Hemophilia

Hemophilia is considered a very old disease with its history dating back to the 2nd century AD. The first modern descriptions of the condition appeared during the 19th century. Extensive work has been done over the centuries regarding the classification, inheritance pattern, and treatment of hemophilia. Hemophilia may be classified into three sub-types based on the lack of functional clotting factors: hemophilia A , hemophilia B, hemophilia C. It can also be divided into different categories based on the severity of the condition. Hemophilia can also be acquired in the setting of antibodies directed against the clotting factors. Hemophilia is a genetic bleeding disorder resulting from the insufficient levels of clotting factors in the body. The clotting factors irregularity causes a lack of clumping of blood required to form a clot to plug a site of a wound. 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 predominantly affects the male population but the sub-type hemophilia C, with an autosomal inheritance pattern, can affect the males as well as females. Hemophilia A, B, and C are caused by mutations in F8, F9, and F11 genes respectively. It can also occur as a result of autoantibodies directed against the clotting factors. Hemophilia must be differentiated from other diseases leading to spontaneous bleeding and bleeding following injuries or surgery such as von Willebrand disease, hepatic failure, thrombocytopenia, vitamin K deficiency, disseminated intravascular coagulation, uremia, congenital afibrinogenemia, factor V deficiency, factor X deficiency as seen in amyloid purpura, glanzmann’s thrombasthenia, Bernard-Soulier syndrome, factor XII deficiency and C1-inhibitor (C1INH) deficiency. The prevalence of hemophilia is estimated to be 20,000 cases in the United States annually. The age-adjusted prevalence of hemophilia in six US states (Oklahoma, Massachusetts, Colorado, Georgia, Louisiana, and New York) in 1994 was 13.4 cases per 100, 000 males. The incidence of hemophilia is estimated to be 1 in 5,000 male births for hemophilia A and 1 in 30,000 births for hemophilia B. The most potent risk factor in the development of hemophilia is the family history of hemophilia. Other risk factors include male sex and malignancies. Initial screening blood investigations for any child with suspected bleeding disorder include platelet count, prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen test. Chorionic villus sampling at 11-14 weeks of gestation can be performed for the genetic diagnosis of hemophilia. Hemophilia can present with a bleeding episode during the neonatal period that is difficult to manage or it can present with signs and symptoms of concealed bleeding into the joint or viscera. If left untreated, hemophilia can result in complications involving multiple organs and in severe bleeding episodes it can result in death. Hemophilia patients can lead an active and healthy life and life expectancy depends on the treatment response and the presence of comorbidities. Complications of hemophilia include AIDS, hepatitis, Vitamin D deficiency, osteoporosis, and renal pathologies. Coagulation tests and coagulation assays are the gold standard for the diagnosis of hemophilia. Prolonged activated partial thromboplastin time (aPTT), normal prothrombin time (PT), prolonged bleeding time (BT), and normal fibrinogen concentration are diagnostic of hemophilia. Coagulation tests should be followed by measuring the clotting factors level by coagulation assays. Once the coagulation discrepancy has been established, individual clotting factor assay can be performed to determine the deficient/absent clotting factor. Bethesda assay can be performed in the case of acquired hemophilia to detect and quantify antibodies directed against factor VIII. Patients with hemophilia can present with a history of excessive bleeding after minor injuries or spontaneous bleeding. They can also report family history of hemophilia. Hemophilia when mild, can be asymptomatic. Common symptoms, when present, include epistaxis, oral mucosal bleeding, joint pain and swelling, lethargy and fatigue, excessive bleeding after dental procedures, prolonged bleeding after circumcision and muscle hematoma after vaccination. Patients with hemophilia usually appear normal. Physical examination of patients with hemophilia is usually remarkable for tachycardia, pallor, bruising, abdominal pain and distension, hypotension, and muscle or joint swelling. Laboratory findings consistent with the diagnosis of hemophilia include normal prothrombin time (PT), prolonged activated partial thromboplastin time (aPTT), prolonged bleeding time (BT), and normal platelet count. There are no ECG findings associated with hemophilia. An x-ray of the joints in the case of hemophilic arthropathy may be helpful in the diagnosis of hemophilia. Pettersson scoring system, designed in 1980, is widely applied for the classification of osteo–chondral changes of hemophilic arthropathy in elbows, knees, and ankles. This scoring system is based on typical findings of hemophilic arthropathy on posterior–anterior and lateral x-rays. Arnold-Hilgartner classification is also a plain radiograph grading system for hemophilic arthropathy. CT scan may be helpful in the diagnosis of hemophilia. Findings on CT scan suggestive of hemophilia include muscle, intracranial, and intraabdominal hematomas, hemophilic pseudotumor, intracranial hemorrhage, muscle ossification, and pseudoaneurysm following arterial trauma. MRI may be helpful in the diagnosis of hemophilia. Findings on MRI suggestive of hemophilic arthropathy include effusion, synovial hypertrophy, erosion, subchondral cyst, cartilage loss, osteonecrosis, fibrocartilage tear, ligament tear, loose body. There are no echocardiography findings associated with hemophilia. Ultrasound may be helpful in the diagnosis and follow-up of hemophilic arthropathy and in diagnosing massive intraabdominal bleeds. Findings on an ultrasound suggestive of hemophilic arthropathy inlcude soft-tissue changes, osteo–chondral changes, joint effusion, synovial hypertrophy, hemosiderin, and osteo–chondral abnormalities. There are no other imaging findings associated with hemophilia. There are no other diagnostic studies associated with hemophilia. Clotting factor replacement is the mainstay of hemophilia treatment. Plasma-derived factor concentrates and recombinant factor concentrates are the two types used in the replacement therapy. Other products used as therapy include desmopressin acetate, antifibrinolytics, and cryoprecipitate. Gene therapy has the potential to change the course of hemophilia therapy and care. Surgery is not recommended for the treatment of hemophilia. Primary prevention of hemophilia encompasses measures taken to raise awareness regarding the genetics of the disease and the genetic transmission of the condition. Having an X-linked mode of transmission, genetic counselling in female carriers and awareness are the main focus for the primary prevention of hemophilia. Effective measures for the secondary prevention of hemophilia include avoidance of invasive fetal monitoring of a hemophilic fetus, avoidance of operative vaginal delivery, administration of vitamin K injection with care, availability of the factor concentrate at the time of delivery, infusion of factor VIII or IX concentrate at least once weekly for ≥ 45 weeks per year, and the use of e-Diaries to improve record keeping of hemophilia patients’ home treatment and bleeding episodes.

