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:
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.
2025-12-08 | 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.
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.
2025-12-08 | 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.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
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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