anatomical abnormalities, and infection-related changes. To this list have been added pathologic conditions associated with coagulation disorders, including congenital and acquired thrombophilia and the complications arising from it: recurrent pregnancy loss, gestosis, preeclampsia/eclampsia, premature detachment of a normally implanted placenta, Intrauterine Growth Restriction (IUGR), HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), and Disseminated Intravascular Coagulation (DIC). Since hereditary thrombophilia represents a group of genetic disorders that promote thrombosis and contribute to a hypercoagulable state, and despite the fact that hereditary thrombophilia accounts for 20–30% of venous thromboembolism cases, universal screening does not exist; however, testing is essential in individuals with high-risk profiles (burdened family history of thrombosis, recurrent venous thromboembolism, pregnancy, or planned surgical intervention). Furthermore: Factor V Leiden mutation (resistance to activated protein C) is the most common form of hereditary thrombophilia (5–7% in Caucasians). A mutation in the F5 gene renders coagulation factors resistant to protein C. Prothrombin gene mutation (G20210A) has a prevalence of 2–3% in Caucasians. The F2 gene mutation increases prothrombin levels and the risk of hypercoagulation. Protein C deficiency is a rare form of hereditary thrombophilia (0.2–0.5%). Protein C inactivates factors Va and VIIIa; deficiency leads to excessive activity of clotting factors and thrombus formation. Protein S deficiency is also rare (0.1–0.7%). Protein S functions as a cofactor for protein C; its deficiency increases the risk of thrombosis. Antithrombin deficiency is another rare inherited thrombophilia (0.02–0.2%). Antithrombin inhibits thrombin and factors Xa, IXa, and XIa; deficiency leads to excessive activity of these factors and development of hypercoagulation. Rare forms include dysfibrinogenemia and hyperhomocysteinemia. Clinical manifestations involve venous thromboembolism (pulmonary embolism, deep vein thrombosis). Thrombosis may also develop in unusual sites—cerebral veins, or veins of internal organs. Thrombophilia is frequently associated with recurrent pregnancy losses at various gestational ages. It is noteworthy that hereditary thrombophilia tends to manifest at a younger age compared with acquired forms. Our aim was to discuss this issue: 1. By reviewing our own retrospective cases (women treated in our clinic during 2023–2025); 2.By summarizing the positive outcomes in the management of relatively complex cases and assessing treatment effectiveness: a. Based on the obtained results, abnormalities of the coagulation–vascular and fibrinolytic systems were identified, requiring treatment both during preconception planning and b. Throughout pregnancy, childbirth, and the postpartum period, with dynamic monitoring of hemostasis markers until full correction; 3. Mathematical modeling of the data was performed using the three-component inclusion–exclusion principle known in combinatorial analysis.
2025-10-01 | The Impact of Prothrombin Complex Concentrate Versus Fresh Frozen Plasma for Hemorrhage Management in Cardiac Surgery: A Systematic Review and Meta-analysis of Randomized Clinical Trials.
To clarify the efficacy and safety endpoints, comparing prothrombin complex concentrate (PCC) versus fresh frozen plasma (FFP) for hemorrhage management in cardiac surgery. Systematic review and meta-analysis of randomized clinical trials (RCTs). Tertiary care. Adult patients who developed hemorrhage related to coagulation factor deficiency during cardiac surgery. PCC or FFP for hemorrhage management in cardiac surgery. A systematic search was conducted in PubMed, Embase, and Cochrane Library and identified RCTs comparing PCC with FFP for hemorrhage management in cardiac surgery. The primary outcome was postintervention hemoglobin levels. Secondary outcomes included 30-day mortality, transfusion requirements, adverse events, postintervention international normalized ratio, and reoperation rates. Categorical values were analyzed using risk ratios with 95% confidence intervals (CIs), whereas continuous values were compared using the mean difference and standardized mean difference with 95% CIs. Statistical analyses were conducted using R software, version 4.4.2. Four RCTs (671 patients) were included, with 343 (51.1%) patients receiving PCC. PCC was associated with higher postintervention hemoglobin levels (mean difference 1.17 g/dL, 95% CI 0.93-1.41, p < 0.01). Compared with FFP, the PCC group required fewer red blood cell transfusions at 24 hours, had reduced use of recombinant factor VII, and demonstrated improved postintervention international normalized ratio. In patients undergoing cardiac surgery with significant bleeding, PCC was associated with higher postintervention hemoglobin levels and reduced transfusion needs compared with FFP, without an increase in adverse events.
