Materiały źródłowe

• #1 Hemophilia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK551607/

  Hemophilia A and B result from factor VIII and factor IX protein deficiency. […] Both hemophilia A and B result from factor VIII and factor IX protein deficiency or dysfunction, respectively, and are characterized by prolonged and excessive bleeding after minor trauma or sometimes even spontaneously. […] Hemophilia is usually an inherited condition and is caused by the deficiency of clotting factors in the blood. It is almost always due to a defect or mutation in the gene for the clotting factor. […] Research has identified over 1000 mutations in the genes encoding factor VIII and IX, and around 30% are due to spontaneous mutation. […] The process of blood clot formation involves the activation of two pathways – the extrinsic or tissue factor (TF) pathway and the intrinsic or contact pathway.

• #1 Hemophilia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK551607/

  When factor VIII and factor IX are deficient or dysfunctional, the intrinsic pathway of the coagulation cascade cannot be appropriately activated, thus making the process of clot formation deficient. […] The major complication of therapy in patients with hemophilia is the development of inhibitors. […] Inhibitors are alloantibodies (IgG) directed against factors VIII and IX that neutralize their action. […] The presence of inhibitors should be suspected if bleeding fails to stop after infusion of clotting factors in a patient who was responsive in the past. […] Inhibitors make the half-life of infused factor concentrate even shorter and thereby decrease their efficiency. […] Immune-tolerance induction has been found to be a proven therapy to eradicate inhibitors. […] This protocol involves repeated and frequent infusion of factor VIII.

• #2 Hemophilia A – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK470265/

  Hemophilia encompasses a group of inherited disorders that alter blood coagulation. Classical hemophilia, also known as hemophilia A, is a hereditary hemorrhagic disorder resulting from a congenital deficit of factor VIII that manifests as protracted and excessive bleeding either spontaneously or secondary to trauma. […] An X-linked, recessive hemorrhagic trait or gene induces Hemophilia A. Hemophilia A’s X-linked trait manifests as a congenital absence or decrease in plasma clotting Factor VIII, a pro-coagulation cofactor and robust initiator of thrombin that is essential for the generation of adequate amounts of fibrin to form a platelet-fibrin plug at sites of endothelial disruption. […] Factor VIII, the deficit of which causes hemophilia A, provides essential enhancement of thrombin generation and promulgation of fibrin formation to inhibit further bleeding. Factor VIII adheres to von Willebrand factor to protect it from proteolytic degradation. Bleeding in hemophilia results from defective fibrin stabilization secondary to inadequate fibrin generation, which results in a failure of secondary hemostasis. Insufficient thrombin in the coagulation cascade results in a deficiency of fibrin.

• #3 Hemophilia: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/hemophilia/

  Hemophilia is a bleeding disorder that slows the blood clotting process. […] The major types of this condition are hemophilia A (also known as classic hemophilia or factor VIII deficiency) and hemophilia B (also known as Christmas disease or factor IX deficiency). […] Variants in the F8 gene cause hemophilia A, while variants in the F9 gene cause hemophilia B. The F8 gene provides instructions for making a protein called coagulation factor VIII. A related protein, coagulation factor IX, is produced from the F9 gene. Coagulation factors are proteins that work together in the blood clotting process. […] Variants in the F8 or F9 gene lead to the production of an abnormal version of coagulation factor VIII or coagulation factor IX, or reduce the amount of one of these proteins. The altered or missing protein cannot participate effectively in the blood clotting process.

• #3 Hemophilia: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/hemophilia/

  The variants that cause severe hemophilia almost completely eliminate the activity of coagulation factor VIII or coagulation factor IX. […] Another form of the disorder, known as acquired hemophilia, is not caused by inherited gene variants. […] Acquired hemophilia results when the body makes specialized proteins called autoantibodies that attack and disable coagulation factor VIII. […] Hemophilia A and hemophilia B are inherited in an X-linked recessive pattern. […] In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. […] In females (who have two X chromosomes), a variant would usually have to occur in both copies of the gene to cause the disorder. However, in some instances, one altered copy of the F8 or F9 gene is sufficient, because the X chromosome with the normal copy of the gene is turned off through a process called X-inactivation.