Hemophilia is considered a very old disease with its history dating back to the 2nd century AD. The first modern descriptions of the condition appeared during the 19th century. Extensive work has been done over the centuries regarding the classification, inheritance pattern, and treatment of hemophilia.

Hemophilia may be classified into three sub-types based on the lack of functional clotting factors: hemophilia A , hemophilia B, hemophilia C. It can also be divided into different categories based on the severity of the condition. Hemophilia can also be acquired in the setting of antibodies directed against the clotting factors.

Hemophilia is a genetic bleeding disorder resulting from the insufficient levels of clotting factors in the body. The clotting factors irregularity causes a lack of clumping of blood required to form a clot to plug a site of a wound. 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 predominantly affects the male population but the sub-type hemophilia C, with an autosomal inheritance pattern, can affect the males as well as females.

Hemophilia A, B, and C are caused by mutations in F8, F9, and F11 genes respectively. It can also occur as a result of autoantibodies directed against the clotting factors.

Hemophilia must be differentiated from other diseases leading to spontaneous bleeding and bleeding following injuries or surgery such as von Willebrand disease, hepatic failure, thrombocytopenia, vitamin K deficiency, disseminated intravascular coagulation, uremia, congenital afibrinogenemia, factor V deficiency, factor X deficiency as seen in amyloid purpura, glanzmann’s thrombasthenia, Bernard-Soulier syndrome, factor XII deficiency and C1-inhibitor (C1INH) deficiency.

