Haemophilia A

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Haemophilia A
Other namesHemophilia A
Protein F8 PDB 1d7p.png
Protein structure of coagulation factor VIII, of which its deficiency is the cause of haemophilia A.
Specialty Haematology
Symptoms Prolonged bleeding from common injuries [1]
CausesFactor VIII deficiency [2]
Diagnostic method Bleeding time, [2] coagulation screen, genetic testing
PreventionHepatitis B vaccine should be considered [2]
TreatmentFactor VIII, factor VIII inhibitors, emicizumab

Haemophilia A (or hemophilia A) is a blood clotting disorder caused by a genetic deficiency in clotting factor VIII, thereby resulting in significant susceptibility to bleeding, both internally and externally. This condition occurs almost exclusively in males born to carrier mothers due to X-linked recessive inheritance. Nevertheless, rare isolated cases do emerge from de novo (spontaneous) mutations. [2] [3] [4]

Contents

The medical management of individuals with hemophilia A frequently entails the administration of factor VIII medication through slow intravenous injection. This intervention aims to address and preempt additional bleeding episodes in affected individuals.

Signs and symptoms

Joint capsule Gray299.png
Joint capsule

Haemophilia A's phenotype has a quite wide range of symptoms encompassing both internal and external bleeding episodes. Individuals with more severe haemophilia tend to experience more intense and frequent bleeding, whereas those with mild haemophilia typically exhibit milder symptoms unless subjected to surgical procedures or significant trauma. Those with moderate haemophilia may display variable symptoms, falling within the spectrum between severe and mild forms.

One common early indicator of haemophilia is prolonged bleeding from venepuncture or heelpricks. These signs often prompt blood tests that confirm the presence of haemophilia. [5] In individuals, especially those with moderate or mild haemophilia, any form of trauma can trigger the first significant bleed. Haemophilia substantially elevates the risk of protracted bleeding from ordinary injuries, and in severe cases, bleeding can occur spontaneously without an apparent cause. Bleeding episodes can manifest anywhere in the body. Superficial bleeding resulting from abrasions or shallow lacerations may persist, with scabs easily breaking due to the deficiency of fibrin, potentially leading to re-bleeding. [1] While superficial bleeding poses challenges, more critical sites of bleeding include: [6]

Complications

One therapeutic conundrum is the development of inhibitor antibodies against factor VIII due to frequent infusions. These develop as the body recognises the infused factor VIII as foreign, as the body does not produce its own copy. In these individuals, activated factor VII, a protein in the extrinsic pathway of the coagulation cascade, can be infused as a treatment for haemorrhage in individuals with haemophilia and antibodies against replacement factor VIII. [1] [7]

Oral Manifestations

The oral manifestations are characterized by frequent bleeding of multiple sites, frequently seen as gingival and postextraction haemorrhages. The symptoms depend on the severity of haemophilia. In the case of severe haemophilia, patients may complain of multiple oral bleeding episodes throughout their life. Haemophilia patients are considered to be a special group of patients as routinely done procedures may be fatal in them. It was seen that almost 14% of all haemophilia patients and 30% of cases with a mild type of haemophilia have been diagnosed early following an episode of severe oral bleeding, of which the most common sites were the labial frenum and the tongue. [8]

Genetics

X linked recessive inheritance X recessive carrier mother.svg
X linked recessive inheritance

Haemophilia A is inherited as an X-linked recessive trait. It occurs in males and in homozygous females (which is only possible in the daughters of a haemophilic male and a carrier or haemophiliac female [9] ). However, mild haemophilia A is known to occur in heterozygous females due to X-inactivation, so it is recommended that levels of factor VIII and IX be measured in all known or potential carriers prior to surgery and in the event of clinically significant bleeding. [1] [10]

About 5-10% of people with haemophilia A are affected because they make a dysfunctional version of the factor VIII protein, while the remainder are affected because they produce factor VIII in insufficient amounts (quantitative deficiency). [10] Of those who have severe deficiency (defined as <1% activity of factor VIII), 45-50% have the same mutation, an inversion within the factor VIII gene that results in total elimination of protein production. [10]

Since both forms of haemophilia can be caused by a variety of different mutations, initial diagnosis and classification is done by measurement of protein activity rather than by genetic tests, though genetic tests are recommended for testing of family members once a known case of haemophilia is identified. [1] [10] Approximately 30% of patients have no family history; their disease is presumably caused by new mutations. [11]

