Chinese Medical Journal, 2000, Vol

Chinese Medical Journal, 2000, Vol. 113 No. 8 : 677-680 Review Article

von Willebrand disease in China WANG Yingchun , LI Zhenyu , GU Jianming , RUAN Changgeng WANG Yingchun First Affiliated Hospital of Suzhou Medical College, Thrombosis and Hemostasis Research Unit Jiangsu Institute of Hematology Suzhou 215006, China; LI Zhenyu First Affiliated Hospital of Suzhou Medical College, Thrombosis and Hemostasis Research Unit Jiangsu Institute of Hematology Suzhou 215006, China; GU Jianming First Affiliated Hospital of Suzhou Medical College, Thrombosis and Hemostasis Research Unit Jiangsu Institute of Hematology Suzhou 215006, China; RUAN Changgeng First Affiliated Hospital of Suzhou Medical College, Thrombosis and Hemostasis Research Unit Jiangsu Institute of Hematology Suzhou 215006, China

Correspondence to: Changgeng Ruan First Affiliated Hospital of Suzhou Medical College, Thrombosis and Hemostasis Research UnitJiangsu Institute of Hematology Suzhou, 215006, China (Tel:0512-5101708 Fax:86-512-5192662 Email:smcklnmb@publicl.su.js.cn ) Keywords: von Willebrand factorvon Willebrand factor genevon Willebrand diseasepoint mutation polymorphismChinese population Abstract: Purpose To review the molecular pathogenesis in Chinese patients with von Willebrand disease (vWD) and polymorphisms of von Willebrand factor (vWF) in Chinese population. Data sources Both Chinese and English language literature search using MEDLINE (1985-1998), and original articles published in main Chinese and international journals.Study selection and data extraction After reviewing of the literature, 19 articles of them were selected that specifically addressed the stated purpose. Results The molecular pathogenesis of vWD was variant. Six cases of point mutation have been found in Chinese patients with vWD. The system of site-directed mutagenesis and expression of vWF gene was constructed. The polymorphisms of vWF gene are very different between Chinese and Gaucasians. Conclusion Combining to gene mutant in vWD patients, the use of site- directed mutagenesis and expression of vWF will help to understand the vWF function. The polymorphisms of vWF gene are useful marker in Chinese for carrier detection and prenatal diagnosis of vWD.

CMJ2000;113(8):677-680

von Willebrand disease (vWD), which is caused by qualitative and quantitative defects in von Willebrand factor (vWF), is one of the most common inherited human bleeding disorders. vWF plays an important role in primary hemostasis by mediating the adhesion of platelets to sites of vascular damaged by binding to specific platelet membrane glycoproteins and to constituents of exposed connective tissue. In addition, vWF is a carrier protein for blood clotting factor (F) and this interaction is required for normal F survival in the circulation.

The human vWF gene is localized to chromosome 12 (12p12-pter),[1,2]spans approximately 180 kb and is composed of 52 exons.[3]The 8.9 kb mRNA encodes a primary translation product is composed of a 22 amino acid signal peptide, a 741 residue pro-peptide and a 2050 amino acid mature vWF subunit. vWF is synthesized in megakaryocytes and endothelial cells by a complex multistep process that results in the assembly of multimers of up to 100 subunits. These high molecular weight (HMW) multimers appear to be most effective in platelet binding.

The increase in information about the molecular structure of vWF has led to a simplified classification of vWD. In 1994, according to the clinical phenotype, pathological characteristics and molecular pathogenesis of vWD, the International Thrombosis and Hemostasis Committee proposed a new classification standard that divides vWD into 3 categories ( Table 1 ).[4]Type 1 refers to a partial quantitative deficiency of vWF and autosomal dominant inheritance. Type 1 is characterized by a concordant reduction in vWF antigen, ristocetin cofactor activity, and F activity, but vWF multimers are normal. Type 2 refers to qualitative deficiencies of vWF and is generally inherited in a dominant manner although rare cases of apparently recessive inheritance have been reported. Type 2 contains subtype 2A, 2B, 2N and 2M, and is characterized by defect in vWF function and often also quantity. Type 2A and 2B are frequently associated with a disproportionately low level of ristocetin cofactor activity relative to vWF antigen, and a decrease or absence of the largest vWF multimers. Type 2M and 2N are associated with specific defects in platelet and F binding functions, respectively. Type 3 is characterized by a virtually complete deficiency of vWF. Type 3 is usually defined as autosomal recessive, this is not a completely consistent finding.