The prevalence of hemophilia is estimated to be 20,000 cases in the United States annually. The age-adjusted prevalence of hemophilia in six US states (Oklahoma, Massachusetts, Colorado, Georgia, Louisiana, and New York) in 1994 was 13.4 cases per 100, 000 males. The incidence of hemophilia is estimated to be 1 in 5,000 male births for hemophilia A and 1 in 30,000 births for hemophilia B.

The most potent risk factor in the development of hemophilia is the family history of hemophilia. Other risk factors include male sex and malignancies.

Initial screening blood investigations for any child with suspected bleeding disorder include platelet count, prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen test. Chorionic villus sampling at 11-14 weeks of gestation can be performed for the genetic diagnosis of hemophilia.

Hemophilia can present with a bleeding episode during the neonatal period that is difficult to manage or it can present with signs and symptoms of concealed bleeding into the joint or viscera. If left untreated, hemophilia can result in complications involving multiple organs and in severe bleeding episodes it can result in death. Hemophilia patients can lead an active and healthy life and life expectancy depends on the treatment response and the presence of comorbidities. Complications of hemophilia include AIDS, hepatitis, Vitamin D deficiency, osteoporosis, and renal pathologies.

Coagulation tests and coagulation assays are the gold standard for the diagnosis of hemophilia. Prolonged activated partial thromboplastin time (aPTT), normal prothrombin time (PT), prolonged bleeding time (BT), and normal fibrinogen concentration are diagnostic of hemophilia. Coagulation tests should be followed by measuring the clotting factors level by coagulation assays. Once the coagulation discrepancy has been established, individual clotting factor assay can be performed to determine the deficient/absent clotting factor. Bethesda assay can be performed in the case of acquired hemophilia to detect and quantify antibodies directed against factor VIII.

Patients with hemophilia can present with a history of excessive bleeding after minor injuries or spontaneous bleeding. They can also report family history of hemophilia. Hemophilia when mild, can be asymptomatic. Common symptoms, when present, include epistaxis, oral mucosal bleeding, joint pain and swelling, lethargy and fatigue, excessive bleeding after dental procedures, prolonged bleeding after circumcision and muscle hematoma after vaccination.

Patients with hemophilia usually appear normal. Physical examination of patients with hemophilia is usually remarkable for tachycardia, pallor, bruising, abdominal pain and distension, hypotension, and muscle or joint swelling.

Laboratory findings consistent with the diagnosis of hemophilia include normal prothrombin time (PT), prolonged activated partial thromboplastin time (aPTT), prolonged bleeding time (BT), and normal platelet count.

There are no ECG findings associated with hemophilia.

An x-ray of the joints in the case of hemophilic arthropathy may be helpful in the diagnosis of hemophilia. Pettersson scoring system, designed in 1980, is widely applied for the classification of osteo–chondral changes of hemophilic arthropathy in elbows, knees, and ankles. This scoring system is based on typical findings of hemophilic arthropathy on posterior–anterior and lateral x-rays. Arnold-Hilgartner classification is also a plain radiograph grading system for hemophilic arthropathy.

CT scan may be helpful in the diagnosis of hemophilia. Findings on CT scan suggestive of hemophilia include muscle, intracranial, and intraabdominal hematomas, hemophilic pseudotumor, intracranial hemorrhage, muscle ossification, and pseudoaneurysm following arterial trauma.

MRI may be helpful in the diagnosis of hemophilia. Findings on MRI suggestive of hemophilic arthropathy include effusion, synovial hypertrophy, erosion, subchondral cyst, cartilage loss, osteonecrosis, fibrocartilage tear, ligament tear, loose body.