Diagnosis

X-Ray- haemoarthritis Medical X-Ray imaging JDH05 nevit.jpg
X-Ray- haemoarthritis
Haemarthrosis on lateral view Medical X-Ray imaging JDG05 nevit.jpg
Haemarthrosis on lateral view

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. [12] 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). [1]

Severity

There are numerous different mutations which can cause haemophilia A, due to differences in changes to the factor VIII gene (and the resulting protein). Individuals with haemophilia often have some level of active clotting factor. Individuals with less than 1% active factor are classified as having severe haemophilia, those with 1–5% active factor have moderate haemophilia, and those with mild haemophilia have between 5–40% of normal levels of active clotting factor. [13]

Differential diagnosis

Two of the most common differential diagnoses are haemophilia B which is a deficiency in Factor IX and von Willebrand Disease which is a deficiency in von Willebrand factor (needed for the proper functioning of Factor VIII [14] ); haemophilia C is also considered. [3]

Treatment

Desmopressin Desmopressin ball-and-stick.png
Desmopressin
Recombinant factor VIII for self-treatment. Faktor-VIII.jpg
Recombinant factor VIII for self-treatment.

Most individuals with severe haemophilia require regular supplementation with intravenous plasma concentrate factor VIII or efanesoctocog alfa, a von Willebrand factor (VWF) independent, recombinant DNA-derived Factor VIII (FVIII) concentrate shown to prevent bleeding in children and adults. [15] [16] Treatment dosing and frequency of plasma concentrate Factor VIII may be variable and individually determined; [6] dosing of efanesoctocog alfa shown effective is an IV injection of once-weekly 50 IU per kilogram of body weight.

In children, an easily accessible intravenous port [17] may have to be inserted to minimise frequent traumatic intravenous cannulation. These devices have made prophylaxis in haemophilia much easier for families because the problems of finding a vein for infusion several times a week are eliminated. However, there are risks involved with their use, the most worrisome being that of infection, studies differ but some show an infection rate that is high. [18] These infections can usually be treated with intravenous antibiotics but sometimes the device must be removed, [19] also, there are other studies that show a risk of clots forming at the tip of the catheter, rendering it useless. Some individuals with severe haemophilia, and most with moderate and mild haemophilia, treat only as needed without a regular prophylactic schedule. [20] Mild haemophiliacs often manage their condition with desmopressin, a drug which releases stored factor VIII from blood vessel walls. [21]

Dental considerations

If numbing is necessary for dental procedures, the nerve block (typically to the inferior alveolar nerve) should only be given after raising clotting factor levels by appropriate replacement therapy, as there is a risk of bleeding into the muscles along with potential airway compromise due to a haematoma in the retromolar or pterygoid space. The intraligamental technique or interosseous technique should be considered instead of the mandibular block. Articaine has been used as a buccal infiltration to anaesthetize the lower molar teeth. A lingual infiltration also requires appropriate factor replacement since the injection is into an area with a rich plexus of blood vessels and the needle is not adjacent to bone. [22]

Gene therapy

In December 2017, it was reported that doctors had used a new form of gene therapy to treat haemophilia A. [23] [24] [25] Current treatment efforts utilize adeno-associated virus (AAV) vectors, however recent studies have found lentiviral vectors (LV) as being a more effective alternative. [26] [27]

Monoclonal antibodies

Monoclonal antibody emicizumab has been approved by the FDA in 2017 for therapy of hemophilia A. [28]

In July 2024, a recent study published in the New England Journal of Medicine demonstrated that efanesoctocog alfa, a bioengineered human factor VIII recombinant protein, prophylaxis for children with severe hemophilia A could have therapeutic benefit leading to effective bleeding prevention. [29] [30]

Prognosis

Two Dutch studies have followed haemophilia patients for a number of years. [31] [32] Both studies found that viral infections were common in haemophiliacs due to the frequent blood transfusions which put them at risk of acquiring blood borne infections, such as HIV, hepatitis B and hepatitis C. In the latest study which followed patients from 1992 to 2001, the male life expectancy was 59 years. If cases with known viral infections were excluded, the life expectancy was 72, close to that of the general population. 26% of the cases died from AIDS and 22% from hepatitis C. [32] However, these statistics for prognosis are unreliable as there has been marked improvement of infection control and efficacy of anti-retroviral drugs since these studies were done.[ citation needed ]

