Bleeding Disorders
Hemophilia A and B
PATHOPHYSIOLOGY
Christmas disease: a condition previously mistaken for haemophilia.
Biggs R, Douglas AS, Macfarlane RG, et al.
Br Med J. 1952;2:1378-1382.
Description: The paper that first differentiated Factor VIII and Factor IX deficiencies. The latter is named after the first patient described in the article, Stephen Christmas, rather than for the Christmas issue of BJM in which the article appeared. This is the article that first suggested the designations Hemophilia A and B and that a numbering system for the coagulation factors should be worked out. It also represents a major advance towards understanding coagulation.
PubMed citation number: 12997790
The role of phospholipids and Factor VIII in the activation of bovine Factor X.
van Dieijen G, Tans G, Rosing J, Hemker HC.
J Biol Chem. 1981;256:3433.
Description: Establishes that Factor VIII has no enzymatic activity itself, but acts as a cofactor to increase the rate of activation of Factor X by Factor IXa in the presence of phospholipids and calcium.
PubMed citation number: 6782101
Factors IXa and Xa play distinct roles in tissue factor-dependent initiation of coagulation.
Hoffman M, Monroe DM, Oliver JA, Roberts HR.
Blood. 1995;86:1794.
Description: Establishes that it is Factor IXa (not Factor Xa) that is the preferred substrate for the tissue factor/VIIa complex, leading to thrombin generation.
PubMed citation number: 7655009
Characterization of the human factor VIII gene.
Gitschier J, Wood WI, Goralka TM, et al.
Nature 1984;312:326-330.
PubMed citation number: 6438525
Structure of human factor VIII.
Vehar GA, Keyt B, Eaton D, et al.
Nature. 1984;312:337-342.
PubMed citation number: 6438527
Description: Two seminal articles that describe the cloning of the human Factor VIII gene (one of the largest known) and characterize the structure of the gene and predicted polypeptide. These works led to a greater understanding of Factor VIII structure and function.
Inversions disrupting the factor VIII gene are a common cause of severe haemophilia.
Lakich D, Kazazian HH Jr, Antonarakis SE, Gitschier JA.
Nat Genet. 1993;5(3):236-41.
PubMed citation number: 8275087
Characteristic mRNA abnormality found in half the patients with severe haemophilia A is due to large DNA inversions.
Naylor J, Brinke A, Hassock S, Green PM, Giannelli F.
Hum Mol Genet. 1993;2:1773-1778.
PubMed citation number: 8281136
Description: These 2 references together represent the first reports of the most common genetic mutation in hemophilia A (45% of cases). Discovery of this intron 22 inversion not only facilitates prenatal screening for hemophilia, but also gives valuable insight into the mechanisms of human mutation. Of interest is that this inversion is thought to occur exclusively during male gametogenesis, and therefore in the maternal grandfather of spontaneously occurring cases (nonfamilial) of hemophilia A with this mutation.
DIAGNOSIS
Diagnostic symptoms of severe and moderate haemophilia A and B: a survey of 140 cases.
Ljung R, Petrini P, Nilsson IM.
Acta Paediatr Scand. 1990;79:196-200.
Description: A (somewhat old) population study that describes the most common presenting features of children (in Sweden) with hemophilia A. The authors find that the mean age at diagnosis was 9 months for severe hemophilia and 22 months for moderate hemophilia, and that 35 of 59 patients with known family history had bleeding episodes before their diagnosis was made. They found that joint bleeds were less common than soft-tissue hemorrhage as a presenting feature.
PubMed citation number: 2321482
TREATMENT
Recombinant clotting factors in the treatment of hemophilia.
Lee C.
Thromb Haemost. 1999;82:516.
Description: A review of clinical data for the various recombinant Factors VIII, IX, and VIIa products that includes information about efficacy, pharmacokinetics, inhibitor development, and economics.
PubMed citation number: 10605745
Inhibitor antibodies to factor VIII and factor IX: management.
Lusher JM.
Semin Thromb Hemost. 2000;26:179-188.
Description: A review of inhibitors in hemophilia A and B that includes information about incidence, clinical importance, and treatment approaches.
PubMed citation number: 10919411
Gene transfer as an approach to treating hemophilia.
High KA.
Semin Thromb Hemost 2003;29:107-120.
Description: A review that describes approaches that have been used in gene transfer therapy for hemophilia A and B, and summarizes preclinical data and early clinical data.
PubMed citation number: 12640573
REVIEW
Congenital hemorrhagic disorders: new insights into the pathophysiology and treatment of hemophilia.