There are no echocardiography findings associated with hemophilia. Ultrasound may be helpful in the diagnosis and follow-up of hemophilic arthropathy and in diagnosing massive intraabdominal bleeds. Findings on an ultrasound suggestive of hemophilic arthropathy inlcude soft-tissue changes, osteo–chondral changes, joint effusion, synovial hypertrophy, hemosiderin, and osteo–chondral abnormalities.

There are no other imaging findings associated with hemophilia.

There are no other diagnostic studies associated with hemophilia.

Clotting factor replacement is the mainstay of hemophilia treatment. Plasma-derived factor concentrates and recombinant factor concentrates are the two types used in the replacement therapy. Other products used as therapy include desmopressin acetate, antifibrinolytics, and cryoprecipitate. Gene therapy has the potential to change the course of hemophilia therapy and care.

Surgical intervention is not recommended for the management of hemophilia.

Primary prevention of hemophilia encompasses measures taken to raise awareness regarding the genetics of the disease and the genetic transmission of the condition. Having an X-linked mode of transmission, genetic counselling in female carriers and awareness are the main focus for the primary prevention of hemophilia.

Effective measures for the secondary prevention of hemophilia include avoidance of invasive fetal monitoring of a hemophilic fetus, avoidance of operative vaginal delivery, administration of vitamin K injection with care, availability of the factor concentrate at the time of delivery, infusion of factor VIII or IX concentrate at least once weekly for ≥ 45 weeks per year, and the use of e-Diaries to improve record keeping of hemophilia patients’ home treatment and bleeding episodes.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Sabawoon Mirwais, M.B.B.S, M.D.[2]

Hemophilia is considered a very old disease with its history dating back to the 2nd century AD. The first modern descriptions of the condition appeared during the 19th century. Extensive work has been done over the centuries regarding the classification, inheritance pattern, and treatment of hemophilia.

• References to a condition associated with bleeding and suggestive of hemophilia date back to the 2nd century AD.^[1][2]
• Ancient religious script compilations, such as The Babylonian Tarmud, have also mentioned the condition along with relative fatal bleeding episode prevention.^[2][3]
• Abu Qasim Khalaf Ibn Abbas Al Zahrawi, a pioneer of modern surgery, known in the West as Albucasis or Zahravius, described suspected hemophilia cases in the 10th century.
• G. W. Consbruch of Bielefeld, Germany, described a bleeding disease very similar to hemophilia in 1793.
• Dr John Conrad Otto, an American physician, takes the credit for the first modern description of hemophilia in 1803. He described a bleeding disorder, transmitted via unaffected females and affecting only males. His work was published under the title “An account of an hemorrhagic disposition existing in certain families”.^[4]
• In 1813, John F. Hay published his first analysis of a hemophilia family tree in the New England Journal of Medicine.^[3]
• Christian Friedrich Nasse, a German physician and psychiatrist, described the genetics of hemophilia in 1820 and his work resulted in Nasse’s law, which states that hemophilia is transmitted entirely by unaffected females to their sons.^[5]
• A German physician, Johann Lukas Schönlein and his student Friedrich Hopff, documented the word “hemophilia” for the first time in 1828 and the condition was described in his dissertation with the title “About hemophilia or the hereditary predisposition to fatal bleeding”.^[6]
• Nasse’s law prompted further scientific debate leading to publications by J. Grandidier in 1855, John Wickham Legg in 1872, and Hermann Immermann in 1879.^[3]
• The analysis of a hemophilia family tree by John F. Hay was followed by the analyses from Sir William Osler in 1885, Kathleen P. Pratt in 1908, F. Koller and his group in 1954, and Victor A. Mckusick and Samuel I. Rapaport in 1962.
• William Bulloch and Paul Gordon Fildes published a detailed description of the early history of hemophilia in 1912 under the title “Treasury of human inheritance“.^[7]

