Hemophilia (from ancient Greek αἷμα haima "blood" and φιλία philia "tendency"), also called hemophilia , is a hereditary disease in which blood clotting is impaired. The blood from wounds does not clot or does so slowly. Frequently, there is also spontaneous bleeding that occurs without visible wounds. Hemophilia occurs mainly in men. Affected people are colloquially referred to as hemophiliacs .
In the narrower sense, there are two known forms of haemophilia as well as other clinical pictures that are sometimes indistinctly subsumed under this term:
- Haemophilia A (X-linked recessive hereditary coagulation defect): This almost invariably affects men, as they only have one X sex chromosome, while women have two of them. Here there is a deficiency of factor VIII (antihemophilic globulin).
- Haemophilia B (X-linked recessive inheritance): Deficiency of factor IX (Christmas factor) of the coagulation cascade with different courses from birth (severe, moderate, mild). Due to this deficiency, blood clotting can only proceed very slowly.
- The very rare autosomal recessive hereditary coagulation defect (e.g. Stuart-Prower factor deficiency, factor X of the coagulation cascade) can be equally pronounced in both sexes, since the same number of autosomes (non-sex-linked chromosomes) occur in both sexes .
- Parahemophilia (hypoproaccelerinaemia, Owren syndrome): autosomal recessive hereditary disease due to a lack of coagulation factor V ( proaccelerin ).
- Angiohemophilia ( Willebrand-Jurgens Syndrome ): It is the most common autosomal dominant inherited coagulation disorder. It arises from a structural defect or a lack of the Von Willebrand factor of varying degrees. Von Willebrand factor is a carrier protein for blood coagulation factor VIII .
- Haemophilia C (Rosenthal syndrome): Here factor XI ( PTA ) of the coagulation cascadeis missing, so that bleeding in joints or minimal injuries occurs easily, especially in children. As with hemophilia A and B, the Quick value is typically normal, while the PTT is extended depending on the severity of the deficiency.
Hemophilia patients bleed longer than healthy people. Depending on the severity, spontaneous bleeding can occur, i. H. without corresponding injury. Such spontaneous bleeding can also occur in healthy people, but they heal quickly and unnoticed. The bleeding can occur anywhere, but certain locations are typical in haemophilia patients, e.g. B. Hemorrhage in the joints.
Serious or severe bleeding caused by an accident can only be kept within limits by administering coagulation factors. If this help is not available in time, it can (even with less severe injuries) mean death by bleeding to death.
In the most common sub-forms of hemophilia, cuts, tears and abrasions initially do not lead to greater blood loss than in healthy people, as the crust formation initially works thanks to the intact blood platelets ( thrombocytes ). Only the delayed blood clotting leads to the fact that the crust can break open again and again and, depending on the severity of the hemophilia, the bleeding is stopped only very slowly or not at all. Subcutaneous or intramuscular hematomas can therefore occur even without external influence .
Female carriers of the genetic defect (so-called conductors) may have an increased bleeding tendency, which can be seen in increased menstrual bleeding , a tendency to bruise (hematomas), in minor interventions such as tooth extractions or during or after childbirth . In rare cases, bleeding similar to that of male patients (e.g. joint bleeding) may occur.
Joint bleeding and its consequences
A common location for bleeding is the joints ( hemarthrosis ). The first bleeding in a joint (also known as initial bleeding) is often caused by an accident / trauma . The large joints are particularly affected. The synovial membrane ( membrana synovialis ) releases enzymes that break down the blood in the joint. In the case of large-volume effusions, the synovia ("joint fluid") increases in size and is more permeated with blood vessels. This increases the likelihood of subsequent bleeding or inflammation. A cycle of inflammation and bleeding is set in motion and a so-called hemarthrosis develops ; In particular, unguided movements as well as torsions and overstretching (also at night), "kinking", stumbling, etc. can result in further joint bleeding (usually ankle, knee, elbow, shoulder or rarely hip bleeding), which usually results in severe pain connected is. Since effective prophylactic therapies have only been available for about 30 years, the frequent bleeding events in older patients usually result in joint stiffness, e.g. T. most severe type, early osteoarthritis - the possible surgical interventions (such as knee arthroscopy , synovectomy up to endoprosthesis (joint replacement)), but also orthopedic aids (orthopedic shoes), walking aids, etc. a. make necessary - as well as malformations of the muscles and bone structure . However, through constant physiotherapy , the mobility of the joints can be kept at a certain level of stress or improved.
