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Hereditary factor VIII deficiency disease(HEMA)

MedGen UID:
5501
Concept ID:
C0019069
Disease or Syndrome
Synonyms: Factor 8 deficiency, congenital; Factor VIII deficiency, congenital; HEM A; HEMA; Hemophilia A; Hemophilia A, congenital; HEMOPHILIA A, SEVERE; Hemophilia, classic
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
X-linked recessive inheritance
MedGen UID:
375779
Concept ID:
C1845977
Finding
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for recessive traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked recessive disorders manifest in males (who have one copy of the X chromosome and are thus hemizygotes), but generally not in female heterozygotes who have one mutant and one normal allele.
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
X-linked recessive inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Congenital factor VIII deficiency (28293008); Hemophilia A (28293008); Hereditary factor VIII deficiency disease (28293008); Classical hemophilia (28293008); AHG deficiency disease (28293008); Sex-linked factor VIII deficiency (28293008); Congenital factor VIII deficiency disease (28293008)
 
Gene (location): F8 (Xq28)
OMIM®: 306700
Orphanet: ORPHA98878

Definition

Hemophilia A is characterized by deficiency in factor VIII clotting activity that results in prolonged oozing after injuries, tooth extractions, or surgery, and delayed or recurrent bleeding prior to complete wound healing. The age of diagnosis and frequency of bleeding episodes are related to the level of factor VIII clotting activity. Individuals with severe hemophilia A are usually diagnosed during the first two years of life following bleeding from minor mouth injuries and large "goose eggs" from minor head bumps. Without prophylactic treatment, they may average up to two to five spontaneous bleeding episodes each month including spontaneous joint bleeds or deep-muscle hematomas, and prolonged bleeding or excessive pain and swelling from minor injuries, surgery, and tooth extractions. Individuals with moderate hemophilia A seldom have spontaneous bleeding; however, they do have prolonged or delayed oozing after relatively minor trauma and are usually diagnosed before age five to six years; the frequency of bleeding episodes varies, usually from once a month to once a year. Individuals with mild hemophilia A do not have spontaneous bleeding episodes; however, without pre- and postoperative treatment, abnormal bleeding occurs with surgery or tooth extractions; the frequency of bleeding episodes varies widely, typically from once a year to once every ten years. Individuals with mild hemophilia A are often not diagnosed until later in life. Approximately 30% of heterozygous females have clotting activity below 40% and are at risk for bleeding (even if the affected family member is mildly affected). After major trauma or invasive procedures, prolonged or excessive bleeding usually occurs, regardless of severity. [from GTR]

