Abstract - 2018 - Research and Practice in Thrombosis and Haemostasis
What Is Hemophilia? Symptoms, Causes, Diagnosis, And Treatment
It's common for people who have or have had family members with hemophilia to get their baby boys tested for the condition shortly after they're born. About one-third of babies who have hemophilia have no relatives with the disorder, so infants may be evaluated if they show symptoms.[9]
Ideally, testing is planned before the baby's birth so that a blood sample can be drawn from the umbilical cord. Umbilical cord blood testing is better at discovering low levels of factor 8 than at finding low levels of factor 9, because factor 9 levels are not at a normal level until a baby is at least 6 months old.
Two types of tests are used for diagnosis: screening tests and clotting factor tests, which are also called factor assays.
Screening TestsScreening tests are blood tests that reveal whether the blood is clotting properly. There are several types of screening tests for hemophilia:
Complete Blood Count (CBC) This test measures the amount of hemoglobin (the red pigment inside red blood cells that carries oxygen), the percentage of blood volume occupied by red blood cells (called the hematocrit), the size and amount of red blood cells, and the amounts of white blood cells and platelets in the blood. The CBC is normal in people with hemophilia, but if you have hemophilia and you have unusually heavy bleeding or bleed for a long period of time, the hemoglobin and the hematocrit can be low.
Activated Partial Thromboplastin Time (APTT) Test This test reveals how much time it takes for blood to clot; specifically, it measures the clotting ability of factors 8, 9, 11, and 12. If any of these clotting factors are diminished, it takes longer than normal for the blood to clot. The results of the APTT test will show a longer clotting time if you have hemophilia A or B.
Prothrombin Time (PT) Test This test also reveals how long it takes for blood to clot. It focuses on the clotting ability of factors 1, 2, 5, 7, and 10. If any of these factors are in short supply, it takes longer for the blood to clot. Most people with hemophilia A and B will have normal results on this test.
Fibrinogen Test This test also reveals how well a person can form a blood clot. Fibrinogen is also known as clotting factor 1.
Clotting Factor TestsClotting factor tests, which are required to diagnose a bleeding disorder, reveal the type of hemophilia and how severe it is. They check the levels of factor 8 or factor 9 in the blood, and show whether you have mild, moderate, or severe hemophilia.
How Hemophilia C Is DiagnosedHemophilia C can be diagnosed via genetic testing.
Prognosis of Hemophilia People with hemophilia are likely to have a relatively normal life expectancy and quality of life if they receive the treatment that they need and are knowledgeable about their condition.[10]
Some people with hemophilia develop inhibitors, which are antibodies that the immune system creates to attack the clotting factors in hemophilia treatment.[11] This happens when the body mistakes the clotting factors in the treatment for foreign intruders. Inhibitors can negatively affect the course of hemophilia, but new medications are currently being developed.
[10]
Around 60 to 70 percent of people with hemophilia A have severe hemophilia, and about 15 percent have moderate hemophilia.[10] The rest have a mild form of the condition.
Acquired hemophilia often goes away with treatment.[11]
Treatment Options For Hemophilia A
Hemophilia A is a genetic bleeding disorder caused by a deficiency in clotting factor VIII. Treatment focuses on managing bleeding episode symptoms with clotting factor replacement therapy, immunotherapies, and gene therapy.
Hemophilia A results from genetic variations to the F8 gene on a person's X chromosome. The F8 gene directs the production of clotting factor VIII, one of many proteins involved in blood clotting during bleeding.
Without enough factor VIII, blood clotting becomes impaired. Clots may not form quickly enough or provide enough structural stability to support wound closure. Bleeding does not speed up in hemophilia A but can persist for longer.
While there is no cure for hemophilia A, various treatment approaches can help manage it. This article looks at the standard treatments used in hemophilia A as well as emerging and novel therapies.
The first-line approach to treating hemophilia A involves replacing missing factor VIII. It involves supplementing clotting factor VIII from human blood plasma (plasma-derived factor VIIII) or factor VIII made in a laboratory using genetic engineering (recombinant factor VIII).
Plasma-derived factor VIII goes through an extensive purification process to reduce the risk of transmitting infectious agents, but a small risk does remain.
Recombinant factor VIII is considered much safer. It does not contain components of human blood.
Factor VIII replacement therapy involves an intravenous infusion.
Depending on the severity of hemophilia A, a person may receive infusions as needed during a bleeding episode, known as on-demand treatment, or on a regular schedule proactively, known as prophylaxis therapy.
On-demand treatment may also consist of desmopressin. Desmopressin is a synthetic hormone that stimulates the release of factor VIII contained within the structures of blood vessels. Doctors can use it in mild hemophilia to help manage a bleeding episode.
Results from a 2022 cohort study suggest that desmopressin can be effective in controlling minor bleeds, especially when added to factor VIII replacement infusions.
Transfusions of fresh frozen human plasma or whole blood only take place if factor VIII concentrates are not available or there is a need to replace additional blood components.
Antifibrinolytic agents are supplementary medications to prevent blood clots from breaking down. Doctors typically use them during minor surgeries, dental procedures, or traumatic injuries to help with bleeding.
Tranexamic acid and aminocaproic acid are antifibrinolytic agents commonly used in hemophilia A.
Doctors consider genetic therapy and other second-line treatments for hemophilia A when a person develops inhibitors to traditional factor VIII replacement. Inhibitors are antibodies the immune system makes that attack replacement factor VIII as if it were a bacteria or virus.
Gene therapy
In hemophilia A, gene therapy aims to counteract the genetic alteration that causes factor VIII deficiency. Doctors do this by inserting a functional copy of the F8 gene into a person's cells using vectors, small molecules that can deliver genetic material into a cell.