Muscle bleeding and its consequences
Muscle bleeding occurs less spontaneously than joint bleeding and is usually caused by trauma. Depending on the location and size of the muscle, however, they can become extremely tedious and lead to crippling through irreversible muscle damage. Muscle bleeding can also occur after intramuscular vaccinations, e.g. B. in the gluteal muscle, upper arm muscle. Blood patients should therefore only receive vaccinations under the skin ("subcutaneous"). Typical dangerous muscle bleeding can be found, for example:
- in the psoas muscle (runs from the abdomen through the pelvis to the leg, so that it is almost impossible to “hold still” during the healing process and the bleeding often returns after it appears to have healed). The resulting pain was confused with appendicitis, especially before the introduction of ultrasound examinations (so-called "pseudoappendicitis").
- in the calf muscle (calf bleeding leads to a shortening of the muscle and thus to the equinus, which in turn can lead to increased stress on the calf when walking and further bleeding)
- in the forearms (bleeding from the forearms can press on the hand nerves and, in addition to extreme pain, cause immobility and misalignment of the hands)
Bone bleeding and pseudotumor
Rarely, repeated bleeding into the bones can lead to increasing osteolysis , with swelling and widening of the bone and a soap-bubble-like appearance in the X-ray, which can lead to the suspicion of a bone tumor and which is why it is referred to as a "hemophilic pseudotumor". The loss of stability leads to pathological bone fractures and sintering, which induce renewed bleeding and can also contribute to shortening, especially in the lower extremities. For therapy, only a complete allogeneic bone replacement with possible joint replacement ( endoprosthesis ) of adjacent joints is possible.
Treatment with the missing factor VIII (hemophilia A) or factor IX (hemophilia B)
The process for producing an antihemophilic factor was discovered in 1964 by Judith Graham Pool of Stanford University and was first approved in the USA in 1971 under the name Cryoprecipitated AHF at the request of the Hoxworth Blood Center of the University of Cincinnati Medical Center . The process in question is known as cryoprecipitation . Along with the development of a system for transporting and storing human plasma in 1965, this marked the first time an effective treatment for hemophilia became available.
The therapy for hemophilia to stop bleeding, which was in use until around 1970 , generally consisted of giving direct blood donation, blood reserves or blood plasma for heavy and acute bleeding, cooling hematomas, and coagulating bleeding wounds with fibrin obtained from bovine blood , which succeeded relatively rarely.
Current therapy generally consists in substituting the missing or defective factor prophylactically or if necessary, bleeding can be largely excluded and the patient can lead a relatively normal life, but z. B. must refrain from sports such as athletics, boxing, winter sports and extreme physical stress. The therapy takes place z. B. in cases of hemophilia A, B or Willebrand syndrome by self-treatment (intravenous) with the missing factors. These factors were mostly obtained from human blood plasma until around 2002, although in the past u. a. many hemophiliacs were also infected with HIV , hepatitis C and B and other viruses. This became known as the so-called " blood scandal ". However, the possibility of infection has been virtually ruled out since around 1988 (the hepatitis C virus was only discovered in the late 1980s) if the existing methods of blood purification and virus inactivation are used as intended.
Factor VIII (haemophilia A) has also been genetically engineered since about 1989 in order to protect against contamination of factor VIII z. B. to offer with viruses and to ensure adequate supply of patients at all times. These so-called recombinant concentrates are considered to be safer than preparations made from human blood plasma. The companies Bayer , Takeda and Pfizer are the main suppliers of such recombinant preparations.
A further development of these preparations consists in the extended half-life so that injections no longer have to be carried out every 2–3 days. B. Damoctocog alfa pegol (trade name: Jivi; manufacturer Bayer) and Turoctocog alfa pegol (trade name Esperoct ; manufacturer Novo Nordisk ) approved in the EU in June 2019 .
The main complication in hemophilia A therapy today is the formation of neutralizing antibodies against factor VIII (FVIII), the so-called inhibitory antibodies or inhibitors . The antibodies reduce the effect of the given FVIII very strongly, so that the necessary increase in the factor level is not achieved, and bleeding occurs again as a result. This complication is also known as inhibitory hemophilia or immune inhibitor hemophilia . Worldwide studies show that about 30% of treated patients or hemophiliacs develop inhibitory antibodies. It is also discussed whether the inhibition occurs solely through the blocking of the FVIII activity, or whether there is an increased clearance of the FVIII through the recognition of the antibodies.
Inhibitor hemophilia can also occur with substitution of factor IX, i.e. in the treatment of hemophilia B. However, it occurs much less often - in 2 to 5 percent of cases.