• #4 Hemophilia A (Factor VIII Deficiency): Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/779322-overview

  Hemophilia A is an X-linked, recessive disorder caused by deficiency of functional plasma clotting factor VIII (FVIII), which may be inherited or arise from spontaneous mutation. […] The development of inhibitory alloantibodies to FVIII can severely complicate the treatment of genetic cases. Rarely, development of autoantibodies to FVIII results in acquired hemophilia A. […] FVIII deficiency, dysfunctional FVIII, or FVIII inhibitors lead to the disruption of the normal intrinsic coagulation cascade, resulting in excessive hemorrhage in response to trauma and, in severe cases, spontaneous hemorrhage. […] Inadequate factor VIII results in the insufficient generation of thrombin by the FIXa and FVIIIa complex by means of the intrinsic pathway of the coagulation cascade. This mechanism, in combination with the effect of the tissue-factor pathway inhibitor, creates an extraordinary tendency for impaired clotting in response to trauma and, especially in persons with severe hemophilia, for spontaneous bleeding.

• #5 Hemophilia | American Society for Clinical Laboratory Science

  https://clsjournal.ascls.org/content/32/1/21

  The cell-based model of coagulation adds further insight into the pathogenesis of hemophilia. This model includes platelet and cell surfaces that are essential in in vivo coagulation. […] In patients with hemophilia, an absent/defective FVIII or FIX results in a nonfunctional intrinsic-tenase complex on the platelet surface. […] Congenital HA and HB are X-linked diseases inherited in a recessive pattern. […] The genes encoding FVIII and FIX are located on the tip of the long arm of the X chromosome: Xq28 and Xq27, respectively. […] The FVIII gene is 186 kb and contains 26 exons that code for a signal peptide and a 2332-amino acid polypeptide. […] More than 2,000 unique molecular defects have been described in the FVIII gene, and about 1,095 genetic variants have been described in the FIX gene.

• #5 Hemophilia | American Society for Clinical Laboratory Science

  https://clsjournal.ascls.org/content/32/1/21

  Acquired hemophilia A (AHA) is a rare autoimmune disease and affects approximately 1.5 million individuals annually. […] AHA occurs when spontaneous production of neutralizing IgG antibodies target FVIII, which prevents it from functioning in the intrinsic-tenase complex. […] The development of inhibitors is a serious iatrogenic complication associated with hemophilia treatment. […] The development of inhibitors is more commonly seen in HA (25%30% of patients) compared to HB (3%5% of patients). […] A prolonged aPTT with a normal PT is the classic finding in the clinical laboratory among patients with hemophilia. […] The prolongation of the aPTT is directly related to the factor activity levels of FVIII and FIX in the patient. […] Hemophilia is a very complex bleeding disease that once was once considered a debilitating disease. […] The only potential cure for hemophilia is gene therapy. However, the challenge remains to develop a safe, viable gene therapy product that is not cost-prohibitive.

• #6 Hemophilia A (Factor VIII Deficiency): Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/779322-overview

  Approximately 40% of cases of severe FVIII deficiency arise from a large inversion that disrupts the FVIII gene. Deletions, insertions, and point mutations account for the remaining 50-60% of the F8C defects that cause hemophilia A. […] The mutation in intron 22 occurs during spermatogenesis and is a common cause of severe factor VIII deficiency; it is present in approximately 40% of patients. It is easily detected using a Southern blot analysis of the patient’s DNA. These patients are more likely to develop an inhibitor to factor VIII.

• #7

  https://haematologica.org/article/view/9037

  Hemophilia A and B are rare X-linked bleeding disorders caused by mutations in the genes encoding coagulation factor VIII (FVIII) and factor IX (FIX). […] The mutations causing hemophilia A and B have been characterized in several thousands of patients. What is immediately evident from the enormous number of mutations that have been elucidated is that the molecular basis of the hemophilias is extremely diverse. […] Previous studies have shown that the mutation type in the FVIII and FIX genes correlates with the residual factor activity in plasma and the bleeding tendency in hemophilia patients, with larger gene defects generally associated with a more severe clinical phenotype. […] The higher prevalence of less severe mutations (missense mutations) in HB could provide a biological basis for a milder bleeding phenotype compared to HA, although clinical evidence is limited.