2025-04-07 | Twenty years of the four-factor prothrombin complex concentrate Octaplex/Balfaxar: A narrative review.
Prothrombin complex concentrate (PCC) is used to boost thrombin potential, support clot formation, and aid in the treatment and prophylaxis of bleeding. The two main forms of PCC are three-factor (3 F-PCC; comprising coagulation factors II, IX, and X) and four-factor (4F-PCC; factors II, VII, IX, X), which contain 25 times the clotting factors found in human plasma. This narrative review summarizes published efficacy and safety data on one 4F-PCC (Octaplex/Balfaxar, Octapharma) within its recognized uses and explores potential applications across different clinical contexts. Clinically available for > 20 years, Octaplex/Balfaxar is supplied as a freeze-dried powder for reconstitution and intravenous infusion. This 4F-PCC contains non-activated forms of coagulation factors as well as anticoagulant proteins C and S, potentially affording a balanced hemostatic effect and mitigating thrombosis risk. Production involves two virus inactivation/removal steps: solvent/detergent treatment and nanofiltration. 4F-PCC is approved for acquired deficiency of vitamin K-dependent clotting factors, such as those induced by vitamin K antagonists (VKAs, e.g., warfarin), and for congenital deficiency of factors II and X. Five published trials in 444 adult patients demonstrated the efficacy of 4F-PCC in VKA reversal, reducing the international normalized ratio (INR) with only two potentially treatment-related thrombotic events reported. While 4F-PCC dosing is currently indicated to be INR-guided, emerging evidence supports fixed dosing as an alternative to conventional weight-based dosing for VKA reversal. Recent guidelines support 4F-PCC use for direct oral anticoagulant-associated bleeding, cardiac surgery and trauma/emergencies. Ongoing studies will further clarify the efficacy and safety of 4F-PCC beyond its approved indications.
2025-03-30 | Prothrombin Complex Concentrate vs Frozen Plasma for Coagulopathic Bleeding in Cardiac Surgery: The FARES-II Multicenter Randomized Clinical Trial.
Excessive bleeding is a common and prognostically important complication of cardiac surgery. For bleeding related to coagulation factor deficiency, frozen plasma is the most used therapy. Preliminary trials indicate that 4-factor prothrombin complex concentrate (PCC) may be a suitable alternative. To compare the efficacy and safety of PCC with frozen plasma in patients undergoing cardiac surgery with coagulopathic bleeding. Unblinded randomized noninferiority controlled clinical trial at 12 hospitals in Canada and the US involving adults (≥18 years) who had developed bleeding related to coagulation factor deficiency after termination of cardiopulmonary bypass during surgery (November 30, 2022, to May 28, 2024). Final 30-day follow-up visit was completed on June 28, 2024. A total of 265 patients were randomized to receive PCC (1500 IU ≤60 kg; 2000 IU >60 kg) and 263, frozen plasma (3 U ≤60 kg; 4 U >60 kg) in the operating room. A second dose was allowed over the next 24 hours if indicated; thereafter, only frozen plasma could be used. The primary outcome was hemostatic response (effective if no hemostatic interventions occurred from 60 minutes to 24 hours after treatment initiation). The noninferiority of PCC vs frozen plasma was assessed using a 10% margin and a 1-sided α of .025, with subsequent testing for superiority if noninferiority was demonstrated. Secondary outcomes included allogeneic blood transfusions and adverse events. Patients were followed up until postoperative day 30. Of 538 enrolled patients, 420 patients (median age, 66 years [IQR, 57-73 years]; 74%, male; 10%, Asian; 1%, Black; and 65%, White) were included in the primary analysis; of those, 296 (70%) underwent complex surgeries. Compared with the 207 patients in the frozen plasma group, the 213 patients in the PCC group had higher hemostatic effectiveness (166 [77.9%] vs 125 [60.4%]; difference, 17.6%; 95% CI, 8.7%-26.4%; P < .001 for noninferiority and superiority) and had received fewer transfusions including red blood cells, platelets, and noninvestigational frozen plasma units (mean, 6.6 units; 95% CI, 5.7-7.7 vs 9.3 units; 95% CI, 8.0-10.8; difference, 2.7; 95% CI, 1.0-4.4; P = .002). Seventy-seven patients (36.2%) in the PCC group vs 98 (47.3%) in the frozen plasma group experienced serious adverse events (relative risk [RR], 0.76; 95% CI, 0.61-0.96; P = .02). Twenty-two patients (10.3%) in the PCC group and 39 (18.8%) in the frozen plasma group had acute kidney injury (RR, 0.55; 95% CI, 0.34-0.89; P = .02). In this unblinded randomized clinical trial, PCC had superior hemostatic efficacy and safety advantages to frozen plasma among patients requiring coagulation factor replacement for bleeding during cardiac surgery. ClinicalTrials.gov Identifier: NCT05523297.