Epidemiology

Haemophilia A occurs in approximately 1 in 5,000 males, [10] while the incidence of haemophilia B is 1 in 30,000 in the male population, [10] of these, 85% have haemophilia A and 15% have haemophilia B. [10]

See also

Related Research Articles

<span class="mw-page-title-main">Haemophilia</span> Genetic disease involving blood clotting

Haemophilia, or hemophilia, is a mostly inherited genetic disorder that impairs the body's ability to make blood clots, a process needed to stop bleeding. This results in people bleeding for a longer time after an injury, easy bruising, and an increased risk of bleeding inside joints or the brain. Those with a mild case of the disease may have symptoms only after an accident or during surgery. Bleeding into a joint can result in permanent damage while bleeding in the brain can result in long term headaches, seizures, or an altered level of consciousness.

<span class="mw-page-title-main">Bleeding</span> Loss of blood escaping from the circulatory system

Bleeding, hemorrhage, haemorrhage or blood loss is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, vagina or anus, or through a puncture in the skin. Hypovolemia is a massive decrease in blood volume, and death by excessive loss of blood is referred to as exsanguination. Typically, a healthy person can endure a loss of 10–15% of the total blood volume without serious medical difficulties. The stopping or controlling of bleeding is called hemostasis and is an important part of both first aid and surgery.

<span class="mw-page-title-main">Haemophilia B</span> Genetic X-linked recessive bleeding disorder

Haemophilia B, also spelled hemophilia B, is a blood clotting disorder causing easy bruising and bleeding due to an inherited mutation of the gene for factor IX, and resulting in a deficiency of factor IX. It is less common than factor VIII deficiency.

<span class="mw-page-title-main">Coagulation</span> Process of formation of blood clots

Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The process of coagulation involves activation, adhesion and aggregation of platelets, as well as deposition and maturation of fibrin.

von Willebrand disease Medical condition

Von Willebrand disease (VWD) is the most common hereditary blood-clotting disorder in humans. An acquired form can sometimes result from other medical conditions. It arises from a deficiency in the quality or quantity of von Willebrand factor (VWF), a multimeric protein that is required for platelet adhesion. It is known to affect several breeds of dogs as well as humans. The three forms of VWD are hereditary, acquired, and pseudo or platelet type. The three types of hereditary VWD are VWD type 1, VWD type 2, and VWD type 3. Type 2 contains various subtypes. Platelet type VWD is also an inherited condition.

<span class="mw-page-title-main">Haemophilia C</span> Medical condition

Haemophilia C (also known as plasma thromboplastin antecedent deficiency or Rosenthal syndrome) is a mild form of haemophilia affecting both sexes, due to factor XI deficiency. It predominantly occurs in Ashkenazi Jews. It is the fourth most common coagulation disorder after von Willebrand's disease and haemophilia A and B. In the United States, it is thought to affect 1 in 100,000 of the adult population, making it 10% as common as haemophilia A.

<span class="mw-page-title-main">Bleeding diathesis</span> High tendency to bleed due to a blood clotting disorder

In medicine (hematology), bleeding diathesis is an unusual susceptibility to bleed (hemorrhage) mostly due to hypocoagulability, in turn caused by a coagulopathy. Therefore, this may result in the reduction of platelets being produced and leads to excessive bleeding. Several types of coagulopathy are distinguished, ranging from mild to lethal. Coagulopathy can be caused by thinning of the skin, such that the skin is weakened and is bruised easily and frequently without any trauma or injury to the body. Also, coagulopathy can be contributed by impaired wound healing or impaired clot formation.

<span class="mw-page-title-main">Desmopressin</span> Medication

Desmopressin, sold under the trade name DDAVP among others, is a medication used to treat diabetes insipidus, bedwetting, hemophilia A, von Willebrand disease, and high blood urea levels. In hemophilia A and von Willebrand disease, it should only be used for mild to moderate cases. It may be given in the nose, by injection into a vein, by mouth, or under the tongue.