The most common vectors in gene therapy for hemophilia A are called adeno-associated virus (AAV) vectors. They use harmless viral variants as their mode of transport.
Gene therapy works by providing a functional copy of F8, which allows the body to produce its own factor VIII.
In 2023, the Food and Drug Administration (FDA) approved the one-time gene therapy Roctavian (valoctocogene roxaparvovec) for hemophilia A treatment. It uses an AAV vector to transport a functional copy of F8 into a person's liver cells.
A 2024 report on the phase 1 clinical trial results of valoctocogene roxaparvovec reported good safety and efficacy during a 7-year follow-up, with the majority of participants maintaining an adequate level of clotting function from the treatment.
Gene therapy may have more benefits than just providing clotting factor VIII. A 2023 review suggests gene therapy in hemophilia A can help reduce the presence of inhibitors through a process called immune tolerance induction (ITI).
In theory, by allowing the body to make its own controlled amounts of factor VIII with genetic modification, a person's immune system could be trained to become more tolerant of synthetic factor VIII replacement.
Immunotherapies
Immunotherapies are treatments that target, modify, or enhance a person's immune function to help treat hemophilia A.
One current targeted immunotherapy medication in hemophilia A is emicizumab.
Emicizumab is a bispecific monoclonal antibody. It works by mimicking the action of factor VIII, which allows the body's clotting cascade to complete and produce stable clots.
Sometimes, suppressing the immune system can benefit a person with inhibitors. In these circumstances, doctors use immunosuppressive treatments (ISTs). ISTs focus on eliminating inhibitor antibodies that compromise traditional therapies.
Standard medications in ISTS include:
Bypassing agents
Bypassing agents work to improve a person's clotting function by enhancing other pathways involved in the clotting process. As with traditional replacement therapy, doctors can administer them on-demand or as prophylaxis treatment.
Examples of available bypassing agents include:
Hemophilia A is a genetic bleeding disorder caused by a genetic alteration in the F8 gene, which results in clotting factor VIII deficiency. Without enough factor VIII, a person's blood is unable to form stable clots, and bleeding can become prolonged.
Replacement of factor VIII is the mainstay of hemophilia A treatment. Doctors can supplement this with other therapies to support clotting processes and address challenges with the development of antibodies called inhibitors.
Gene therapy, immunotherapy, and bypassing agents are all second-line treatments that can help improve outcomes.
Centessa Discontinues Development Of SerpinPC For Hemophilia
Centessa Pharmaceuticals is discontinuing the clinical development of SerpinPC, its experimental under-the-skin therapy for people with hemophilia A and hemophilia B with or without inhibitors. The therapy was being evaluated in several Phase 2 clinical trials.
The decision follows the recent approval of Pfizer's Hympavzi (marstacimab), an antibody-based treatment that's designed to increase the production of thrombin, a protein that promotes blood clotting, in a mechanism similar to SerpinPC's.
Although Centessa's treatment was found to be safe and well tolerated in the Phase 2 PRESent-2 trial (NCT05789524), the company determined that more time and investment would be required to continue developing its hemophilia treatment candidate, and decided the approval of Hympavzi made that not worth the effort.
The company will explore potential strategic alternatives for SerpinPC and is channeling its resources to boost the development of its orexin receptor 2 (OX2R) agonists for several sleep-waking disorders, including narcolepsy and excessive daytime sleepiness.
"Moving forward, we intend to prioritize our resources and reallocate net savings of approximately $200 million associated with the planned commercial launch of SerpinPC toward expanding our potential best-in-class OX2R agonist franchise, where we see significant opportunities to both address unmet patient needs and create shareholder value," John Crowley, Centessa's chief financial officer, said in a company press release.
Favorable responses to Centessa's SerpinPCHemophilia is mainly caused by mutations in genes that encode proteins, called blood clotting factors, needed for the blood to clot. In each type of hemophilia, one of these factors is missing or malfunctions, making patients susceptible to excessive, prolonged, or spontaneous bleeding. Hemophilia A is caused by a deficiency in factor VIII, while hemophilia B is driven by a lack of factor IX.
Replacement therapies that provide patients with their missing clotting protein are considered the standard treatment for hemophilia. Some patients develop inhibitors, or neutralizing antibodies against the clotting factors, however, which can reduce their efficacy.
SerpinPC reduces the levels of activated protein C, which normally regulates blood clotting by limiting the production of thrombin, an enzyme involved in coagulation. Through this, SerpinPC could help increase thrombin production and promote blood clotting, regardless of disease severity or the presence of inhibitors.
The therapy was evaluated in a Phase 1/2a trial (NCT04073498) where it was given by injections under the skin, or subcutaneously, at various dosing regimens. It was found to have a favorable safety and tolerability profile in healthy volunteers and men with hemophilia A or B. The treatment also significantly decreased the total annualized bleed rates by 96% and spontaneous bleeds by 95% after up to three years of treatment.
The safety and efficacy of different dosing regimens of SerpinPC were also being evaluated in a group of adolescents and adults with moderate to severe hemophilia B without inhibitors, or severe hemophilia A with or without inhibitors who participated in the PRESent-2 trial. In another Phase 2 clinical trial, called PRESent-3 (NCT05789537), the therapy was being tested in people with hemophilia B with inhibitors.
The company was also conducting a long-term open-label extension study called PRESent-6 (NCT06568302) to evaluate the safety and efficacy of SerpinPC for up to 25 months in patients who had completed other trials of the therapy.
SerpinPC was granted fast track and orphan drug status by the U.S. Food and Drug Administration for hemophilia B. The designations are intended to speed the development of treatments that have the potential to fulfill an unmet need in serious and rare disorders, respectively.
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