Additional descriptions

From GeneReviews
Hemophilia A is characterized by deficiency in factor VIII clotting activity that results in prolonged oozing after injuries, tooth extractions, or surgery, and delayed or recurrent bleeding prior to complete wound healing. The age of diagnosis and frequency of bleeding episodes are related to the level of factor VIII clotting activity. Individuals with severe hemophilia A are usually diagnosed during the first two years of life following bleeding from minor mouth injuries and large "goose eggs" from minor head bumps. Without prophylactic treatment, they may average up to two to five spontaneous bleeding episodes each month including spontaneous joint bleeds or deep-muscle hematomas, and prolonged bleeding or excessive pain and swelling from minor injuries, surgery, and tooth extractions. Individuals with moderate hemophilia A seldom have spontaneous bleeding; however, they do have prolonged or delayed oozing after relatively minor trauma and are usually diagnosed before age five to six years; the frequency of bleeding episodes varies, usually from once a month to once a year. Individuals with mild hemophilia A do not have spontaneous bleeding episodes; however, without pre- and postoperative treatment, abnormal bleeding occurs with surgery or tooth extractions; the frequency of bleeding episodes varies widely, typically from once a year to once every ten years. Individuals with mild hemophilia A are often not diagnosed until later in life. Approximately 30% of heterozygous females have clotting activity below 40% and are at risk for bleeding (even if the affected family member is mildly affected). After major trauma or invasive procedures, prolonged or excessive bleeding usually occurs, regardless of severity.  https://www.ncbi.nlm.nih.gov/books/NBK1404
From OMIM
Hemophilia A is an X-linked recessive bleeding disorder caused by a deficiency in the activity of coagulation factor VIII. The disorder is clinically heterogeneous with variable severity, depending on the plasma levels of coagulation factor VIII: mild, with levels 6 to 30% of normal; moderate, with levels 2 to 5% of normal; and severe, with levels less than 1% of normal. Patients with mild hemophilia usually bleed excessively only after trauma or surgery, whereas those with severe hemophilia have an annual average of 20 to 30 episodes of spontaneous or excessive bleeding after minor trauma, particularly into joints and muscles. These symptoms differ substantially from those of bleeding disorders due to platelet defects or von Willebrand disease (193400), in which mucosal bleeding predominates (review by Mannucci and Tuddenham, 2001).  http://www.omim.org/entry/306700
From GHR
Hemophilia is a bleeding disorder that slows the blood clotting process. People with this condition experience prolonged bleeding or oozing following an injury, surgery, or having a tooth pulled. In severe cases of hemophilia, continuous bleeding occurs after minor trauma or even in the absence of injury (spontaneous bleeding). Serious complications can result from bleeding into the joints, muscles, brain, or other internal organs. Milder forms of hemophilia do not necessarily involve spontaneous bleeding, and the condition may not become apparent until abnormal bleeding occurs following surgery or a serious injury.The major types of this condition are hemophilia A (also known as classic hemophilia or factor VIII deficiency) and hemophilia B (also known as Christmas disease or factor IX deficiency). Although the two types have very similar signs and symptoms, they are caused by mutations in different genes. People with an unusual form of hemophilia B, known as hemophilia B Leyden, experience episodes of excessive bleeding in childhood but have few bleeding problems after puberty.  https://ghr.nlm.nih.gov/condition/hemophilia