2024-11-05 | Tetraspanin CD37 Regulates Platelet Hyperreactivity and Thrombosis
Psychosocial stress increases the risk of a myocardial infarction 2-fold and is associated with a 40% higher risk of death following an acute thrombotic event. With approximately a third of US adults reporting overwhelming stress levels most days, defining the mechanisms by which stress contributes to adverse thrombosis is paramount. Platelets are key contributors to thrombotic cardiovascular events, with platelet hyperreactivity associated with thrombosis and psychosocial stress. In humans and mouse models, psychosocial stress induces a hyperreactive platelet phenotype and increases the risk of thrombosis. To investigate how stress contributes to platelet hyperreactivity, platelets were isolated from 1) mice that experienced chronic variable stress and stress-free controls (n=8/group) and 2) human subjects with self-reported high and no stress levels (n=18/group) and RNA-sequencing performed. By comparison of mutually expressed transcripts, we identified a subset of genes differentially expressed following psychosocial stress in both human and mouse platelets. To assess the contribution of the identified transcripts to platelet functional responses that underlie thrombosis, the association of identified genes with platelet aggregation to epinephrine (0.4 μM) was assessed. Amongst screened candidates, the tetraspanin CD37 was significantly associated with platelet aggregation in a cohort of participants whose platelet aggregation and platelet transcriptome were measured simultaneously (R=0.30, p=0.0002, n=145). Following confirmation of CD37 expression in platelets at the transcriptomic and protein level in humans and mice, we assessed the functional outcome of platelet CD37 deficiency. Cd37-/- platelets spread significantly less relative to wild-type platelets on both poly-D-lysine and fibrinogen (p<0.01 and p<0.005, respectively) and underwent a minimal change in morphology following fibrinogen adhesion. Platelet solidity, a proxy measure inversely proportional to efficient maximal spreading mediated by filopodial-to-lamellipodial transitions, was significantly decreased in wild-type platelets relative to Cd37-/- (p<0.0001), indicative of a spreading dysfunction in CD37 deficient platelets. In whole blood flood cytometry, platelet expression of activated integrin αIIbβ3 (JON/A) and CD63 is significantly attenuated on Cd37-/- platelets relative to wild-type following stimulation with PAR4-AP (p<0.0001, p<0.05, respectively). However, JON/A and CD63 expression is unaltered under resting conditions between Cd37-/- and wild-type platelets. Consistent with a role for CD37 in regulating thrombosis-relevant platelet activation responses, chimeric mice that received Cd37-/- bone marrow experienced a significantly increased time to vessel occlusion (p<0.05) in the carotid artery FeCl3 model, relative to mice reconstituted with wild-type bone marrow. CD37 deficiency does not alter hemostasis, as platelet count, coagulation metrics, prothrombin time, and partial thromboplastin time do not differ in Cd37-/- mice relative to wild-type mice. Consistent with this, bleeding time does not differ between wild-type and Cd37-/- mice following tail tip transection. In humans and mice, platelet CD37 positively associates with platelet aggregation and phenotypic responses that underlie thrombosis. Cd37-deficient platelets exhibit impaired integrin αIIbβ3 signaling, characterized by reduced platelet fibrinogen spreading and decreased agonist-induced αIIbβ3 activation. Notably, CD37 deficiency significantly reduces thrombotic risk without altering hemostasis or bleeding susceptibility. This study provides new insight into a platelet-associated stress-induced mechanism contributing to accelerated thrombotic risk and provides the first direct evidence for CD37 as a regulator of platelet activation responses and thrombosis.