• A. E. Wright was the first who documented the prolonged clotting time of hemophilic blood in a capillary tube in 1893.^[8]
• In 1908, P. Morawitz and J. Lossen proposed a deficiency in thrombokinase associated with hemophilia and disproved the association with calcium deficiency.^[8]
• In 1911, T. Addis investigated several blood and tissue factors and concluded that the hemophilic blood has defective prothrombin.^[9]
• In 1931, P. Govaerts and A. Gatia proposed that the platelets from hemophilic blood behaved normally when shifted to normal plasma. This finding hinted towards a deficiency in the plasma.^[3]
• In 1934, S. Van Creveld demonstrated that a “dispersed protein” fraction obtained from the serum decreased the clotting time of hemophilic blood.^[10]
• In 1936, A.J. Patek and F.H.L. Taylor proposed in their publication in Science that in normal blood and in citrated normal plasma rendered free from platelets by Berkefeld filtration, a substance was identified which, in small quantities, reduced the clotting time of hemophilic blood. Between 1936 and 1946, this research group published multiple papers supporting their original hypothesis^[11][12]
• A.J. Quick, M. Stanley-Brown, F.W. Bancroft solved the question of whether prothrombin or one of its derivatives is the deficient factor in hemophilia. They concluded that the hemophilic blood has a normal prothrombin content.^[13]
• In 1939, Brinkhous et al. confirmed A.J. Quick’s findings and showed that the hemophilic blood has a delayed prothrombin conversion rate.^[14]
• In 1947, A.j. Quick and K.M. Brinkhous independently demonstrated that the antihemophilic globulin and platelets react together in a fashion to generate thromboplastin. They also proposed that a deficiency in antihemophilic globulin caused defective coagulation due to defects in the generation of thromboplastin.^[15][14]

• In 1832, J.L. Schönlein proposed the use of blood transfusion.
• In 1840, Samuel Armstrong Lane treated a case of severe postoperative bleeding by blood transfusion.^[16]
• A German surgeon, Ernst von Bergmann, proposed the idea of using modified saline solution as an alternative to blood transfusion.^[17]
• In 1879, H. Kronecker and J. Sander introduced the administration of saline and it was subsequently improved by Sydney Ringer with the addition of electrolytes.^[18]
• In 1930, Karl Landsteiner won the Nobel Prize for his discovery of the human blood groups published under the title “The agglutination phenomenon of normal human blood“.^[19][20]
• W. Schulz applied the findings of Karl Landsteiner. He cross-matched blood before he transfused it and noted that agglutination and subsequent transfusion resulted in a severe collapse, while a negative cross-matching without agglutination did not have the same result.^[21]
• Reuben Ottenberg and David J. Kaliski improved the cross-matching of W. Schulz to avoid transfusion-related adverse reactions and proposed the major and minor test.^[22]
• In 1916, Thomas Addis reported that the coagulation time of hemophilic blood reduced after the intravenous infusion of fresh human serum.^[23]
• In 1935, W.M. Bendien and S. Van Creveld published their work on the isolation and intravenous or intramuscular administration of a “coagulation-promoting” substance which in 1934 they demonstrated as a “dispersed protein” fraction obtained from serum. They proposed that this “coagulation-promoting” substance, which was low on protein, had the ability to decrease the coagulation time of hemophilic blood to within normal values.^[10][24]

Year	Therapy
1840	First successful transfusion of whole blood[16]
1911	Identification of globulin fraction from plasma which reduced the coagulation time of hemophilic blood[9]
1916	Intravenous infusion of fresh human serum reduced the coagulation time of hemophilic blood[23]
1934	Russell’s viper venom (“Stypen”) was first used for the local control of bleeding in patients with hemophilia A, bleeding diathesis, and in healthy controls[25]
1935	A “coagulation-promoting” substance isolated from normal plasma reduced the coagulation time of hemophilic blood to within normal values when administered intravenously or intramuscularly[10][24]
1936	First evidence of a precipitate of whole blood plasma to correct bleeding time of hemophilic blood[26]
1946	“Antihemophilic globulin” introduced as a term[27][28]
1953	First prothrombin complex concentrate (ACC 76®) is marketed by Behringwerke AG
1958	Hemophilia A prophylaxis begins in Sweden[29]
1965	The revolution in the treatment of hemophilia with cryoprecipitate [30]