Clinical features

Joint hemorrhage
MedGen UID:
5479
Concept ID:
C0018924
Pathologic Function
Bleeding into the joints. It may arise from trauma or spontaneously in patients with hemophilia.
Petechiae
MedGen UID:
10680
Concept ID:
C0031256
Disease or Syndrome
A group of small reddish or purplish spots in skin or mucous membrane as a result of localized hemorrhage.
Purpura
MedGen UID:
19584
Concept ID:
C0034150
Disease or Syndrome
A small blood vessel hemorrhage into the skin and/or mucous membranes. Newer lesions appear reddish in color. Older lesions are usually a darker purple color and eventually become a brownish-yellow color.
Bruising susceptibility
MedGen UID:
140849
Concept ID:
C0423798
Finding
An ecchymosis (bruise) refers to the skin discoloration caused by the escape of blood into the tissues from ruptured blood vessels. This term refers to an abnormally increased susceptibility to bruising. The corresponding phenotypic abnormality is generally elicited on medical history as a report of frequent ecchymoses or bruising without adequate trauma.
Joint hemorrhage
MedGen UID:
5479
Concept ID:
C0018924
Pathologic Function
Bleeding into the joints. It may arise from trauma or spontaneously in patients with hemophilia.
Petechiae
MedGen UID:
10680
Concept ID:
C0031256
Disease or Syndrome
A group of small reddish or purplish spots in skin or mucous membrane as a result of localized hemorrhage.
Purpura
MedGen UID:
19584
Concept ID:
C0034150
Disease or Syndrome
A small blood vessel hemorrhage into the skin and/or mucous membranes. Newer lesions appear reddish in color. Older lesions are usually a darker purple color and eventually become a brownish-yellow color.
Prolonged partial thromboplastin time
MedGen UID:
66815
Concept ID:
C0240671
Finding
An abnormal laboratory test result in which the partial thromboplastin time is found to be greater than the control value. As a possible indicator of coagulopathy, a prolonged partial thromboplastin time (PTT) may occur in a variety of diseases and disorders, both primary and related to treatment.
Bruising susceptibility
MedGen UID:
140849
Concept ID:
C0423798
Finding
An ecchymosis (bruise) refers to the skin discoloration caused by the escape of blood into the tissues from ruptured blood vessels. This term refers to an abnormally increased susceptibility to bruising. The corresponding phenotypic abnormality is generally elicited on medical history as a report of frequent ecchymoses or bruising without adequate trauma.
Abnormal bleeding
MedGen UID:
264316
Concept ID:
C1458140
Pathologic Function
A coagulation disorder characterized by a tendency for excessive bleeding.
Persistent bleeding after trauma
MedGen UID:
375403
Concept ID:
C1844374
Finding
Reduced factor VIII activity
MedGen UID:
488140
Concept ID:
C3494187
Disease or Syndrome
Reduced activity of coagulation factor VIII. Factor VIII (fVIII) is a cofactor in the intrinsic clotting cascade that is activated to fVIIIa in the presence of minute quantities of thrombin. fVIIIa acts as a receptor, for factors IXa and X.
Joint hemorrhage
MedGen UID:
5479
Concept ID:
C0018924
Pathologic Function
Bleeding into the joints. It may arise from trauma or spontaneously in patients with hemophilia.
Osteoarthritis susceptibility 1
MedGen UID:
45244
Concept ID:
C0029408
Disease or Syndrome
Osteoarthritis (OA) is a degenerative disease of the joints characterized by degradation of the hyaline articular cartilage and remodeling of the subchondral bone with sclerosis (Meulenbelt et al., 2006). Clinical problems include pain and joint stiffness often leading to significant disability and joint replacement. Osteoarthritis exhibits a clear predilection for specific joints; it appears most commonly in the hip and knee joints and lumbar and cervical spine, as well as in the distal interphalangeal and the first carpometacarpal (base of thumb) and proximal interphalangeal joints of the hand; however, patients with osteoarthritis may have 1, a few, or all of these sites affected (Stefansson et al., 2003). According to a conservative estimate, greater than 70% of the population of the United States at age 65 years is affected by the disease, reflecting its age dependence. Genetic Heterogeneity of Susceptibility to Osteoarthritis Susceptibility to osteoarthritis has been associated with variation in other genes: OS2 (140600) with variation in the MATN3 gene (602109) on chromosome 2p24; OS3 (607850) with variation in the ASPN gene (608135) on chromosome 9q22; and OS5 (612400) with variation in the GDF5 gene (601146) on chromosome 20q11. Other susceptibility loci for osteoarthritis have been mapped to chromosomes 2q33 (OS4; 610839) and 3p24 (OS6; 612401).
Petechiae
MedGen UID:
10680
Concept ID:
C0031256
Disease or Syndrome
A group of small reddish or purplish spots in skin or mucous membrane as a result of localized hemorrhage.
Purpura
MedGen UID:
19584
Concept ID:
C0034150
Disease or Syndrome
A small blood vessel hemorrhage into the skin and/or mucous membranes. Newer lesions appear reddish in color. Older lesions are usually a darker purple color and eventually become a brownish-yellow color.
Bruising susceptibility
MedGen UID:
140849
Concept ID:
C0423798
Finding
An ecchymosis (bruise) refers to the skin discoloration caused by the escape of blood into the tissues from ruptured blood vessels. This term refers to an abnormally increased susceptibility to bruising. The corresponding phenotypic abnormality is generally elicited on medical history as a report of frequent ecchymoses or bruising without adequate trauma.

