H E M A T O L O G Y
C L I N I C
Von Willebrand disease Introduction Von Willebrand disease (VWD) is an inherited defect of blood coagulation that may cause excessive bleeding. Coagulation (also called clotting) is the capacity of blood to change from a liquid state to something like glue, thus avoiding the exit of blood from our body. Von Willebrand factor (VWF) has an important role in this process. Thanks to blood coagulation, we are not alarmed when we experience some bleeding after minor trauma or superficial cuts or dentistry, since we know that after a few minutes bleeding will stop. In patients suffering from excessive bleeding, one or more components that promote blood clotting are not properly working. The coagulation component defective in patients with VWD is called VWF. VWF acts in cooperation with several other players, including platelets and the many activators of clotting such as factor VIII and IX (lacking in hemophilia A and B, the best known hemorrhagic diseases). At the end of the clotting process, a resistant plug made up of fibrin (the end product of the coagulation) and platelets is produced. The precise function of VWF is multitasking: to trigger the process at the appropriate site (where coagulation is required), to recruit platelets, to consolidate the clot and to anchor it to the vessel wall, and to provide sufficient factor VIII (which circulates linked to VWF).
Causes VWD is a genetic disorder. Usually the defect is transmitted to the newborn by one of the parents who is the carrier of a mutation in the DNA sequence of the gene responsible for the production of VWF. In fact, we have two copies of VWF gene, the second healthy gene corrects in part the defect and the disease is attenuated (autosomal dominant inheritance). Not infrequently, bleeding manifestations are not manifested or are of very limited relevance in the parent that transmit the disease because the abnormal gene is fully manifesting only in the offspring. In much rarer instances both parents are healthy but their children can be affected by a severe form of the disease. This happens because not one but two abnormal genes are transmitted, one from the mother and the other from the father (recessive inheritance). This means that two abnormal genes are required to cause the bleeding,
370
© W. S. Maney & Son Ltd 2014 DOI 10.1179/1024533214Z.000000000292
which is usually more severe. In this case parents do not bleed because they still have a normal copy of the gene and the second abnormal copy is unable to produce the disease (autosomal recessive inheritance). VWF is made up of long chains of basic subunits (multimers) each containing binding sites for collagen (a component of blood vessels which is exposed when vessels are damaged), for platelet and for factor VIII which is carried around by VWF. All these molecular activities are required to VWF to accomplish its role in coagulation. The longer the multimers, the more potent is VWF.
Symptoms and signs Depending on the level of VWF and factor VIII remaining in the circulation blood of the patients, the bleeding manifestations may vary from very mild to severe (see Figure 1). Patients with VWD may have hemorrhages that vary from very mild to severe. The mildest form of the disease is very frequent, up to 1% of population and most cases go unrecognized and enjoy a normal life. Cases of intermediate severity may hit up to 1–10 subjects every 100 000. In these cases epistaxis may be frequent and disturbing, particularly in childhood and easy bruising or prolonged bleeding after superficial cuts may be also noticed. Heavy periods are frequently reported by females. Severe cases are very rare, around 2–5 every 1 000 000; they may manifest spontaneous bleeding and will require assistance by specialized centers in case of surgery, dentistry, or at the time of delivery for pregnant women.
Tests The results of the common coagulation tests usually done for general screening or before surgery may be normal in patients with mild VWD. In suspected cases, the diagnosis should be made by specifically measuring VWF and factor VIII, preferably in specialized centers. Actually, factor VIII is usually also decreased since it is transported by VWF. Genetic mutations causing VWD do not only impact on the basic subunit or on its specific binding sites but may have a major effect in the multimeric assembly. The consequence can be a variable decreased production of VWF or the production of non-functioning VWF subunit or multimers that are too short and not properly working.
Hematology
2014
VOL.
19
NO.