• #8 Hemophilia – Hematology and Oncology – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/hematology-and-oncology/coagulation-disorders/hemophilia

  Hemophilia is an inherited disorder that results from mutations, deletions, or inversions affecting the factor VIII or factor IX gene. […] The gene abnormalities with severe hemophilia (factor levels 1%) are typically large deletions or inversions or point mutations that disrupt gene expression. In contrast, hemophilia that is mild or moderate typically involves with point mutations that result in an amino acid change (missense mutation). […] In one study, 55% of patients with severe hemophilia A and 43% of patients with severe hemophilia B were sporadic cases. […] After repeated exposure to factor VIII or IX replacement, about 30% of patients with severe hemophilia A and 3% with hemophilia B develop factor VIII or factor IX isoantibodies (alloantibodies) that inhibit the coagulant activity of any additional factor VIII or factor IX infused. […] Gene therapy using adeno-associated virus (AAV) vectors has been shown in clinical trials to result in sustained factor VIII and factor IX expression. […] Both VWF and factor VIII are stored in the Weibel-Palade bodies of endothelial cells and secreted in response to endothelial cell stimulation.

• #9 Haemophilia – Wikipedia

  https://en.wikipedia.org/wiki/Haemophilia

  Acquired haemophilia is associated with cancers, autoimmune disorders, and pregnancy. […] The most common mutation that causes severe cases of haemophilia A is an inversion within intron 22 of the factor VIII gene (F8) which is located near the tip of the X chromosome, leading to an abnormal crossover during meiosis. About 30% of cases of haemophilia B are the result of a spontaneous gene mutation. […] A non-genetic form of haemophilia is caused by autoantibodies against factor VIII and so is known as acquired haemophilia A. It is a rare but potentially life-threatening bleeding disorder caused by the development of autoantibodies (inhibitors) directed against plasma coagulation factors.

• #10 Hemophilia B (Factor IX Deficiency): Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/779434-overview

  Factor IX deficiency, dysfunctional factor IX, or factor IX inhibitors lead to disruption of the normal coagulation cascade, resulting in spontaneous hemorrhage and/or excessive hemorrhage in response to trauma. […] FIX, a vitamin K-dependent single-chain glycoprotein, is synthesized first by the hepatocyte as a precursor protein. Before secretion from the hepatocyte, the FIX protein undergoes extensive posttranslational modifications, which include gamma carboxylation, beta hydroxylation, and removal of the signal peptide and propeptides, addition of carbohydrates, sulfation, and phosphorylation. […] The gamma-carboxylated region of FIX is essential for calcium binding and is the site at which vitamin K-dependent coagulation proteins bind to cell surface phospholipids and efficient coagulation reactions take place.

• #11 Haemophilia: pathophysiology and management | Nursing Times

  https://www.nursingtimes.net/haematology/haemophilia-pathophysiology-and-management-14-10-2003/

  Haemophilia is a rare inherited disorder of the bodys blood clotting mechanism. This X-linked recessive disorder occurs in 1:10,000 live male births a year and there are no variations of incidence in different ethnic groups. […] Haemophilia can be divided into two categories: haemophilia A and B – characterised by a deficiency or absence of clotting factor VIII and IX respectively. […] Three mechanisms work together to facilitate healing when a blood vessel is injured. First, the blood vessel constricts to limit the volume of blood that is lost. Second, circulating platelets form a plug at the site of injury. Finally, the blood undergoes coagulation. A number of clotting factor proteins, defined by Roman numerals, must be activated in sequence for coagulation to take place. This process allows the platelet plug to be stabilised by a fibrin matrix that is formed over its surface, thereby ensuring that the vessel wall can heal.

• #12 Haemophilia: pathophysiology and management | Nursing Times

  https://www.nursingtimes.net/haematology/haemophilia-pathophysiology-and-management-14-10-2003/

  Factors VIII and IX are only two of the 13 proteins that are involved in the cascade process of coagulation. If there is an absence or deficiency of any of these proteins the coagulation process will be initiated but not completed: the platelet plug will remain unstable and bleeding will continue over a prolonged period of time.