<span class="mw-page-title-main">Coagulopathy</span> Condition involving impaired blood clotting ability

Coagulopathy is a condition in which the blood's ability to coagulate is impaired. This condition can cause a tendency toward prolonged or excessive bleeding, which may occur spontaneously or following an injury or medical and dental procedures.

<span class="mw-page-title-main">Fresh frozen plasma</span> Liquid portion of whole blood

Fresh frozen plasma (FFP) is a blood product made from the liquid portion of whole blood. It is used to treat conditions in which there are low blood clotting factors or low levels of other blood proteins. It may also be used as the replacement fluid in plasma exchange. Using ABO compatible plasma, while not required, may be recommended. Use as a volume expander is not recommended. It is administered by slow injection into a vein.

Congenital afibrinogenemia is a rare, genetically inherited blood fibrinogen disorder in which the blood does not clot normally due to the lack of fibrinogen, a blood protein necessary for coagulation. This disorder is autosomal recessive, meaning that two unaffected parents can have a child with the disorder. The lack of fibrinogen expresses itself with excessive and, at times, uncontrollable bleeding.

<span class="mw-page-title-main">Hemarthrosis</span> Bleeding into joint spaces

Hemarthrosis is a bleeding into joint spaces. It is a common feature of hemophilia.

<span class="mw-page-title-main">Factor VIII (medication)</span> Pharmaceutical drug

Factor VIII is a medication used to treat and prevent bleeding in people with hemophilia A and other causes of low factor VIII. Certain preparations may also be used in those with von Willebrand's disease. It is given by slow injection into a vein.

Moroctocog alfa is a recombinant antihemophilic factor genetically engineered from Chinese hamster ovary (CHO) cell line. Chemically it is a glycoprotein. It is manufactured by Genetics Institute, Inc. and used to control and prevent hemorrhagic bleeding and prophylaxis associated with surgery or to reduce the number of spontaneous bleeding episodes in patients with hemophilia A. It is partially a recombinant coagulation factor VIII since it has an amino acid sequence which compares to the 90 + 80 kDa form of factor VIII (BDDrFVIII). It also has posttranslational modifications which are similar to those of the plasma-derived molecule. It can not prevent hemorrhagic bleeding associated with von Willebrand's disease since it is not a von Willebrand factor.

Recombinant factor VIIa (rfVIIa) is a form of blood factor VII that has been manufactured via recombinant technology. It is administered via an injection into a vein. It is used to treat bleeding episodes in people who have acquired haemophilia, among other indications. There are several disimilar forms, and biosimilars for each. All forms are activated.

<span class="mw-page-title-main">Jeanne Lusher</span> American physician

Jeanne Marie Lusher, M.D. was an American physician, pediatric hematologist/oncologist, and a researcher in the field of bleeding disorders of childhood, and has served as the director of Hemostasis Program at the Children's Hospital of Michigan until her retirement on June 28, 2013.

Turoctocog alfa is a recombinant antihemophilic factor VIII used for the treatment of and prophylaxis of bleeding patients with haemophilia A. It is marketed by Novo Nordisk. It was approved in the United States, the European Union, and Japan in 2013.

Damoctocog alfa pegol, sold under the brand name Jivi is a recombinant DNA-derived, Factor VIII concentrate used to treat hemophilia A.

Etranacogene dezaparvovec, sold under the brand name Hemgenix is a gene therapy used for the treatment of hemophilia B. Etranacogene dezaparvovec is an adeno-associated virus vector-based gene therapy which consists of a viral vector carrying a gene for clotting Factor IX. The gene is expressed in the liver to produce Factor IX protein, to increase blood levels of Factor IX and thereby limit bleeding episodes. Hemophilia B is a genetic bleeding disorder resulting from missing or insufficient levels of blood clotting Factor IX, a protein needed to produce blood clots to stop bleeding.

Efanesoctocog alfa, sold under the brand name Altuviiio, is a medication used for the treatment of hemophilia A.