Professional guidelines

PubMed

Collins PW, Chalmers E, Hart DP, Liesner R, Rangarajan S, Talks K, Williams M, Hay CR; UK Haemophilia Centre Doctors.
Br J Haematol 2013 Jan;160(2):153-70. Epub 2012 Nov 15 doi: 10.1111/bjh.12091. PMID: 23157203
Keeney S, Cumming T, Jenkins PV, O'Donnell JS, Nash MJ
Eur J Hum Genet 2011 Nov;19(11) Epub 2011 Jun 8 doi: 10.1038/ejhg.2011.107. PMID: 21654722Free PMC Article

Recent clinical studies

Etiology

Barg AA, Livnat T, Kenet G
Thromb Res 2017 Mar;151 Suppl 1:S82-S85. doi: 10.1016/S0049-3848(17)30074-9. PMID: 28262242
Franchini M, Lippi G
Thromb Res 2016 Dec;148:96-100. Epub 2016 Oct 27 doi: 10.1016/j.thromres.2016.10.024. PMID: 27816852
Shi Q, Schroeder JA, Kuether EL, Montgomery RR
J Thromb Haemost 2015 Jul;13(7):1301-9. Epub 2015 Jun 11 doi: 10.1111/jth.13001. PMID: 25955153Free PMC Article
Lanchon R, Robin F, Brissaud O, Marro M, Nouette-Gaulain K
Ann Fr Anesth Reanim 2014 Mar;33(3):e43-5. Epub 2014 Feb 21 doi: 10.1016/j.annfar.2014.01.005. PMID: 24560953
Franchini M, Mannucci PM
Blood Rev 2013 Jul;27(4):179-84. Epub 2013 Jun 28 doi: 10.1016/j.blre.2013.06.002. PMID: 23815950

Diagnosis

Barg AA, Livnat T, Kenet G
Thromb Res 2017 Mar;151 Suppl 1:S82-S85. doi: 10.1016/S0049-3848(17)30074-9. PMID: 28262242
Badawy SM, Rossoff J, Yallapragada S, Liem RI, Sharathkumar AA
Hematol Oncol Stem Cell Ther 2017 Mar;10(1):29-32. Epub 2016 Apr 22 doi: 10.1016/j.hemonc.2016.04.001. PMID: 27178624
Wrobel M, Comio E, Gay V, Baroudi N, Meyer P, Chuniaud-Louche C, Hacini M, Pica GM
J Med Case Rep 2016 May 7;10(1):115. doi: 10.1186/s13256-016-0897-4. PMID: 27154067Free PMC Article
Hansson KM, Gustafsson D, Skärby T, Frison L, Berntorp E
J Thromb Haemost 2015 Jul;13(7):1293-300. Epub 2015 Jun 8 doi: 10.1111/jth.12997. PMID: 25944555
Franchini M, Mannucci PM
Blood Rev 2013 Jul;27(4):179-84. Epub 2013 Jun 28 doi: 10.1016/j.blre.2013.06.002. PMID: 23815950

Therapy

Badawy SM, Rossoff J, Yallapragada S, Liem RI, Sharathkumar AA
Hematol Oncol Stem Cell Ther 2017 Mar;10(1):29-32. Epub 2016 Apr 22 doi: 10.1016/j.hemonc.2016.04.001. PMID: 27178624
Franchini M, Lippi G
Thromb Res 2016 Dec;148:96-100. Epub 2016 Oct 27 doi: 10.1016/j.thromres.2016.10.024. PMID: 27816852
Wrobel M, Comio E, Gay V, Baroudi N, Meyer P, Chuniaud-Louche C, Hacini M, Pica GM
J Med Case Rep 2016 May 7;10(1):115. doi: 10.1186/s13256-016-0897-4. PMID: 27154067Free PMC Article
Hazendonk HC, Lock J, Mathôt RA, Meijer K, Peters M, Laros-van Gorkom BA, van der Meer FJ, Driessens MH, Leebeek FW, Fijnvandraat K, Cnossen MH
J Thromb Haemost 2016 Mar;14(3):468-78. Epub 2016 Feb 19 doi: 10.1111/jth.13242. PMID: 26714028
Young G, Mahlangu J, Kulkarni R, Nolan B, Liesner R, Pasi J, Barnes C, Neelakantan S, Gambino G, Cristiano LM, Pierce GF, Allen G
J Thromb Haemost 2015 Jun;13(6):967-77. Epub 2015 Apr 23 doi: 10.1111/jth.12911. PMID: 25912075