antibodies
2024-12-18 | Deficiency of neutrophil gelatinase-associated lipocalin elicits a hemophilia-like bleeding and clotting disorder in mice.
Coagulation is related to inflammation, but the key pathway, especially innate immune system and coagulation regulation, is not well understood and need to be further explored. Here, we demonstrated that neutrophil gelatinase-associated lipocalin (NGAL), an innate immune inflammatory mediator, is upregulated in patients with thrombosis. Furthermore, it contributes to the initiation and amplification of coagulation, hemostasis, and thrombosis. This occurs by enhancing tissue factor expression on the cell surface, potentiating various clotting factors such as thrombin, kallikrein, factor XIa (FXIa), and FVIIa, promoting thrombin-induced platelet aggregation, and inhibiting antithrombin. NGAL knockout led to strikingly prolonged clot reaction time and kinetic time in thromboelastography analysis, along with reduced thrombus generation angle and lower thrombus maximum amplitude, which were in line with remarkably prolonged activated partial thromboplastin time and prothrombin time. In several mouse hemostasis and thrombosis models, NGAL overexpression or IV administration promoted coagulation and hemostasis and aggravated thrombosis, whereas NGAL knockout or treatment with anti-NGAL monoclonal antibody significantly prolonged bleeding time and alleviated thrombus formation. Notably, NGAL knockout prolonged mouse tail bleeding time or artery occlusion time to over 40 or 60 minutes, respectively, resembling uncontrollable bleeding and clotting disorder seen in hemophilic mice. Furthermore, anti-NGAL monoclonal antibody treatment markedly reduced the formation of blood clots in inflammation-induced thrombosis models. Collectively, these findings unveil a previously unidentified role of NGAL in the processes of coagulation, hemostasis, and thrombosis, as well as the cross talk between innate immunity, inflammation, and coagulation. Thus, modulating NGAL levels could potentially help balance thrombotic and hemorrhagic risks.
2016-12-02 | Treatment of rare factor deficiencies in 2016
Rare bleeding disorders (RBDs) are a heterogeneous group of coagulation disorders characterized by fibrinogen, prothrombin, factors V, VII, X, XI, or XIII (FV, FVII, FX, FXI, or FXIII, respectively), and the combined factor V + VIII and vitamin K-dependent proteins deficiencies, representing roughly 5% of all bleeding disorders. They are usually transmitted as autosomal, recessive disorders, and the prevalence of the severe forms could range from 1 case in 500 000 for FVII up to 1 in 2-3 million for FXIII in the general population. Patients affected with RBDs may present a wide range of clinical symptoms, varying from mucocutaneous bleeding, common to all types of RBDs to the most life-threatening symptoms such as central nervous system and gastrointestinal bleeding. Treatment of these disorders is mainly based on the replacement of the deficient factor, using specific plasma-derived or recombinant products. In countries where these facilities are not available, bleedings could be managed using cryoprecipitate, fresh frozen plasma (FFP), or virus-inactivated plasma. Minor bleedings could be managed using antifibrinolytic agents. Recently, 2 novel drugs, recombinant FXIIIA and a plasma-derived FX, have been added to the list of available specific hemostatic factors; only prothrombin and FV deficiencies still remain without a specific product. Novel no-replacement therapies, such as monoclonal antibody anti-tissue factor pathway inhibitor, RNA interference, and a bispecific antibody that is an FVIIIa mimetic, enhancing thrombin generation through different mechanisms, were developed for patients with hemophilia and may in the future be a good therapeutic option also in RBDs.