Year	Therapy
1981	First pasteurized factor VIII concentrate (Haemate® P) became available in Germany
1990	A highly purified pasteurized factor VIII concentrate Beriate® P registered in Germany
1992	The first recombinant factor VIII product is introduced and registered
2004 – current	Developmental breakthroughs in the recombinant factor VIII products

Hemophilia has been called “the disease of the kings” or “the royal disease” as several members of the European royal family have been affected by it.^[31] The following are a few famous cases of hemophilia:

• The Queen of England, Queen Victoria (1837–1901), was a carrier of hemophilia and she passed it onto her son, Leopold, who died of a brain hemorrhage when he was 31.^[31]
• The disease spread to other royal families in Germany, Russia and Spain through Queen Victoria’s two daughters.
• The best known case of “the royal disease” was Tsarevich Alexei, son of the Russian Czar Nicholas II.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Sabawoon Mirwais, M.B.B.S, M.D.[2]Simrat Sarai, M.D. [3]

Hemophilia may be classified into three sub-types based on the lack of functional clotting factors: hemophilia A , hemophilia B, hemophilia C. It can also be divided into different categories based on the severity of the condition. Hemophilia can also be acquired in the setting of antibodies directed against the clotting factors.

• Hemophilia may be classified into:

1. Hemophilia A: A recessive X-linked genetic disorder involving a lack of functional clotting factor VIII and representing approximately 80% of hemophilia cases.^[1]
2. Hemophilia B: A recessive X-linked genetic disorder involving a lack of functional clotting factor IX and comprising approximately 20% of hemophilia cases.^[1]
3. Hemophilia C: An autosomal genetic disorder involving a lack of functional clotting factor XI. This condition is not completely recessive, as heterozygous individuals also show increased bleeding.^[2]
4. Acquired Hemophilia: An acquired condition resulting from autoantibodies directed against the clotting factors. This usually occurs in the setting of a malignancy.^[3]

• Hemophilia may be classified as severe, moderate or mild based on the levels of factor VIII or factor IX.^[4]

Severity	Levels of Factor VIII or IX in the blood
Normal (as in a person who does not have hemophilia)	50% to 100%
Mild	Greater than 5% but less than 50%
Moderate	1% to 5%
Severe	Less than 1%
Adapted from CDC Hemophilia Diagnosis> “CDC Hemophilia Diagnosis”.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sabawoon Mirwais, M.B.B.S, M.D.[2]Simrat Sarai, M.D. [3]Vahid Eidkhani, M.D.Fahd Yunus, M.D. [4]

Hemophilia must be differentiated from other diseases leading to spontaneous bleeding and bleeding following injuries or surgery such as von Willebrand disease, hepatic failure, thrombocytopenia, vitamin K deficiency, disseminated intravascular coagulation, uremia, congenital afibrinogenemia, factor V deficiency, factor X deficiency as seen in amyloid purpura, glanzmann’s thrombasthenia, Bernard-Soulier syndrome, factor XII deficiency and C1-inhibitor (C1INH) deficiency.

Hemophilia must be differentiated from other diseases leading to spontaneous bleeding and bleeding following injuries or surgery such as:

• Von Willebrand Disease^[1][2]
• Vitamin K deficiency or Warfarin use^[3][4]
• Lupus Anticoagulant^[5]
• Heparin administration
• Disseminated intravascular coagulation^[6]
• Dysfibrinogenemia^[7]
• Thrombocytopenia
• Hepatic failure^[8][9][10]
• Uremia^[11]
• Congenital afibrinogenemia^[12][13]
• Factor V deficiency^[14][15]
• Amyloid purpura^[16]
• Glanzmann’s thrombasthenia^[17]
• Bernard-Soulier syndrome^[18][19]
• Factor XII deficiency^[20][21]
• C1-inhibitor (C1INH) deficiency^[22][23]