Hedner U, Ginsburg D, Lusher JM, High KA.
Hematology (Am Soc Hematol Educ Program). 2000;241- 265.
PubMed citation number: 11701545
Congenital bleeding disorders.
Rick ME, Walsh CE, Key NS.
Hematology (Am Soc Hematol Educ Program). 2003:559- 574.
PubMed citation number: 14633799
Description: Together, these comprehensive and current reviews summarize the molecular genetics of hemophilia, treatment of patients with hemophilia, the epidemiology and management of hemophilia patients with factor inhibitors, and gene transfer therapy for hemophilia. The second article also reviews von Willebrand Disease.
von Willebrand Disease
DIAGNOSIS
The effect of ABO blood group on the diagnosis of von Willebrand disease.
Gill JC, Endres-Brooks J, Bauer PJ, Marks WJ Jr, Montgomery RR.
Blood. 1987;69:1691-1695.
Description: Clinical study based on analysis of blood from healthy volunteers that found those with blood type O had the lowest levels of VW antigen, which impacts interpretation of screening tests.
PubMed citation number: 3495304
A revised classification of von Willebrand disease: for the Subcommittee on von Willebrand Factor of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis.
Sadler JE.
Thromb Haemost. 1994;71:520-525.
Description: As the title suggests, this is the proposed classification of VWD into Type I (partial deficiency), Type II (qualitative defect), and Type III (severe deficiency), including subcategories.
PubMed citation number: 8052974
Von Willebrand disease type 1: a diagnosis in search of a disease.
Sadler JE.
Blood. 2003;101:2089-2093.
Description: The study argues that there is considerable overlap between low-normal levels of VWF and mild bleeding symptoms, making diagnosis of Type I VWD disease both difficult and of questionable utility other than for a minority of patients. The author suggests that an empirical epidemiologic approach towards risk factors for bleeding and thrombosis would be of more clinical utility for those with mild bleeding tendencies.
PubMed citation number: 12411289
TREATMENT
Treatment of von Willebrand's Disease.
Mannucci PM.
N Engl J Med. 2004;351:683-694.
Description: Recent review that summarizes the treatment of VWD.
PubMed citation number: 15306670
REVIEW
Impact, diagnosis, and treatment of von Willebrand disease.
Sadler JE, Mannucci PM, Berntorp E, et al.
Thromb Haemost. 2000;84:160-174.
Description: A very comprehensive and scholarly review that encompasses VWF structure and function, epidemiology, clinical characteristics, diagnosis, and treatment. This review can serve as a source of references for further reading.
PubMed citation number: 10959685
Rare Inherited Bleeding Disorders
Recessively inherited coagulation disorders.
Mannucci PM, Duga S, Peyvandi F.
Blood. 2004;104:1243-1252.
Description: Summarizes clinical features, genetics, and management of the rare bleeding disorders such as deficiencies of fibrinogen, prothrombin, and Factors V, VII, X, XI, and XIII. The data are based on 2 large series of patients from Italy and Iran.
PubMed citation number: 15138162
Recovery from hemophilia B Leyden: an androgen-responsive element in the factor IX promoter.
Crossley M, Ludwig M, Stowell KM, De Vos P, Olek K, Brownlee GG.
Science. 1992;257:377-379.
Description: Study in Hemophilia B Leiden, a rare disorder in which persons with severe Hemophilia B (< 1% of normal Factor IX levels) gradually improve to a normal phenotype (about 60% Factor IX levels) at puberty. This and subsequent studies show that the genetic mutations thought causative are in the promoter region of the Factor IX gene and that there is likely an androgen responsive element. Though the exact mechanism of hematologic recovery is not yet well understood, this rare bleeding disorder provides valuable insight into control of gene transcription by promotor regions.
PubMed citation number: 1631558
Acquired Bleeding Disorders
Acquired von Willebrand syndrome: from pathophysiology to management.
Veyradier A, Jenkins CS, Fressinaud E, Meyer D.
Thromb Haemost. 2000;84:175-182.
Description: Review article in which acquired von Willebrand syndrome is described, including epidemiology, associated conditions, proposed pathophysiologic mechanisms, and treatment options.
PubMed citation number: 10959686
Acquired haemophilia: review and meta-analysis focused on therapy and prognostic factors.
Delgado J, Jimenez-Yuste V, Hernandez-Navarro F, Villar A.
Br J Haematol. 2003;121:21-35.
Description: Review article and meta-analysis that summarizes clinical features, laboratory diagnosis, and treatment of acquired Factor VIII inhibitor, the most common of acquired factor inhibitors.
PubMed citation number: 1267032