6
H E M A T O L O G Y
Figure 1
C L I N I C
Bleeding manifestations of VWD and principles of treatment
The classification of VWD into several different types and subtypes is based on analysis of these aspects but require the assistance of reference specialized laboratories. Fortunately, this detailed diagnosis it not strictly required in the generality of cases.
Treatment options More than 80% of patients secrete VWF into their blood after administration (intravenously or subcutaneously or by nasal spray) of desmopressin (DDAVP) which causes the release of VWF from body storage sites. A parallel increase of factor VIII is observed. In some cases, the increase of VWF and factor VIII is not sufficient or not sufficiently sustained, or an abnormal VWF is released. To select patients that could benefit from this cheap and well-tolerated treatment, a trial infusion is recommended in most cases. In intermediate or severe patients, it is recommended to avoid aspirin or other drugs that inhibit platelet function and medicines commonly used to prevent thrombosis, like heparin, warfarin, or non-warfarin anticoagulants, unless strictly necessary and under the supervision of a physician. Aspirin can be tolerated in mild cases. Ancillary
treatments are represented by antifibrinolytics (like Tranex) in case of minor, open bleedings (to be avoided if there is blood in the urine) or continuous administration of estroprogestinic pill, with or without antifibrinolytics, to control menorrhagia. Iron deficiency due to blood losses should be looked for and treated.
Outlook Most cases experience minor bleeding and do not risk major hemorrhages during the entire course of their life. Intermediate and severe cases greatly benefit from supervision by an expert doctor to treat disturbing hemorrhages with antifibrinolytics or desmopressin (DDAVP) without resorting to replacement therapy with blood substitutes containing VWF and factor VIII. Pregnancy is not contraindicated. Genetic counseling is advised in severe cases.
Additional resources Rodeghiero F, Castaman G, Tosetto A. How I treat Von Willebrand disease. Blood. 2009;114:1158. Francesco Rodeghiero Department of Cell Therapy and Hematology, San Bortolo Hospital, Viale Rodolfi, 37 36100 Vicenza, Italy. Email: [email protected]
Hematology
2014
VOL.
19
NO.
6
371
C L I N I C
Von Willebrand disease Introduction Von Willebrand disease (VWD) is an inherited defect of blood coagulation that may cause excessive bleeding. Coagulation (also called clotting) is the capacity of blood to change from a liquid state to something like glue, thus avoiding the exit of blood from our body. Von Willebrand factor (VWF) has an important role in this process. Thanks to blood coagulation, we are not alarmed when we experience some bleeding after minor trauma or superficial cuts or dentistry, since we know that after a few minutes bleeding will stop. In patients suffering from excessive bleeding, one or more components that promote blood clotting are not properly working. The coagulation component defective in patients with VWD is called VWF. VWF acts in cooperation with several other players, including platelets and the many activators of clotting such as factor VIII and IX (lacking in hemophilia A and B, the best known hemorrhagic diseases). At the end of the clotting process, a resistant plug made up of fibrin (the end product of the coagulation) and platelets is produced. The precise function of VWF is multitasking: to trigger the process at the appropriate site (where coagulation is required), to recruit platelets, to consolidate the clot and to anchor it to the vessel wall, and to provide sufficient factor VIII (which circulates linked to VWF).
Causes VWD is a genetic disorder. Usually the defect is transmitted to the newborn by one of the parents who is the carrier of a mutation in the DNA sequence of the gene responsible for the production of VWF. In fact, we have two copies of VWF gene, the second healthy gene corrects in part the defect and the disease is attenuated (autosomal dominant inheritance). Not infrequently, bleeding manifestations are not manifested or are of very limited relevance in the parent that transmit the disease because the abnormal gene is fully manifesting only in the offspring. In much rarer instances both parents are healthy but their children can be affected by a severe form of the disease. This happens because not one but two abnormal genes are transmitted, one from the mother and the other from the father (recessive inheritance). This means that two abnormal genes are required to cause the bleeding,
370
© W. S. Maney & Son Ltd 2014 DOI 10.1179/1024533214Z.000000000292
which is usually more severe. In this case parents do not bleed because they still have a normal copy of the gene and the second abnormal copy is unable to produce the disease (autosomal recessive inheritance). VWF is made up of long chains of basic subunits (multimers) each containing binding sites for collagen (a component of blood vessels which is exposed when vessels are damaged), for platelet and for factor VIII which is carried around by VWF. All these molecular activities are required to VWF to accomplish its role in coagulation. The longer the multimers, the more potent is VWF.