Prognosis

Shurkhina ES, Polyanskaya TY, Zorenko VY, Nesterenko VM
Bull Exp Biol Med 2017 Mar;162(5):676-678. Epub 2017 Mar 31 doi: 10.1007/s10517-017-3685-2. PMID: 28361432
Barg AA, Livnat T, Kenet G
Thromb Res 2017 Mar;151 Suppl 1:S82-S85. doi: 10.1016/S0049-3848(17)30074-9. PMID: 28262242
Franchini M, Lippi G
Thromb Res 2016 Dec;148:96-100. Epub 2016 Oct 27 doi: 10.1016/j.thromres.2016.10.024. PMID: 27816852
Tabriznia-Tabrizi S, Gholampour M, Mansouritorghabeh H
Expert Rev Hematol 2016 Sep;9(9):903-13. Epub 2016 Aug 16 doi: 10.1080/17474086.2016.1208554. PMID: 27367203
Hazendonk HC, Lock J, Mathôt RA, Meijer K, Peters M, Laros-van Gorkom BA, van der Meer FJ, Driessens MH, Leebeek FW, Fijnvandraat K, Cnossen MH
J Thromb Haemost 2016 Mar;14(3):468-78. Epub 2016 Feb 19 doi: 10.1111/jth.13242. PMID: 26714028

Clinical prediction guides

Franchini M, Lippi G
Thromb Res 2016 Dec;148:96-100. Epub 2016 Oct 27 doi: 10.1016/j.thromres.2016.10.024. PMID: 27816852
Hazendonk HC, Lock J, Mathôt RA, Meijer K, Peters M, Laros-van Gorkom BA, van der Meer FJ, Driessens MH, Leebeek FW, Fijnvandraat K, Cnossen MH
J Thromb Haemost 2016 Mar;14(3):468-78. Epub 2016 Feb 19 doi: 10.1111/jth.13242. PMID: 26714028
Melchiorre D, Linari S, Manetti M, Romano E, Sofi F, Matucci-Cerinic M, Carulli C, Innocenti M, Ibba-Manneschi L, Castaman G
Haematologica 2016 Feb;101(2):219-25. Epub 2015 Oct 22 doi: 10.3324/haematol.2015.133462. PMID: 26494839Free PMC Article
Gupta S, Garg K, Singh J
Indian J Pediatr 2015 Dec;82(12):1101-6. Epub 2015 May 8 doi: 10.1007/s12098-015-1759-6. PMID: 25947262
Young G, Mahlangu J, Kulkarni R, Nolan B, Liesner R, Pasi J, Barnes C, Neelakantan S, Gambino G, Cristiano LM, Pierce GF, Allen G
J Thromb Haemost 2015 Jun;13(6):967-77. Epub 2015 Apr 23 doi: 10.1111/jth.12911. PMID: 25912075

Recent systematic reviews

Chai-Adisaksopha C, Nevitt SJ, Simpson ML, Janbain M, Konkle BA
Cochrane Database Syst Rev 2017 Sep 25;9:CD011441. doi: 10.1002/14651858.CD011441.pub2. PMID: 28944952
Kruse-Jarres R, Kempton CL, Baudo F, Collins PW, Knoebl P, Leissinger CA, Tiede A, Kessler CM
Am J Hematol 2017 Jul;92(7):695-705. Epub 2017 Jun 5 doi: 10.1002/ajh.24777. PMID: 28470674
Zeng Y, Zhou R, Duan X, Long D, Yang S
Cochrane Database Syst Rev 2014 Aug 28;(8):CD010761. doi: 10.1002/14651858.CD010761.pub2. PMID: 25165992
Boehlen F, Graf L, Berntorp E
Eur J Haematol Suppl 2014 Aug;76:2-15. doi: 10.1111/ejh.12369. PMID: 24957102
Kempton CL, Allen G, Hord J, Kruse-Jarres R, Pruthi RK, Walsh C, Young G, Soucie JM
Am J Hematol 2012 Sep;87(9):933-6. Epub 2012 Jun 26 doi: 10.1002/ajh.23269. PMID: 22733686Free PMC Article

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