• #13 Hemophilia pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Hemophilia_pathophysiology

  Hemophilia is a genetic bleeding disorder resulting from the insufficient levels of clotting factors in the body. The genes involved in the pathogenesis of hemophilia include the F8 gene in hemophilia A, F9 gene in hemophilia B, and F11 gene in C. […] Hemophilia is an X-linked bleeding disorder caused by a deficiency or complete absence of coagulation factor VIII (hemophilia A) or factor IX (hemophilia B). […] Bleeding in hemophilia occurs due to the failure of secondary hemostasis. […] Primary hemostasis and the formation of platelet plug occurs normally but stabilization of the plug by fibrin is defective because of the generation of inadequate amounts of thrombin. […] Clinical expression of hemophilia usually correlates with the activity of the coagulation factor and the disease can be classified as: Mild (factor level 0.05-0.40 IU/mL), Moderate (factor level 0.01-0.05 IU/mL), Severe (factor level 0.01 IU/mL).

• #14

  https://link.springer.com/article/10.1007/s11357-024-01317-7

  Acquired hemophilia A (AHA) is a rare autoimmune bleeding disorder characterized by the development of neutralizing autoantibodies (inhibitors) against coagulation factor VIII (FVIII). […] AHA is a rare and potentially life-threatening bleeding disorder caused by autoantibodies against coagulation factor VIII (FVIII), which causes increased clearance and neutralization of FVIII. […] The pathogenesis of AHA is of a typical autoimmune nature, in which the immune system mistakenly recognizes FVIII as a foreign antigen and mounts an immune response against it. This autoimmune response leads to the production of inhibitory antibodies, also known as inhibitors, that specifically target FVIII and neutralize its activity and increase its clearance. […] One hypothesis suggests that AHA arises from the breakdown of immune tolerance to FVIII. Under normal circumstances, the immune system tolerates self-antigens, including FVIII, to prevent autoimmunity. However, in AHA, there is a failure in immune tolerance mechanisms, leading to the production of inhibitory antibodies.

• #15 Pathogenesis and Treatment of Hemophilia | Oncohema Key

  https://oncohemakey.com/pathogenesis-and-treatment-of-hemophilia/

  The presence of neutralizing alloantibodies (inhibitors) to therapeutic FVIII is a serious complication in hemophilia A, occurring in approximately 30% of patients classed as severe. In those individuals, the inhibitors usually develop during the first 2030 days of exposure and appear to result from a multi-causal immune response involving both patient-related and treatment-related factors. A gene defect is thought to contribute to about 40% of the risk of inhibitor formation, although the immunology of inhibitor development remains to be fully understood. Large deletions and nonsense mutations seem to present the highest risk, whereas missense and splicing mutations mediate the lowest risk. The most common acquired risk factor is the intensity of exposure to FVIII concentrate. In non-severe hemophilia A patients and different from severe hemophilia A, inhibitors usually arise when the immune system is under intense stimulation or when exposure to FVIII concentrates is unusually high, independent of exposure days, in particular in the postoperative period. Mutations leading to an abnormal conformation of FVIII are associated with a high risk of inhibitor development in mild hemophilia A, especially in those patients with mutations in the A2 and A3C1C2 domains (e.g., Arg593Cys and Arg2150His, respectively).

• #16 Current Challenges in the Management of Hemophilia

  https://www.ajmc.com/view/ace0024_mar15_hemophilia_bauer

  An inhibitor is an antibody directed against either factor VIII or IX that may be created by the body following treatment to replenish the missing factor. Inhibitor antibodies form in 20% to 33% of patients with hemophilia A and are less likely to be a clinical problem in patients with factor IX deficiency; formation of inhibitors occurs in 1% to 6% of patients with hemophilia B. […] The development of an inhibitor is influenced by several factors. The risk of inhibitors is increased in younger patients receiving the first several doses of factor. […] The process of identifying the optimal treatment regimen for hemophilia patients is likely to grow more complex as managed care organizations determine how to integrate new agents into the current treatment paradigm, posing another challenge to the optimal management of hemophilia.