The most important differential diagnoses are enlisted in the table below:^{[24][25][26][27][28][29][30]}

Diseases	Clinical Manifestations						Para-clinical Findings									Additional Findings
	Symptoms			Physical Examination
							Lab Findings
	Joint Bleeding	Gastrointestinal Bleeding	Genitourinary Bleeding	Skin Bruises	Skeletal Deformity	Muscle Hematoma	CBC	PT	PTT	BT	Factor VIII	Factor IX	Fibrinogen	U/A:RBC	S/E:RBC
Hemophilia A	+	+	+	+	+	+	N	N	↑	N	↓	N	N	+	+	-/+Family history
Hemophilia B	+	+	+	+	+	+	N	N	↑	N	N	↓	N	+	+	-/+Family history
von Willebrand disease	-/+	-/+	-/+	-/+	-/+	-/+	N	N	↑/N	↑	↓/N	N	N	-/+	-/+	-/+Family history
Vitamin K deficiency	-/+	+	-/+	+	–	-/+	N	↑	↑/N	N	N	↓	N	+	+	Mostly in infants/GI disorders
Warfarin Toxicity	-/+	+	-/+	+	–	-/+	N	↑	↑/N	N	N	↓	N	+	+	+Drug history
Platelets disorders	–	-/+	-/+	+	–	–	↓Plt	N	N	↑	N	N	N	-/+	-/+	Cause-based specific findings
Liver Failure	–	+	+	-/+	–	-/+	↓Plt/N	↑	↑	↑/N	↑/N	↓	↑/N	-/+	+	Neurological findings/Ascites

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sabawoon Mirwais, M.B.B.S, M.D.[2]

The prevalence of hemophilia is estimated to be 20,000 cases in the United States annually. The age-adjusted prevalence of hemophilia in six US states (Oklahoma, Massachusetts, Colorado, Georgia, Louisiana, and New York) in 1994 was 13.4 cases per 100, 000 males. The incidence of hemophilia is estimated to be 1 in 5,000 male births for hemophilia A and 1 in 30,000 births for hemophilia B.

• The mean incidence of hemophilia from 1982-91 was 1 in 5,032 live male births.^[1]
• The incidence of congenital hemophilia A is 1 in 5000 boys/men.^[1][2]
• The incidence of congenital hemophilia B is about 1 in 30,000 boys/men.^[1]
• 400 hemophilic babies are born every year in the United States.^[1][3][4]

• The age-adjusted prevalence of hemophilia in six US states (Oklahoma, Massachusetts, Colorado, Georgia, Louisiana, and New York) in 1994 was 13.4 cases per 100, 000 males.^[1]
• The prevalence of hemophilia in Swedish population was 13.7 per 100, 000 males in 1980.^[1][5]
• The prevalence of hemophilia in other countries identified through contact with specialized hemophilia treatment centers range from 9.7 to 20.5 per 100, 000 males.^{[1][6][7][8][9][10]}

• In the United Kingdom, during 1977-1999, the all-cause mortality rate in severe hemophilia was higher than the corresponding age- and calendar year–specific all-cause mortality rate in the general male population by a factor of 2.69, while for patients with moderate/mild hemophilia it was increased by a factor of 1.19.^[11]
• The overall life expectancy of the patients with hemophilia did not notably change between 1972 and 2001.^[12]
• AIDS is the main cause of death (26%) and 22% of the deaths are because of hepatitis C.^[12]

• Prevalence rates are higher among 5-14 year olds.^[1]

• Hemophilia affects people from all racial and ethnic groups. However heterozygous factor XI deficiency occurs very frequently among Ashkenazi Jews.^[13][14]

• With an X-linked inheritance pattern, congenital hemophilia exclusively affects boys and/or men.^[1][15]
• Hemophilia C with an autosomal transmission can affect the male and as well as female population.^[16][17]

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sabawoon Mirwais, M.B.B.S, M.D.[2]Simrat Sarai, M.D. [3]Fahd Yunus, M.D. [4]Vahid Eidkhani, M.D.