1940-04-01 | Experimental Hypoprothrombinemia with Anti-Prothrombin Serum
An antiprothrombin serum may be prepared in the guinea pig by injecting it with fibrinogen-free prothrombin isolated from rabbit plasma. Intravenous injections of this antiserum in fasting rabbits produce a hypoprothrombinemia of a transient and moderate character.
proteins
2026-05-24 | Molecular Modeling of Protein-Peptide Complexes Mimicking Factor Xa-Prothrombin Using AlphaFold-Multimer and Molecular Dynamics Simulations for Functional Prediction.
Accurately predicting how point mutations influence protease activity is a major challenge in protein engineering and in the study of coagulation disorders. Factor Xa (FXa) catalyzes the proteolytic activation of prothrombin, a critical step in thrombin generation, yet the molecular details of direct enzyme-substrate recognition and the impact of pathogenic variants remain incompletely defined. Here, we combined AlphaFold-Multimer modeling with explicit-solvent molecular dynamics (MD) simulations to investigate simplified FXa-substrate interactions using prothrombin-derived peptides encompassing the Arg271 and Arg320 cleavage sites in the absence of the full prothrombinase complex. AlphaFold predictions identified catalytically competent peptide orientations, while subsequent MD simulations and free energy analyses identified key contributions of the P1 and P4 cleavage site residues to FXa binding. Distinct stability and affinity differences between the two cleavage sites were highlighted. Active site variants associated with factor X deficiency demonstrated variant-specific disruptions in peptide engagement, implicating key residues within the FXa active site as critical determinants of catalytic activity. Experimental validation with recombinant FXa variants was consistent with the computational predictions, indicating comparable inhibition by the prothrombin peptides. Together, these findings establish an integrative computational-experimental framework for probing local protease-substrate recognition, rationalizing the effects of disease-causing mutations, and guiding the design of therapeutic protease variants.
2026-03-02 | Factor II and Factor V Deficiencies: Current Management, Care Gaps and Call to Action for Therapeutic Advances.
Among rare inherited coagulation disorders (RICDs), prothrombin (factor II) and factor V (FV) deficiency are still orphans of treatments, lacking availability of single-factor replacement products. This clinical care gap is hampering the implementation of prophylactic and episodic treatment regimens in patients. We chose to produce a narrative review to evaluate to which degree bleeding prophylaxis, that is the standard of care for inherited coagulation disorders, has been implemented in these RICDs with the currently available therapeutics, that is fresh frozen plasma and prothrombin complex concentrates. The outcome of the episodic treatment of acute bleeding episodes and invasive procedures was also reviewed. Perusal of the published case reports shows a paucity of prophylaxis implementation even after life-threatening bleeding episodes such as intracerebral hemorrhage and ovulation-associated hemoperitoneum: only seven cases for prothrombin and three for FV deficiency. By the same token, there are relatively few reports on the acute treatment of bleeding episodes (particularly for prothrombin deficiency), as well as on the episodic treatment at the time of surgery or invasive procedures. Our review indicates that currently available therapeutics are largely suboptimal and justify a call to action in order to streamline regulatory pathways for single-factor concentrate development, as well as for the potential evaluation of prophylaxis of coagulation-rebalancing, non-replacement products.