• #17

  https://www.jci.org/articles/view/159925

  A major complication of hemophilia A therapy is the development of alloantibodies (inhibitors) that neutralize intravenously administered coagulation factor VIII (FVIII). […] Here, we demonstrated that immune tolerance against FVIII under nonhemophilic conditions was maintained by programmed death (PD) ligand 1-expressing (PD-L1-expressing) regulatory T cells (Tregs) that ligated PD-1 on FVIII-specific B cells, causing them to undergo apoptosis. […] In summary, we showed that PD-1-mediated B cell tolerance against FVIII operated in healthy individuals and in patients with hemophilia A without inhibitors, and that ITI reengaged this mechanism. […] Our findings suggest that this molecular mechanism is critical also for induction of tolerance to FVIII under nonhemophilic conditions, as well as for establishing and maintaining tolerance toward FVIII during ITI in hemophilia A patients.

• #18

  https://www.jci.org/articles/view/159925

  We demonstrated this by establishing a murine model that mimics important aspects of the ITI protocols for treating humans. […] Our findings suggest that ITI operates at least in part by inducing FVIII-specific Tregs that promote apoptosis of FVIII-specific B cells, thereby stopping inhibitor formation. […] These findings indicated that Tregs were necessary for suppressing FVIII-specific B cells. […] These findings demonstrated the existence of PD-L1-expressing Tregs in humans and supported their role in PD-1-mediated tolerance to FVIII.

• #19 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20221027/Study-elucidates-mechanism-that-is-crucial-for-making-hemophilia-therapy-effective.aspx

  For factor VIII, this means that it is no longer effective in hemophilia treatment. […] Regulatory T cells prevent an immune response from being too strong or lasting too long. […] The researchers have now found a new type among them that can act specifically against certain B cells rather than just non-specifically against all immune responses. […] „We were able to show that immunotolerance therapy results in the generation of regulatory T cells that exclusively induce B cells against factor VIII to commit suicide,” says Dr. Janine Becker-Gotot. […] By activating it, it starts a program in the B cell that results in its death. […] The more PD-1 buttons the B cells against factor VIII carry on their surface, the easier it is for them to be driven to suicide by immune tolerance therapy. […] If PD-1 levels go up shortly after starting immune tolerance therapy and then stay up, that’s a clear sign that the treatment is going to be successful. […] „Our findings have great basic scientific value,” explains Prof. Kurts.

• #20 Learn About The Latest Developments In Hemophilia Care

  https://hemhorizonhcp.com/

  Innovative approaches include gene therapy, a potential one-time infusion that introduces a functional gene that provides for production of factor VIII or factor IX, and inhibition of TFPI, antithrombin, or activated protein complex (APC), all rebalancing approaches that target anticoagulant components within the cascade. […] Gene therapy for hemophilia involves the use of a viral vector to deliver the gene to liver cells. Liver cells are targeted because they are responsible for synthesis of factor VIII and factor IX. […] Because both hemophilia A and B are each caused by a variation in a single gene, gene therapy holds the potential to directly address the pathophysiologic basis and may allow the body to produce the missing factor. Gene therapy aims to meet key unmet goals of achieving steady-state clotting factor levels after a one-time infusion, which may offer long-term bleed protection.

• #21 Learn About The Latest Developments In Hemophilia Care

  https://hemhorizonhcp.com/

  TFPI, short for tissue factor pathway inhibitor, is an anticoagulant protein and a core component of the coagulation cascade. TFPI naturally limits coagulation activity at multiple stages of the coagulation cascade. […] An agent that inhibits TFPI has the potential to block TFPI’s normal anticoagulation properties. […] TFPI inhibition offers the potential to achieve clotting even when factor VIII or factor IX is absent or deficient. […] Antithrombin is a natural anticoagulant and the primary inhibitor of thrombin. Thrombin is an enzyme needed to produce fibrin in the final stages of clot formation. […] An agent that reduces antithrombin production has the potential to promote sufficient thrombin production to rebalance the process and may allow a clot to form when factor VIII or factor IX is absent or deficient.