The most potent risk factor in the development of hemophilia is the family history of hemophilia. Other risk factors include male sex and malignancies.

• Family history of hemophilia/bleeding.
• Male sex

• Malignancy

• Pregnancy
• Autoimmune disorders (SLE, rheumatoid arthritis)
• Infections (Hepatitis C, AIDS)
• Drugs (Interferon-alpha)
• Dermatological conditions (Pemphigus, psoriasis)

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sabawoon Mirwais, M.B.B.S, M.D.[2]

Initial screening blood investigations for any child with suspected bleeding disorder include platelet count, prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen test. Chorionic villus sampling at 11-14 weeks of gestation can be performed for the genetic diagnosis of hemophilia.

• Initial screening blood investigations for any child with suspected bleeding disorder include platelet count, prothrombin time (PT), and activated partial thromboplastin time (aPTT), and fibrinogen test.^[1][2][3]
• Bethesda assay (to detect and quantify factor VIII antibodies in acquired hemophilia)^[4][5]
• Chorionic villus sampling at 11-14 weeks of gestation can be performed for the genetic diagnosis of hemophilia.^[1]

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sabawoon Mirwais, M.B.B.S, M.D.[2]

Hemophilia can present with a bleeding episode during the neonatal period that is difficult to manage or it can present with signs and symptoms of concealed bleeding into the joint or viscera. If left untreated, hemophilia can result in complications involving multiple organs and in severe bleeding episodes it can result in death. Hemophilia patients can lead an active and healthy life and life expectancy depends on the treatment response and the presence of comorbidities. Complications of hemophilia include AIDS, hepatitis, Vitamin D deficiency, osteoporosis, and renal pathologies.

• The initial presentation of hemophilia can be subtle and the finding of abnormal coagulation values can be incidental.^[1]
• Hemophilia can present as early as the very first day of life with uncontrollable bleeding after a minor/major injury such as circumcision.^[1][2]
• It can also manifest as hemarthroses or muscle hematomas which has the potential of being misdiagnosed.^[2][3]
• Recurrent bleeding into the joints can lead to severe progressive arthropathy.^[4]
• If left untreated, hemophilia patients can experience life-threatening bleeding episodes such as retroperitoneal or intracranial bleeds.^[2][5]

Common complications of hemophilia include:

• AIDS^[6][7]
• Hepatitis^{[8][6][9][10][8][11]}
• Transfusion related infections^[11]
• Extracranial and intracranial hemorrhage^{[12][13][2][5]}
• Splenic rupture^[12]
• Hemarthrosis^[2]
• Muscle hematomas^[2]
• Arthropathy^[14]
• Vitamin D deficiency^[15][16]
• Menorrhagia^[17]
• Epistaxis^[17]
• Inhibitor (Autoantibodies directed against the replenished clotting factors) development^[18]
• Septic arthritis^[19]
• Ulcerative Colitis^[20]
• Respiratory obstruction^[21]
• Acute obstructive renal failure^[22]
• Cardiorenal syndrome^[22]
• Urinary bladder rupture^[23]
• Myositis ossificans^[24]
• Lumbar plexopathy^[25]

• Prognosis depends on the severity of the disease and the presence of comorbidities.
• High-quality factor VIII concentrates and the widespread use of prophylaxis have greatly improved the hemophilia care in the recent years.^[26]
• The quality of life and life expectancy of hemophilia patients have approached those of males in the general population.^[26][27]
• Hemophilia patients have lower mortality rates due to cardiovascular events compared to the general population.^[28][29][30]
• A survey of hemophilia patients in the United States showed a 50-fold higher risk of mortality from renal disease than in the general population.^[31]
• HCV and/or HIV infections and arthropathy remain the leading cause of morbidity in the elderly hemophilics who had little or no access to replacement therapy during the young age.^[32]
• Inhibitor development increases the risk of morbidity and permanent disability.^[33]

Template:WH Template:WS