Japanese researchers have succeeded in developing a so-called bispecific , monoclonal antibody that takes on the role of factor VIII and is not inactivated by antibodies (inhibitors) directed against factor VIII. In a small dose-finding study with 18 patients over 12 weeks, an effect of the treatment could also be shown in antibody-producing patients. The development of this antibody, known as emicizumab , is now very advanced. The Japanese pharmaceutical company Chugai further developed emicizumab together with Roche and Genentech . In November 2017, emicizumab was approved by the US FDA . It was approved for Europe in February 2018. Emicizumab has also proven itself in patients without inhibitory antibodies. In March 2019, approval was extended for patients of all ages with severe haemophilia A, even without inhibitors.
Compared to substitution with factor VIII, it has the advantage that it only has to be administered subcutaneously once a month and not intravenously two to three times a week. Compared to on-demand therapy, weekly prophylactic treatment with emicizumab reduced the number of treatment-requiring bleeding by 96 percent and by 97 percent for bi-weekly treatment. The number of joint hemorrhages that required treatment was also reduced by 95 percent. A four-week therapy also achieved similarly good results.
Research has been going on for decades to develop gene therapies that could replace lifelong hemophilia therapy with a single treatment. In December 2017, a promising phase I / II study was published in the New England Journal of Medicine (NEJM), in which a gene therapy for hemophilia B over a longer period of time proved to be effective for the first time. In January 2020, a study on gene therapy in 15 adults with severe haemophilia A was published in the NEJM. The summary says: Treatment with AAV5-hFVIII-SQ led to a sustained, clinically relevant benefit, measured by a significant reduction in annual bleeding rates and the complete waiver of prophylactic factor VIII in all participants.
The disease is inherited as a gonosomal X recessive trait. Women can be carriers of the inheritance of haemophilia A or B without suffering from the disease themselves. For example, a wearer ( Konduktorin ) of the defective gene for hemophilia, in which the feature is not pronounced, gets sons, where the probability is 50% to be hemophiliacs (see also genetic information ). If this carrier has daughters, statistically 50% of them can pass the gene on to the next generation without being affected by this disease themselves. As soon as these girls have male offspring again, it is then also possible that these girls are hemophiliacs. Due to this probability, however, the disease can also skip several generations if daughters were repeatedly present as carriers. If male hemophiliacs have sons, they do not pass the disease on to them, as it is inherited on the X chromosomal. Male hemophiliacs can only pass the disease on to their daughters.
In rare cases, haemophilia A or B is possible in women. If the father is a hemophiliacs and the mother is a carrier and the daughter inherits the trait-bearing X chromosome from the mother (50 percent probability), the daughter will be a hemophiliacs. Furthermore, there is the possibility of developing hemophilia as a woman in connection with Turner syndrome , since in this case only one X chromosome is present. However, there are only isolated, mostly very poorly documented cases of haemophilia in women. The occasional mention of haemophilic women in literature and fiction is explained by a miscalculation of other coagulation disorders.
Probably the earliest mention of the disease can be found in the 5th century in the Talmud , which exempts a boy from ritual circumcision, whose two brothers died during circumcision.
In the past, an above-average number of members of the European nobility and ruling families suffered from haemophilia, which is why it was also called the "disease of kings". Well-known examples of this are the British royal and Russian royal families . The starting point as the carrier of the disease was probably Queen Victoria of Great Britain , whose granddaughter Alix von Hessen-Darmstadt married the Tsar Nicholas II and passed the disease on to their son Alexei , the last Tsarevich .
- Mario von Depka Prondzinski, Karin Kurnik: Hemophilia. A guide for patients . Trias-Verlag Stuttgart, 2008, ISBN 978-3-8304-3432-0 .
- Mario von Depka: blood clotting. Current aspects of physiology, pathophysiology, clinic, diagnostics, prophylaxis and therapy . UNI-MED, Bremen / London / Boston 2002, ISBN 3-89599-554-1 .
- Stephen Pemberton: The Bleeding Disease: Hemophilia and the Unintended Consequences of Medical Progress . The Johns Hopkins University Press, 2011, ISBN 1-4214-0115-0 .
- Austrian Hemophilia Society
- Swiss Hemophilia Society
- German Hemophilia Society
- World Federation of Hemophilia (English, Spanish, French)
- Interest group haemophiles e. V. (patient association for the clinical picture haemophilia)
- Siegfried Sormann: Hemophilia (hemophilia). In: NetDoktor.at. October 2004, archived from the original on March 26, 2009 .
- Astrid Leitner: Hemophilia (blood disease). In: NetDoktor.at. October 2019 .