2026-01-31 | CONSTITUTIONAL PROTHROMBIN DEFICIENCY REVEALED BY A FAMILY INVESTIGATION
Congenital prothrombin (factor II) deficiency is an extremely rare inherited coagulation disorder transmitted in an autosomal recessive manner and characterized by wide clinical variability, ranging from mild bleeding manifestations to life threatening hemorrhage. We report a familial case of severe congenital factor II deficiency diagnosed in the hematology laboratory of the Mohammed V Military Teaching Hospital in Rabat. The index case was a 6 year old girl born to a second degree consanguineous marriage, referred for cutaneous bleeding manifestations associated with recurrent knee pain, in a context of prolonged activated partial thromboplastin time and reduced prothrombin time. Coagulation studies revealed an isolated and severe reduction in factor II activity to 3%, with normal levels of the other coagulation factors.Family investigation identified a similar severe deficiency in both brothers, with variable hemorrhagic manifestations, whereas the parents were asymptomatic and exhibited moderately reduced factor II activity, consistent with a heterozygous carrier state.The combination of clinical and biological findings supported the diagnosis of severe constitutional factor II deficiency, most likely type I. This case highlights the importance of family investigation and consideration of consanguinity in the diagnosis of rare bleeding disorders, and underscores the central role of the laboratory in early identification, patient management, and genetic counseling.
2026-01-10 | Use of Plasma-Derived FVII Concentrate in Surgical Patients with Factor VII Deficiency: A Case Series.
Congenital factor VII (FVII) deficiency is the most common rare hemorrhagic disorder. Acquired FVII deficiency can be isolated or associated with other low coagulation factor levels. FVII levels do not accurately predict a patient's bleeding risk. In the case of surgery, the perioperative management needs to be evaluated on a case-by-case basis, considering the patient's bleeding history and the type of surgery. We present 12 patients with congenital or acquired FVII deficiency and describe the perioperative management with plasma-derived nonactivated FVII (pd-FVII) concentrate. Patients with factor VII deficiency treated with pd-FVII for perioperative hemostasis, between April 2022 and May 2025. We report thirteen procedures in 12 patients (11 males and 1 female; age range: 15-78 years). Two patients were affected by acquired deficiency, and 10 patients presented congenital deficiency. Perioperative prophylaxis with pd-FVII was performed at doses ranging from 20 to 40 IU/kg/dose. Total pd-FVII consumption ranged between 20 and 320 IU/kg. During and after surgery, there were no major bleeding or thrombotic events. In the postoperative period, only one patient presented with hematuria.
2025-08-05 | CO35 | Bleeding phenotype characterization in patients with congenital bleeding disorders: a multigenic approach using next generation sequencing to identify coagulation-modulating variants
Background and Aims: Congenital bleeding disorders, including hemophilia A (HA), hemophilia B (HB), and rare bleeding disorders (RBDs), often display variable clinical phenotypes not fully explained by a single pathogenic variant. Additional genetic variants modulating the coagulation cascade may influence bleeding severity. This study aimed to investigate such variants using a multigenic sequencing approach. Methods: Eighteen patients with a previously confirmed diagnosis of congenital bleeding disorder were selected for analysis. The cohort included individuals with HA, HB, FV deficiency, FXI deficiency, and plasminogen deficiency, all followed at the Hemophilia Center of Padua University Hospital. Genetic analysis was performed using a custom Next-Generation Sequencing (NGS) panel (xGen™ Hyb Panel, Integrated DNA Technologies) targeting 33 coagulation-related genes: A2M, CPB2, F2, F3, F5, F7, F8, F9, F10, F11, F12, F13A1, F13B, FGA, FGB, FGG, KLKB1, KNG1, PLAT, PLG, PROC, PROCR, PROS1, PROZ, SERPINA5, SERPINA10, SERPINC1, SERPIND1, SERPINE1, SERPINF2, TFPI, THBD, VWF. Sequencing was performed on the Illumina NextSeq550 platform. Variants with a minor allele frequency <0.1% were