• #22 Learn About The Latest Developments In Hemophilia Care

  https://hemhorizonhcp.com/

  Activated protein C (APC) is a natural trypsin-like serine protease, which has anticoagulant properties. APC directly inhibits activated factor V and factor VIII complexes leading to indirect inhibition of thrombin generation. […] When factor VIII or factor IX is absent or deficient, an agent that inhibits APC activity may allow for sufficient thrombin generation to rebalance the coagulation cascade and allow a clot to form.

• #23 Fresh Look at Mechanism Suggests an 'Important Role’ in Hemophilia AEnvelope icon

  https://hemophilianewstoday.com/news/fresh-look-mechanism-finds-important-role-fviii-regulation-mouse-study/

  A mechanism largely left unexplored was shown to help regulate factor VIII (FVIII) — the clotting protein that is missing or defective in people with hemophilia A — in a study in mice. […] The importance of this regulatory mechanism is well-established; mutations that weaken the binding of the A2 domain to the other subunits cause some cases of hemophilia A. […] „Our studies with FVIII-QQ show that APC has an important role in FVIIIa regulation in vivo,” the researchers concluded, adding that this mechanism of FVIIIa inactivation has long been thought to be relatively unimportant. […] Researchers speculated that this finding could help in developing new therapies for hemophilia A.

• #24 Unique Blood-Clotting Mechanism in Saliva May Explain Reduced Bleeding in Hemophilia – Hematology Advisor

  https://www.hematologyadvisor.com/news/hemophilia-blood-clotting-mechanism-saliva-reduced-bleeding-treatment-risk/

  Saliva from patients with hemophilia A can independently trigger blood coagulation, despite FVIII deficiency. […] Extracellular vesicles present in saliva from patients with hemophilia A expose extrinsic tenase complexes, consisting of tissue factor and activated factor VII (FVIIa), which can activate factor X (FXa) and subsequently trigger coagulation. […] Further examination confirmed that the coagulant effect of saliva from patients with hemophilia operates independently of FVIII levels. […] This indicates that the salivary extracellular vesicle-mediated coagulation in hemophilia A operates separately from plasma FVIII, further supporting the potential for saliva to aid in coagulation through an FVIII-independent pathway. […] In summary, we propose that the presence or absence of functional extrinsic tenase complexes in saliva explains part of the difference in bleeding phenotypes of persons with severe hemophilia A and severe FVII deficiency.

• #25 Hemophilia A and B mice, but not VWF−/−mice, display bone defects in congenital development and remodeling after injury | Scientific Reports

  https://www.nature.com/articles/s41598-019-50787-9

  While joint damage is the primary co-morbidity of hemophilia, osteoporosis and osteopenia are also observed. Coagulation factor VIII deficient (FVIII/) mice develop an osteoporotic phenotype in the absence of induced hemarthrosis that is exacerbated two weeks after an induced joint injury. […] We found FVIII/ and FIX/ mice, but not VWF/ mice, developmentally have an osteoporotic phenotype. Unilateral induced hemarthrosis causes further bone damage in both FVIII/ and FIX/ mice, but has little effect on VWF/ bone health, indicating that the FVIII.VWF complex is not required for normal bone remodeling in vivo. […] Elevated ratio of osteoprotegerin (OPG)/receptor activator of nuclear factor-kappa B ligand (RANKL), increased osterix+ osteoblastic cells, and decreased smoothness of the cortical bone surface were evident within several days of injury, indicative of acute heterotopic mineralization along the cortical surface.

• #26 Hemophilia A and B mice, but not VWF−/−mice, display bone defects in congenital development and remodeling after injury | Scientific Reports

  https://www.nature.com/articles/s41598-019-50787-9

  The injured limbs of FVIII/ and FIX/ mice showed significantly elevated scores at two weeks post-injury compared to the non-injured limb and to injured WT littermate controls. […] MicroCT scans revealed significant changes in surface morphometry and trabecular structure of the injured limb within the FVIII/ and FIX/ cohorts when compared to the contralateral control or WT littermates but not in VWF/ mice. […] The high OPG/RANKL ratios in FVIII/ and FIX/ mice mark a significant swing towards the inhibition of osteoclastogenesis and a shift away from bone resorption at two weeks following injury. […] We report here for the first time that congenital deficits in bone development as well as defective bone remodeling following injury are shared by FIX/ or FVIII/ mice, as is defective bone remodeling in bones adjacent to joint hemorrhage. […] Our results are consistent with the hypothesis that thrombin generation and signalling are important for the maintenance of normal bone phenotype.

