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P.M. Mannucci et al.
rately established than for the hemophilias, but, in gener- al, they tend to be less clinically severe at the same level of plasma deficiency.4,5 The inherited bleeding disorder von Willebrand disease (vWD) is not included among coagula- tion disorders because the primary defect is in the gene encoding the huge multimeric protein von Willebrand fac- tor (vWF), essential for platelet-vessel wall interactions and the formation of the primary hemostatic plug.6 However, in vWD, there is often the additional deficiency of coagulation FVIII secondary to the primary defect of vWF that functions as a physiological stabilizer of FVIII to which is complexed in blood, and thus explains mechanis- tically the secondary coagulation defect.6 vWF is encoded by a large gene on chromosome 12 (band 12p13.31), and vWD is transmitted as an autosomal dominant trait or as a recessive trait in the most severe and rarest type 3 (prevalence: 1 in 1-2 million).6 The prevalence in the gen- eral population of clinically relevant cases is similar to that of HA,7 although mild vWF deficiencies of little clinical significance are much more frequent in the frame of pop- ulation studies.8 In general, most patients with vWD are less severely affected clinically than those with the hemo- philias, but they suffer more frequently from bleeding from mucosal tracts, such as epistaxis, menorrhagia, and gastrointestinal bleeding.6 Soft tissue bleeding, such as hemarthrosis and postoperative hemorrhages, is only fre- quent in cases associated with moderately severe FVIII deficiency, i.e. type 3 vWD.6
Besides this general background on the inherited coagula- tion disorders, in this article it will be emphasized that, in the last decade, there has been tremendous progress in the available therapeutic armentarium, particularly for patients with the hemophilias. Recent review articles show the progress regarding rare coagulation disorders and vWD.5,9
Early therapeutic progress in hemophilia
One hundred years ago, at the time when Haematologica was first published, there was practically no treatment for the hemophilias or for the other inherited coagulation disorders. Whole blood was the only treat- ment approach available and this was of poor clinical effi- cacy (Figure 1), such that the life expectancy of hemophil- iacs was 10-15 years, even in the most favorable circum- stances. The few cases that survived were compromised by severe musculoskeletal damage that confined them to bed or to a wheelchair, and ice, analgesics and splinting were the only measures that could be used to alleviate
Table 1. Prevalence of inherited deficiencies of coagulation proteins and corresponding encoding genes and chromosomes.
Protein
Fibrinogen
Prothrombin Factor V Factor VII Factor VIII Factor IX Factor X Factor XI Factor XIII
Case prevalence in the general population*
1 in 1 million
1 in 2 million
1 in 1 million
1 in 500,000
6 in 100,000 males 1 in 100,000 males 1 in million
1 in 1 million
1 in 3 million
Gene and chromosome
FGA, FGB (4q31.3), FGG (4q32.1)
F2 (11p11.2) F5 (1q24.2) F7 (13q34) F8 (x928) F9 (x927.1) F10 (13q34) F11 (4q35.2)
F13A1 (6p25.1) F13B (1q31.3)
Figure 1. Progress in hemophilia therapy. Each decade of the last and current century features the main weapons available at the time for the treatment of patients with hemophilia. Each column represents a decade.
*Prevalences refer to the severe forms of the diseases due to homozygous or com- pound heterozygous gene mutations.
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