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. […] 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.

• #2 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.

• #3 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.

• #4 Hemophilia | American Society for Clinical Laboratory Science

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

  When either FVIII or FIX are absent, severely decreased, or defective, the clot that forms is insufficient to support normal hemostasis. […] 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. […] 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. […] The range of mutations for HA and HB include point mutations, insertions, deletions, and inversions. […] It has been suggested that the reduced frequency of HB compared to HA may be because of the smaller size of the genes involved: 33.5 kb for FIX and 187 kb for FVIII.

• #5 Hemophilia – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/hemophilia/symptoms-causes/syc-20373327

  Hemophilia is a rare disorder in which the blood doesn’t clot in the typical way because it doesn’t have enough blood-clotting proteins (clotting factors). […] Hemophilia is almost always a genetic disorder. Treatment includes regular replacement of the specific clotting factor that is reduced. Newer therapies that don’t contain clotting factors also are being used. […] Hemophilia occurs when a clotting factor is missing or levels of the clotting factor are low. […] Congenital hemophilia is classified by the type of clotting factor that’s low. […] Acquired hemophilia is a variety of the condition that occurs when a person’s immune system attacks clotting factor 8 or 9 in the blood. […] In the most common types of hemophilia, the faulty gene is located on the X chromosome. […] Most women with the defective gene are carriers who have no signs or symptoms of hemophilia. But some carriers can have bleeding symptoms if their clotting factors are moderately decreased.

• #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 Haemophilia – Wikipedia

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

  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.

• #8

  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. […] Point mutations, deletions, insertions, and rearrangements/inversions have all been found either in F8 and F9 genes. However, the relative frequency of these mutations differs between HA and HB. In particular, gross genetic abnormalities account for approximately 7% of HB cases in contrast to HA in which gene rearrangements account for almost half of severe cases, with intron 22 inversion being the most common defect.

• #9

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

  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. […] The different prevalence of mutations predicting a null allele also explains a higher proportion of HB patients that can be classified as cross-reacting material positive (CRM). […] The mutations thought to be responsible for CRM HA are generally missense mutations found in the A2-domain of FVIII. […] It is also interesting to note that for some FIX nonsense gene mutations in HB, usually categorized as null mutations, the mechanism of ribosome readthrough could restore translation impaired by mutations and could account for minimal full-length protein biosynthesis.

• #10 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. […] Normal hemostasis occurs when factor VIII and IX levels are 50% of normal. 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 point mutations that result in an amino acid change (missense mutation). […] 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 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.

• #11 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. […] When the vascular endothelium sustains an injury, the hemostatic process initiates the coagulation cascade to restore vascular integrity and prevent further bleeding. Platelet activation occurs at the site of vascular rupture, initiating promulgation of clotting factors and fibrin formation, resulting in a platelet-fibrin plug to inhibit further bleeding. 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.

• #12 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. Hemorrhage sites include joints (eg, knee, elbow), muscles, central nervous system (CNS), GI system, genitourinary (GU) system, pulmonary system, and cardiovascular system. […] 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. Ca2+ binding to the Gla region results in a conformational change leading to exposure of previously buried hydrophobic residues in the FIX molecule, which then can be inserted into the lipid bilayer.

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

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

  Following activation, the single-chain FIX becomes a two-chain molecule, in which the two chains are linked by a disulfide bond attaching the enzyme to the Gla domain. Activated factor VIII (FVIIIa) is the specific cofactor for the full expression of FIXa activity. […] Many feedback loops exist in the coagulation pathway, and some evidence suggests that FIXa can activate FVII and FVIII in addition to FX. Support for the important role of FIX in producing FVIIa, essential for normal hemostasis in vivo, was provided by a study using a sensitive, highly specific FVIIa assay, which showed that healthy individuals had basal FVIIa levels of 4.34 ng/mL. […] The demonstration that thrombi generated in plasmas obtained from patients with hemophilia A or B underwent premature lysis generated the hypothesis that bleeding in patients with hemophilia may be due not only to failure of adequate thrombin generation and clot formation, but also to a failure of adequate suppression of fibrinolysis leading to accelerated clot removal.

• #14 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).

• #15 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.

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

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

  A reduction in the level of FIX via reduction of thrombin generation reduces TAFI activation and increases fibrinolysis, whereas persistence of FVa (as is the case with co-inheritance of factor V [FV] Leiden) leads to increased (persistent) thrombin production and TAFI activation, thereby inhibiting fibrinolysis. […] The concept of coagulation as a waterfall or cascade, with a series of reactions each impacting the subsequent reaction, dates back to the 1960s. The fact that fluid-phase reactions are inefficient and that platelets and other cell surfaces provide the anionic phospholipids needed for complex formation so that reactions can proceed efficiently also has been recognized. […] In this model, three phases are proposed, including (1) initiation of coagulation on the surface of a TF-bearing cell, with formation of FXa, FIXa, and thrombin; (2) amplification of this reaction next on the platelet surface as platelets are activated, adhere, and accumulate factors/cofactors on their surfaces; and (3) the propagation phase, in which the large second burst of thrombin occurs on the platelet surface, resulting from the interaction of proteases with their cofactors, resulting in fibrin polymerization.