classified according to ACMG criteria. Results: The study population consisted of 10 patients with HA (1 mild, 1 moderate, 8 severe), 2 with HB (1 mild, 1 severe), 1 with FV deficiency, 1 with FXI deficiency, and 4 with plasminogen deficiency. On average, 150 variants per patient were observed. NGS identified class 5 pathogenic variants in 8 patients with HA (F8, including intron 22 inversion) and in 2 with HB (F9), and class 4 likely pathogenic variants in 3 patients (F8 [n=2] and, F11 [n=1]). Although only class 3 variants were identified in patients with plasminogen deficiency (n=4) and FV deficiency (n=1), these were located in the gene associated with the clinical phenotype (PLG and F5, respectively). Moreover, two plasminogen-deficient patients harboured two distinct variants in PLG. Beyond the causative mutations, 11 out of 18 patients (61%) harboured at least one variant of class 3 or 4 with potential modulatory effect. These were found in F2, F5, F10, F13A1, KNG1, VWF, SERPINA5, SERPINC1, PROS1, and PLG and included well-characterized variants such as FV Leiden, the prothrombin G20210A mutation (prothrombotic), and the Friuli FX variant (bleeding phenotype). Moreover, two predisposing variants were identified in F13A1 (n=2, pro-hemorrhagic) and F2 (n=1, prothrombotic). The distribution of class 3, 4, and 5 variants and predisposing variants is illustrated in Figure 1. Conclusions: NGS identified the putative causative mutation in all patients and revealed additional coagulation-related variants in the majority of the cohort. These results support a multigenic model influencing the bleeding phenotype in congenital bleeding disorders. Functional and segregation studies are warranted to clarify the role and clinical impact of the predisposing variants identified.
gene therapies
2025-08-01 | Molecular Aspects of Rare Coagulation Factor Deficiencies.
Rare coagulation factor deficiencies are inherited disorders affecting factors I, II, V, VII, X, XI, XIII, and combined forms. They mainly present with bleeding symptoms of variable severity. These deficiencies show significant clinical heterogeneity, with no consistent correlation between factor levels and bleeding intensity. Prevalence is higher in populations with high consanguinity rates. Understanding relies on the study of genetic and molecular mechanisms. Diagnosis is based on hemostasis testing, including prothrombin time (PT), activated partial thromboplastin time (aPTT), and factor activity assays. In case of abnormalities, Molecular analysis is undertaken using genomic DNA extracted from peripheral blood samples. Depending on the clinical context and the level of detail required, sequencing is performed using either Sanger sequencing or next-generation sequencing (NGS) platforms, enabling the identification of pathogenic variants responsible for the coagulation disorder. Variant interpretation follows American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) guidelines. Large deletions or duplications are assessed via Multiplex Ligation-dependent Probe Amplification (MLPA) or Copy number variations (CNV) analysis. Molecular analysis revealed a wide range of mutations depending on the deficient factor. Missense mutations are the most common, followed by nonsense, splicing, and insertion/deletion mutations. Some mutations prevent factor production, while others alter its structure or secretion. Each mutation type has a distinct impact on the bleeding phenotype. Genetic characterization improves diagnostic accuracy and guides clinical management. Modern molecular tools have enhanced the understanding of these disorders' pathophysiology. A multidisciplinary approach is essential for optimal patient care. Ongoing research is key to developing targeted therapies.
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Drug Discovery Landscape
2 orphan drug designations for Congenital factor II deficiency, including 1 approved therapy.
2 orphan drug designations for Congenital factor II deficiency, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
alteplase | — | FDA | 2003-01-27 | — | Daniel F. Hanley, MD |
tranexamic acid [Cyklokapron] | small molecules | FDA | 1985-12-03 | 1986-12-30 | Pharmacia Inc. |
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