- Zeng Li, Xisheng Weng: Hemophilic pseudotumor New England Journal of Medicine 2020, Volume 382, Issue 21 May 21, 2020, Page 2033, DOI: 10.1056 / NEJMicm1914118
- Judith G. Pool, Edwabd J. Hersh Gold, Albert R. cardboard Hagen: High-potency Antihæmophilic Factor Concentrate prepared from cryoglobulin Precipitate . In: Nature . tape 203 , no. 4942 , July 1964, ISSN 0028-0836 , p. 312-312 , doi : 10.1038 / 203312a0 ( nature.com [accessed May 20, 2019]).
- B. Nascimento, LT Goodnough, JH Levy: Cryoprecipitate therapy . In: British Journal of Anesthesia . tape 113 , no. 6 , December 2014, p. 922-934 , doi : 10.1093 / bja / aeu158 ( elsevier.com [accessed May 20, 2019]).
- Alphabetical List of Licensed Establishments Including Product Approval Dates as of 30-APR-2019 . FDA.
- Judith Graham Pool, Angela E. Shannon: Production of High-Potency Concentrates of Antihemophilic Globulin in a Closed-Bag System: Assay in Vitro and in Vivo . In: New England Journal of Medicine . tape 273 , no. 27 , December 30, 1965, ISSN 0028-4793 , p. 1443–1447 , doi : 10.1056 / NEJM196512302732701 ( nejm.org [accessed May 20, 2019]).
- Coagulation preparations for haemophilia A patients , accessed on November 12, 2019
- Genetically engineered factor VIII preparations with an extended half-life , accessed on November 12, 2019
- H. Renz-Polster , S. Krautzig: Basic textbook internal medicine . Urban & Fischer-Verlag Munich 2008, 4th edition, p. 342 ff. ISBN 978-3-437-41053-6 .
- Midori Shima, Hideji Hanabusa, Masashi Taki, Tadashi Matsushita, Tetsuji Sato et alia: Factor VIII – Mimetic Function of Humanized Bispecific Antibody in Hemophilia A N Engl J Med 2016; 374: 2044-2053May 26, 2016, doi : 10.1056 / NEJMoa1511769
- Positive phase III results for Roche's emicizumab in haemophilia A published in The New England Journal of Medicine , PM Roche of July 10, 2017, accessed on July 13, 2017
- Roche's Hemlibra significantly reduced bleeds in phase III study in haemophilia A , PM Roche, November 20, 2017, accessed on November 22, 2017
- FDA approves new treatment to prevent bleeding in certain patients with hemophilia A , PM FDA dated November 16, 2017, accessed on November 22, 2017
- Hemlibra® (emicizumab) receives EU approval for routine prophylaxis of haemophilia A with inhibitors against coagulation factor VIII , Roche PM dated February 28, 2018, accessed on February 28, 2018
- European Commission approves Roche's Hemlibra for people with severe haemophilia A without factor VIII inhibitors , PM Roche from March 14, 2019, accessed on March 16, 2019
- European Commission grants approval extension for Roche substance , PM Roche (German / only for experts) from March 14, 2019, accessed on March 16, 2019
- J Mahlangu, J Oldenburg, I Paz ‑ Priel, C Negrier, M Niggli, ME Mancuso, C Schmitt, V Jiménez ‑ Yuste, C Kempton, C Dhalluin, MU Callaghan, W Bujan, M Shima, JI Adamkewicz, E Asikanius, GG Levy, R Kruse ‑ Jarres: Emicizumab Prophylaxis in Patients Who Have Hemophilia A without Inhibitors. In: The New England Journal of Medicine . tape 379 , no. 9 , 2018, p. 811-822 , doi : 10.1056 / NEJMoa1803550 .
- Treatment of haemophilia A with Hemlibra® (emicizumab) , on the website of the German Haemophilia Society (DHG), accessed on November 20, 2019
- The latest development , www.haemophilietherapie.de, accessed on November 20, 2019
- Superiority of a Roche substance also compared to factor VIII preparations in the prophylaxis of haemophilia A , PM Roche (German / only for experts) from May 22, 2018, accessed on March 16, 2019
- George Lindsey A. et al .: Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant . In: New England Journal of Medicine . No. 377, 2017, pp. 2215–2227. doi : 10.1056 / NEJMoa1708538 .
- K. John Pasi, et al .: Multi Year Follow-up of AAV5 hFVIII SQ Gene Therapy for Hemophilia A . In: New England Journal of Medicine . No. 382, 2020, pp. 29-40. doi : 10.1056 / NEJMoa1908490 .