• #17 Haemophilia A – Wikipedia

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

  The diagnosis of haemophilia A may be suspected as coagulation testing reveals an increased partial thromboplastin time (PTT) in the context of a normal prothrombin time (PT) and bleeding time. PTT tests are the first blood test done when haemophilia is indicated. However, the diagnosis is made in the presence of very low levels of factor VIII. A family history is frequently present, although not essential. Recently, genetic testing has been made available to determine an individual’s risk of attaining or passing on haemophilia. Diagnosis of haemophilia A also includes a severity level, which can range from mild to severe based on the amount of active and functioning factor VIII detected in the blood. Factor VIII levels do not typically change throughout an individual’s lifetime. Severe haemophilia A is the most common severity, occurring in the majority of affected people. Individuals with mild haemophilia often experience few or no bleeding episodes except in the case of serious trauma (i.e. tooth extraction, or surgery).

• #18 Hemophilia: MedlinePlus GeneticsLock

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

  Another form of the disorder, known as acquired hemophilia, is not caused by inherited gene variants. This rare condition is characterized by abnormal bleeding into the skin, muscles, or other soft tissues, usually beginning in adulthood. Acquired hemophilia results when the body makes specialized proteins called autoantibodies that attack and disable coagulation factor VIII. The production of autoantibodies is sometimes associated with pregnancy, immune system disorders, cancer, or allergic reactions to certain drugs. In about half of cases, the cause of acquired hemophilia is unknown.

• #19 Thieme E-Journals – Seminars in Thrombosis and Hemostasis / Abstract

  https://doi.org/10.1055/s-0040-1722294

  There have been several recent reports of the development of acquired hemophilia in patients who received alemtuzumab treatment for multiple sclerosis. […] This monoclonal antibody is increasingly noted to be associated with secondary autoimmune disorders since its approval for use in multiple sclerosis a decade ago. […] With the addition of acquired hemophilia to this list, it may be useful to examine whether this unusual complication may shed some light on the pathogenesis of acquired hemophilia. […] Autoimmune disorders such as acquired hemophilia are characterized by the development of antibodies to self-antigens. […] This balance is upset in older individuals, in particular those in whom the tolerance may fail and lead to an autoimmune condition like acquired hemophilia. […] Alemtuzumab depletes the T-cells as part of its mechanism of action.

• #20 Thieme E-Journals – Seminars in Thrombosis and Hemostasis / Abstract

  https://doi.org/10.1055/s-0040-1722294

  During this period, there is a surge of hyperreactive, antibody-producing B cells which can generate autoantibodies that are not cleared by the (reduced/regenerating) regulatory T cells. […] This double-hit model may account for the rarity of autoimmune disorders with alemtuzumab use and also the peak incidence 2 to 3 years after alemtuzumab administration. […] The above model would also support the usefulness of rituximab as a therapeutic agent since antibody production by hyperreactive B cells would be blocked by this B-cell-depleting drug. […] In summary, case reports linking acquired hemophilia development following alemtuzumab use stimulate interest in examining regulatory T cells’ role in its pathophysiology.

• #21 Inhibitors in hemophilia: Mechanisms, prevalence, diagnosis, and eradication – UpToDate

  https://www.uptodate.com/contents/inhibitors-in-hemophilia-mechanisms-prevalence-diagnosis-and-eradication

  One of the most challenging aspects of hemophilia management is the care of a patient who develops an inhibitor, an antibody directed against infused factor that inhibits the function of the factor. Individuals who develop inhibitors often can no longer use standard factor replacement to treat bleeding or to provide prophylaxis against bleeding. […] This topic discusses the mechanisms and risk factors for inhibitor development and the routine management of individuals with inhibitors, including immune tolerance induction (ITI) to eradicate inhibitors and alternative types of prophylaxis.

• #22 Current Challenges in the Management of Hemophilia

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

  Factor IX is produced entirely by the liver. […] 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. […] This variability in inhibitor type, level, and development is likely reflective of the heterogeneity of genetic mutations in hemophilia, particularly in hemophilia A. […] Gene therapy can potentially eliminate the challenges associated with factor replacement therapy. For example, inserting the gene for FIX into a patient’s tissue could permanently restore clotting factor levels in the circulation for the life of the patient. Hemophilia B is an ideal target for gene therapy because it is caused by diminished function of a single protein, which in turn is caused by alteration (mutation or deletion) of a single gene. […] Therefore, restoring a functional copy of the affected gene could potentially ameliorate the clinical manifestations of the disease.