References

  1. 1 2 3 4 5 6 Konkle, Barbara A.; Josephson, Neil C.; Nakaya Fletcher, Shelley (1993-01-01). Pagon, Roberta A.; Adam, Margaret P.; Ardinger, Holly H.; Wallace, Stephanie E.; Amemiya, Anne; Bean, Lora J.H.; Bird, Thomas D.; Fong, Chin-To; Mefford, Heather C. (eds.). Hemophilia A. Seattle (WA): University of Washington, Seattle. PMID   20301578.update 2014
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  4. ↑ World Health Organization (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary 2008. World Health Organization. pp. 259–60. hdl: 10665/44053 . ISBN   9789241547659.
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  6. 1 2 "How Is Hemophilia Treated? - NHLBI, NIH". www.nhlbi.nih.gov. Retrieved 2016-07-08.
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  8. ↑ Sonu Acharya, Karishma Rathore, Upasana Mahapatra, Sashikant Sethi, Nikita Sahu (2018). "An unusual oral manifestation of hemophilia in a child". Journal of International Oral Health. Retrieved 2019-12-20.
  9. ↑ Nair, Preethi S.; Shetty, S.; Ghosh, Kanjaksha (2012-01-01). "A homozygous female hemophilia A". Indian Journal of Human Genetics. 18 (1): 134–136. doi: 10.4103/0971-6866.96685 . ISSN   0971-6866. PMC   3385172 . PMID   22754241.
  10. 1 2 3 4 5 6 7 Kliegman, Robert (2011). Nelson textbook of pediatrics (19th ed.). Philadelphia: Saunders. pp. 1700–1. ISBN   978-1-4377-0755-7.
  11. ↑ Bowen, D J (2002). "Haemophilia A and haemophilia B: molecular insights". Molecular Pathology. 55 (1): 1–18. doi:10.1136/mp.55.1.1. PMC   1187139 . PMID   11836440.
  12. ↑ "OMIM Entry - # 306700 - HEMOPHILIA A; HEMA". omim.org. Retrieved 2016-07-08.
  13. ↑ Hemophilia A at eMedicine
  14. ↑ "Von Willebrand's Disease. About Von Willebrand's Disease | Patient". Patient. Retrieved 2016-07-08.
  15. ↑ von Drygalski, Annette; Chowdary, Pratima; Kulkarni, Roshni; Susen, Sophie; Konkle, Barbara A.; Oldenburg, Johannes; Matino, Davide; Klamroth, Robert; Weyand, Angela C.; Jimenez-Yuste, Victor; Nogami, Keiji; Poloskey, Stacey; Winding, Bent; Willemze, Annemieke; Knobe, Karin (2023-01-26). "Efanesoctocog Alfa Prophylaxis for Patients with Severe Hemophilia A". New England Journal of Medicine. 388 (4): 310–318. doi:10.1056/NEJMoa2209226. ISSN   0028-4793. PMID   36720133.
  16. ↑ Malec, Lynn; Peyvandi, Flora; Chan, Anthony K.C.; Königs, Christoph; Zulfikar, Bulent; Yuan, Huixing; Simpson, Mindy; Álvarez Román, Maria Teresa; Carcao, Manuel; Staber, Janice M.; Dunn, Amy L.; Chou, Sheng-Chieh; d'Oiron, Roseline; Albisetti, Manuela; Demissie, Marek (2024-07-18). "Efanesoctocog Alfa Prophylaxis for Children with Severe Hemophilia A". New England Journal of Medicine. 391 (3): 235–246. doi:10.1056/NEJMoa2312611. ISSN   0028-4793. PMID   39018533.
  17. ↑ Ma, Alice D.; Roberts, Harold R.; Escobar, Miguel A. (2012-10-03). Hemophilia and Hemostasis: A Case-Based Approach to Management. John Wiley & Sons. ISBN   9781118439302.Google books no page
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  19. ↑ "Guidelines for the Prevention of Intravascular Catheter-Related Infections". www.cdc.gov. Retrieved 8 July 2016.
  20. ↑ Ljung, Rolf (2007-09-01). "The risk associated with indwelling catheters in children with haemophilia". British Journal of Haematology. 138 (5): 580–586. doi: 10.1111/j.1365-2141.2007.06703.x . ISSN   1365-2141. PMID   17686052. S2CID   25748135.