Symptoms and signs Depending on the level of VWF and factor VIII remaining in the circulation blood of the patients, the bleeding manifestations may vary from very mild to severe (see Figure 1). Patients with VWD may have hemorrhages that vary from very mild to severe. The mildest form of the disease is very frequent, up to 1% of population and most cases go unrecognized and enjoy a normal life. Cases of intermediate severity may hit up to 1–10 subjects every 100 000. In these cases epistaxis may be frequent and disturbing, particularly in childhood and easy bruising or prolonged bleeding after superficial cuts may be also noticed. Heavy periods are frequently reported by females. Severe cases are very rare, around 2–5 every 1 000 000; they may manifest spontaneous bleeding and will require assistance by specialized centers in case of surgery, dentistry, or at the time of delivery for pregnant women.
Tests The results of the common coagulation tests usually done for general screening or before surgery may be normal in patients with mild VWD. In suspected cases, the diagnosis should be made by specifically measuring VWF and factor VIII, preferably in specialized centers. Actually, factor VIII is usually also decreased since it is transported by VWF. Genetic mutations causing VWD do not only impact on the basic subunit or on its specific binding sites but may have a major effect in the multimeric assembly. The consequence can be a variable decreased production of VWF or the production of non-functioning VWF subunit or multimers that are too short and not properly working.
Hematology
2014
VOL.
19
NO.
6
H E M A T O L O G Y
Figure 1
C L I N I C
Bleeding manifestations of VWD and principles of treatment
The classification of VWD into several different types and subtypes is based on analysis of these aspects but require the assistance of reference specialized laboratories. Fortunately, this detailed diagnosis it not strictly required in the generality of cases.
Treatment options More than 80% of patients secrete VWF into their blood after administration (intravenously or subcutaneously or by nasal spray) of desmopressin (DDAVP) which causes the release of VWF from body storage sites. A parallel increase of factor VIII is observed. In some cases, the increase of VWF and factor VIII is not sufficient or not sufficiently sustained, or an abnormal VWF is released. To select patients that could benefit from this cheap and well-tolerated treatment, a trial infusion is recommended in most cases. In intermediate or severe patients, it is recommended to avoid aspirin or other drugs that inhibit platelet function and medicines commonly used to prevent thrombosis, like heparin, warfarin, or non-warfarin anticoagulants, unless strictly necessary and under the supervision of a physician. Aspirin can be tolerated in mild cases. Ancillary
treatments are represented by antifibrinolytics (like Tranex) in case of minor, open bleedings (to be avoided if there is blood in the urine) or continuous administration of estroprogestinic pill, with or without antifibrinolytics, to control menorrhagia. Iron deficiency due to blood losses should be looked for and treated.
Outlook Most cases experience minor bleeding and do not risk major hemorrhages during the entire course of their life. Intermediate and severe cases greatly benefit from supervision by an expert doctor to treat disturbing hemorrhages with antifibrinolytics or desmopressin (DDAVP) without resorting to replacement therapy with blood substitutes containing VWF and factor VIII. Pregnancy is not contraindicated. Genetic counseling is advised in severe cases.
Additional resources Rodeghiero F, Castaman G, Tosetto A. How I treat Von Willebrand disease. Blood. 2009;114:1158. Francesco Rodeghiero Department of Cell Therapy and Hematology, San Bortolo Hospital, Viale Rodolfi, 37 36100 Vicenza, Italy. Email: [email protected]
Hematology
2014
VOL.
19
NO.
6
371