• #23

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

  A possible explanation for a milder phenotype in HB patients may lie in differences in the molecular characteristics and different pharmacokinetics of FVIII and FIX proteins. […] Altogether, the information available so far on the pharmacokinetic and pharmacodynamic characteristics of FIX suggest some potential mechanisms that could explain a difference in bleeding tendency between HB and HA patients. […] The occurrence of high affinity anti-FVIII or anti-FIX antibodies that neutralize the activity of the infused clotting factor is a major complication of replacement therapy in hemophilia patients. […] Overall, it is successful in approximately 60-70% of HA patients. The results of a randomized, controlled study comparing high-dose (200 IU/Kg/day) and low-dose (50 IU/Kg/3 times a week) protocols in a cohort of severe HA patients with high-titer inhibitor showed a similar overall success rate and no statistically significant differences in time to achieve tolerance, but the median time to negative inhibitor titer was 4.6 months (range: 2.8-13.8).

• #24 Selected Important Safety Information for NovoSeven® RT

  https://www.novomedlink.com/rare-bleeding-disorders/products/treatments/novosevenrt/about/pharmacology.html

  NovoSeven RT is recombinant Factor VIIa. It can support thrombin generation for patients with congenital hemophilia A or B with inhibitors. […] NovoSeven RT enters the bloodstream and targets the site of injury. It can support thrombin generation for patients with congenital hemophilia (FVIII or FIX deficiency) who have inhibitors to replacement factor. […] NovoSeven RT binds directly to activated platelets, activating FX to produce FXa. FXa complexes with other factors to convert prothrombin to thrombin. […] The burst of thrombin leads to the formation of fibrin, which is the foundation of a stable clot. […] NovoSeven RT resolves the bleed by allowing the formation of a stable hemostatic plug.

• #25 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.

• #26 Pathogenesis and Treatment of Hemophilia | CoLab

  https://colab.ws/articles/10.1007%2F978-981-10-3886-0_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. […] Development of this therapy had improved the quality of life of hemophiliacs more dramatically than before. […] There remain some issues such as frequent intravenous injection, however. […] However, in 2030% 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.

• #27 Haemophilia – Irish Haemophilia Society

  https://haemophilia.ie/about-bleeding-disorders/haemophilia/

  Haemophilia is an inherited bleeding disorder in which there is a life-long defect in the clotting mechanism of the blood. In haemophilia one of the clotting factor proteins important for blood clotting is either partly or completely missing. […] People with haemophilia bleed for a longer period of time than those without haemophilia. People with haemophilia may also experience what are known as spontaneous bleeds, whereby they bleed into joints and muscles without having incurred an injury. […] Most bleeding in haemophilia occurs internally, into the joints or muscles. The joints that are most often affected are the knee, ankle and elbow. Repeated bleeding without prompt treatment can result in long term damage to the joint or muscle. When bleeding occurs in a vital organ, especially the brain, this can be very serious.

• #28 Hemophilia | Calgary Guide

  https://calgaryguide.ucalgary.ca/hemophilia/hemophilia-2/

  Hemophilia: Pathogenesis and clinical findings […] Genetic defect on the X chromosome affecting the factor VIII or factor IX gene […] Deficiency of functional factor VIII (Hemophilia A) or factor IX (Hemophilia B) in blood […] Insufficient clotting action when faced with a bleeding challenge […] Factor VIII/IX deficiency slows intrinsic clotting pathway […] Chronic hemophilia arthropathies (main contributor to disability and reduced QoL) […] In severe patients, repeated joint bleeds common […] Recurrent bleeding into joints damages cartilage.

• #29 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. […] 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. […] Further elucidation of the shared mechanisms underlying abnormal bone homeostasis in the absence of FVIII or FIX is needed to guide evidence-based approaches to the screening and treatment of the prevalent bone defects in hemophilia A and B.

• #30 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

  Tight control of bone structure and phosphocalcic balance is essential to maintain skeletal integrity and depends upon the proper coordination of bone osteoclast and osteoblast activity. […] The FVIII.VWF complex may act as an anti-resorption factor both in normal physiology and following hemarthrosis. […] Our findings demonstrate that mice congenitally deficient for either factor VIII or factor IX demonstrate similar deficits of BMD and trabecular bone integrity. […] Hemarthrosis exacerbated these congenital BMD and structural differences in hemophilia mice. […] The joint swelling that developed in FVIII/ mice was qualitatively different from WT and similar to VWF/ in regards to the persistence of swelling throughout the first week following the induced hemorrhage. […] 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.