  21. ↑ Franchini, Massimo; Lippi, Giuseppe (2011-10-01). "The use of desmopressin in acquired haemophilia A: a systematic review". Blood Transfusion. 9 (4): 377–382. doi:10.2450/2011.0113-10. ISSN   1723-2007. PMC   3200405 . PMID   21839010.
  22. ↑ Andrew Brewer, Maria Elvira Correa (May 2006). "Guildelines for Dental Treatment of Patients with Inherited Bleeding Disorders" (PDF). Treatment of Hemophilia. 40: 9 – via World Federation of Hemophilia (WFH).
  23. ↑ "Groundbreaking gene therapy trial set to cure haemophilia A". Barts Health NHS Trust. 14 December 2017. Retrieved 14 December 2017.
  24. ↑ "Haemophilia A trial results 'mind-blowing'". BBC. 14 December 2017. Retrieved 14 December 2017.
  25. ↑ Rangarajan, Savita; Walsh, Liron; Lester, Will; Perry, David; Madan, Bella; Laffan, Michael; Yu, Hua; Vettermann, Christian; Pierce, Glenn F.; Wong, Wing Y.; Pasi, K. John (16 December 2017). "AAV5–Factor VIII Gene Transfer in Severe Hemophilia A". New England Journal of Medicine. 377 (26): 2519–2530. doi: 10.1056/NEJMoa1708483 . hdl: 10044/1/57163 . PMID   29224506.
  26. ↑ Marchesini, Emanuela; Morfini, Massimo; Valentino, Leonard (2021-06-15). "Recent Advances in the Treatment of Hemophilia: A Review". Biologics: Targets and Therapy. 15: 221–235. doi: 10.2147/BTT.S252580 . PMC   8214539 . PMID   34163136.
  27. ↑ Milani, Michela; Canepari, Cesare; Assanelli, Simone; Merlin, Simone; Borroni, Ester; Starinieri, Francesco; Biffi, Mauro; Russo, Fabio; Fabiano, Anna; Zambroni, Desirèe; Annoni, Andrea; Naldini, Luigi; Follenzi, Antonia; Cantore, Alessio (2024-04-29). "GP64-pseudotyped lentiviral vectors target liver endothelial cells and correct hemophilia A mice". EMBO Molecular Medicine. 16 (6): 1427–1450. doi:10.1038/s44321-024-00072-8. ISSN   1757-4684. PMC   11178766 . PMID   38684862.
  28. ↑ HEMLIBRA- emicizumab injection, solution drug label/data at DailyMed from U.S. National Library of Medicine , National Institutes of Health .
  29. ↑ Malec, Lynn; Peyvandi, Flora; Chan, Anthony K.C.; Königs, Christoph; Zulfikar, Bulent; Yuan, Huixing; Simpson, Mindy; Álvarez Román, Maria Teresa; Carcao, Manuel; Staber, Janice M.; Dunn, Amy L.; Chou, Sheng-Chieh; d’Oiron, Roseline; Albisetti, Manuela; Demissie, Marek (2024-07-18). "Efanesoctocog Alfa Prophylaxis for Children with Severe Hemophilia A". New England Journal of Medicine. 391 (3): 235–246. doi:10.1056/NEJMoa2312611. ISSN   0028-4793. PMID   39018533.
  30. ↑ Chowdary, Pratima (2024-07-18). Phimister, Elizabeth G. (ed.). "Bioengineered Factor VIII — More Innovation for Hemophilia A". New England Journal of Medicine. 391 (3): 277–282. doi:10.1056/NEJMe2313795. ISSN   0028-4793. PMID   39018538.
  31. ↑ Triemstra, Mattanja (1995-12-01). "Mortality in Patients with Hemophilia: Changes in a Dutch Population from 1986 to 1992 and 1973 to 1986". Annals of Internal Medicine. 123 (11): 823–7. doi:10.7326/0003-4819-123-11-199512010-00002. ISSN   0003-4819. PMID   7486463. S2CID   22008880.
  32. 1 2 Plug, I.; Van Der Bom, J. G.; Peters, M.; Mauser-Bunschoten, E. P.; De Goede-Bolder, A.; Heijnen, L.; Smit, C.; Willemse, J.; Rosendaal, F. R. (2006-03-01). "Mortality and causes of death in patients with hemophilia, 1992–2001: a prospective cohort study1". Journal of Thrombosis and Haemostasis. 4 (3): 510–516. doi:10.1111/j.1538-7836.2006.01808.x. hdl: 1887/5021 . ISSN   1538-7836. PMID   16460432. S2CID   13651790.

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