• #27 Pathogenesis and Treatment of Hemophilia | SpringerLink

  https://link.springer.com/chapter/10.1007/978-981-10-3886-0_9

  Hemophilia A and B are congenital inherited bleeding disorders, occurred by genetic abnormalities of blood coagulation factor (F)VIII and FIX molecules, respectively. […] The clinical abnormality is associated with bleeding episodes affecting especially joints and muscles, and repeated hemorrhage results in chronic arthropathy finally associated with loss of joint movement. […] In 20-30% of severe hemophilia A and 35% of hemophilia B which had multi-transfused, anti-FVIII (FIX) alloantibodies (inhibitors) appeared, resulting in difficulty of hemostatic management. […] Immune tolerance induction therapy to eradicate inhibitors has been actively conducted. […] The bypassing agent therapy is treated for hemophilia patients with inhibitor. […] Subcutaneous injection therapy such as FVIII-mimetic bispecific antibody or gene therapy is currently ongoing in the clinical trials for the future prospective therapy.

• #28 MOLECULAR MECHANISMS OF INHIBITOR DEVELOPMENT IN HEMOPHILIA | Mediterranean Journal of Hematology and Infectious Diseases

  https://www.mjhid.org/index.php/mjhid/article/view/2020.001

  The development of neutralizing antibodies in hemophilia is a serious complication of factor replacement therapy. […] The understanding of the pathophysiological mechanism leading to the development of inhibitors in patients with hemophilia has improved considerably over the last 2 decades. […] In this review, we aim to summarize the molecular mechanisms of inhibitor development in hemophilia and to identify potential areas in need of further investigation. […] The molecular mechanisms of immunomodulation and tolerance induction to factor VIII. […] Mechanisms of action of immune tolerance induction against factor VIII in patients with congenital haemophilia A and factor VIII inhibitors.

• #29 Advances in the management of haemophilia: emerging treatments and their mechanisms | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-021-00760-4

  Mainstay haemophilia treatment, namely intravenous factor replacement, poses several clinical challenges including frequent injections due to the short half-life of recombinant factors, intravenous administration (which is particularly challenging in those with difficult venous access), and the risk of inhibitor development. […] Several novel pharmacological therapies developed for haemophilia aim to rebalance the clotting cascade and potentially circumvent the aforementioned challenges. These therapies utilise a range of different mechanisms, namely: the extension of the circulating half-life of standard recombinant factors; the mimicking of factor VIII cofactor activity; rebalancing of coagulation through targeting of natural anticoagulants such as antithrombin and tissue factor pathway inhibitor; and inducing the production of endogenous factors with gene therapy.

• #30 Advances in the management of haemophilia: emerging treatments and their mechanisms | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-021-00760-4

  Given its limitations, improving haemophilia management remains an important aim and has attracted a large amount of research. This review will discuss novel mechanisms of treating haemophilia, potentially circumventing the limitations of current factor replacement therapy. […] Emicizumab, a recombinant humanised bispecific IgG antibody, mimics the cofactor function of the missing FVIII in HA. It simultaneously binds activated FIX (FIXa) and factor X (FX), bringing them into spatial proximity to promote FIXa-catalysed FX activation, thereby restoring haemostasis. […] Fitusiran (ALN-AT3), a novel therapy applicable to both HA and HB, consists of the amino acid, N-Acetylgalactosamine (GalNAc), the ligand of the hepatic asialoglycoprotein receptors, conjugated to a synthetic siRNA. Administered subcutaneously, it targets and degrades a region of the SERPINC1 gene mRNA, preventing antithrombin production and enhancing thrombin generation.

Zobacz więcej