• #31 Hemophilia: Causes, types, symptoms, and treatment

  https://www.medicalnewstoday.com/articles/154880

  Hemophilia is typically an inherited disorder, which means that a person is born with the condition. The CDC states that hemophilia is a sex-linked recessive condition. […] The genetic change that causes hemophilia is a recessive change in the X chromosome. Males have one copy of the genes in the X chromosome, and females have two copies. […] As a result, males have a 50% chance of developing hemophilia if their biological mother is a carrier of the gene. If they inherit the affected X chromosome, they have hemophilia. […] Rarely, a person may develop acquired hemophilia. They typically have no family or personal history of hemophilia. Instead, acquired hemophilia is an autoimmune condition where the body’s immune system starts to attack the clotting factors found in the blood. […] Hemophilia A occurs due to a lack of clotting factor VIII. This type of hemophilia is four times more common than hemophilia B.

• #32 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.

• #33 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.

• #34 Haemophilia – Don’t Forget the Bubbles

  https://dontforgetthebubbles.com/haemophilia/

  Haemophilia is a clotting factor deficiency. Clotting factors are proteins in the blood that help control bleeding. When you bleed, your clotting factors form a blood clot. Haemophilia is a bleeding disorder due to low levels of a specific clotting factor. […] The severity of haemophilia is determined by the percentage of clotting factor remaining in the bloodstream, the baseline factor level. […] Factor inhibitors can develop, reducing the effectiveness of treatment. During treatment, some patients develop antibodies against Factor VIII/IX. These antibodies are called inhibitors and develop in approximately 25% of haemophilia A patients (half transient and half persistent) and 3% of haemophilia B patients (associated with significant morbidity and the unique occurrence of anaphylactic reactions and nephrotic syndrome). […] Emicizumab (or Hemlibra) is a modern treatment for haemophilia A. Emicizumab is a humanised bispecific antibody that does Factor VIIIs job by binding activated Factor IX to inactive Factor X, thus activating it.

• #35 Hemophilia – Knowledge @ AMBOSS

  https://www.amboss.com/us/knowledge/hemophilia/

  Hemophilia is caused by an X-linked recessive defect (inherited or spontaneous mutation) or antibody production against clotting factors. […] The degree of bleeding and, therefore, severity of hemophilia depends on residual factor activity levels; normal reference activity is 50%. […] Emicizumab: Mechanism of action: bridges activated factor IX and factor X by binding to both factors (thereby replacing the deficient factor VIII) activation of factor X restored clotting cascade.

• #36 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

  Concizumab (mAb 2021) is an IgG4 monoclonal antibody targeting tissue factor pathway inhibitor (TFPI). […] Gene therapy presents a novel and effective treatment modality for haemophilia, potentially bypassing complications of other therapies. Gene therapy regimens consist of single infusions of a viral vector, which result in transduction of a gene coding for the deficient factor into patient hepatocytes. […] Current gene therapy regimens for haemophilia predominantly utilise adeno-associated virus (AAV) vectors to deliver the required gene.

• #37 Learn About The Latest Developments In Hemophilia Care

  https://hemhorizonhcp.com/

  Gene therapy for hemophilia involves the use of a viral vector to deliver the gene to liver cells. […] 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. […] TFPI inhibition offers the potential to achieve clotting even when factor VIII or factor IX is absent or deficient. […] 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. […] 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.

• #38 Hemophilia

  https://patienteducation.asgct.org/disease-treatments/hemophilia

  Hemophilia is a genetic disease that prevents blood from clotting properly leading to prolonged internal and external bleeding. […] Hemophilia A is caused by a gene variant that leads to a deficiency (not enough) of clotting factor VIII. […] Hemophilia B is caused by a gene variant that leads to a deficiency (not enough) of clotting factor IX. […] Gene therapy aims to be given one time with the goal of eliminating the need for recurring treatments. Gene therapy for hemophilia A or hemophilia B would deliver a working copy of the faulty gene into the liver cells with instructions to produce the missing clotting factor. […] By delivering the vector with the working gene into liver cells, the cells is given instructions to produce stable amounts of clotting factors to control bleeds. Gene therapy has been shown to reduce the rate of annual bleeds with hopes of improving the quality of life for people living with the disease.

• #39 Hemophilia

  https://patienteducation.asgct.org/disease-treatments/hemophilia

  Researchers are also exploring the use of gene editing to correct clotting factor production. Gene editing goes directly inside the cell to edit pieces of DNA using technology that is highly precise to make this change. […] Gene therapy can be an alteration for the lifetime, so people should be aware that there could be long term effects (both good and bad) that are not known at this time. […] Gene therapy aims to be a one-time treatment with lasting positive effects that slow or stop disease progression for a lifetime. However, there is no guarantee. If gene therapy is received earlier in the course of disease, it has the potential to stop damage before it occurs.

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