The prevalence of von Willebrand disease ranges from 3 or 4 per 100 000 to as h igh as 1.3% of the population.[5-7]Precise determination of prevalenc e is difficult because of the variable expression and reduced penetrance. The e xact prevalence estimate of vWD in China is unknown. In the past years, patient s with various types of inherited bleeding disorders, such as hemophilia A (HA), hemophilia B (HB), Glanzman's thrombasthenia (GT) and vWD were assessed in our hospital. Ninety-one (42.13 %) of them were vWD patients. Of all the vWD pat ients, 56 (61.5%) were type 1, 26 (28.6%) type 2 and 9 (9.89%) type 3. Genet ic analysis was performed in some of patients with type 2 and type 3 vWD by dena turing gradient gel electrophoresis (DGGE) and sequencing.

Mutations of von Willebrand factor gene in Chinese patients with vWD Given the complexity of vWF biosysthesis, section and function, defects at a number of genetic loci could potentially result in a vWD phenotype. Analysis of the vWF gene was performed in some type 2 and type 3 vWD patients by denaturing gradient gel electrophoresis and sequencing. From 1996 to 1998 we found six cases of point mutation in these patients with vWD ( Table 2 ).

Type 2A vWD is the most common qualitative variant, accounting for approximately 10%-15% of all vWD diagnosis. Most of the mutations responsible for type 2A vWD cluster within exon 28, which is 1.4 kb in length, and is the largest of all vWF exons. It encodes the entire A1 and A2 repeats, including the proteolysis site of vWF. Analysis of the type 2A vWD phenotype and study of its molecular pathogenesis will contribute to further understanding of vWF structure and function and direct gene diagnosis.

Three mutations have been found in these 14 patients with type 2A vWD.[8 9]They are Arg611His, Ala737Glu and Arg834Trp and all are hot point mut ations locating on the GpC island. Arg611His substitution has been reported i n 2 unrelated families[10]and locates on the A1 domain of vWF. Most type 2B vWD mutations have been found in this domain, but the mutation reported here is associated with decreased ristocetin cofactor activity and the absence of la rge and intermediate vWF multimers. Arg611His mutation resulted in a decrease d affinity of vWF for glycoprotein Ib. This type is often identified as a type 2A vWD variant.

Arg834Trp is the most common mutation in 2A vWD. In vitro expression confirmed that Arg834Trp did not disturb the assembly and secretion of multimers of vWF in cells, but the absence of large and intermediate vWF multimers was due to the high susceptibility of vWF to proteolysis in plasma.[11]

Two patients from the same hemorrhagic family showed prolonged bleeding times, markedly decreased ristocentin induced platelet aggregation, decrease of vWFAg and FVIIIAg, and the absence of large and intermediate molecular weight form of von Willebrand factor multimers in plasma, were studied recently. A novel missense mutation of C to A transition was detected, which resulted in Ala737Glu substitution. The type 2A vWD family with Ala737Glu mutation showed the characteristics of autosomal dominant inheritance. Among 19 members within 4 generations 9 possessed similar bleeding symptoms. The mutation located within the A2 domain of vWF, within which most type 2A vWD were clustered. The Ala737Glu substitution is considered a new mutation in the vWD database.[12]

We constructed an expression plasmid pSVA737EvWF containing the full length cDNA of vWF which included the Ala737Glu substitution by site-direct mutagenesis. Recombinant vWF containing the candidate mutation was transitorily expressed in COS-7 cells. Compared with wild type, recombinant vWF expressed in conditioned media was 76.4%, while in cell lysate was 98.8%. The multimer pattern of extracellular pSVA737EvWF was indistinguishable from that of the wild type, and both were comprised of a variety of molecular weights. The existence of many molecular weight multimers in platelets from patients indicated that the mutant didn't disturb the conformation of structure and secretion of vWF. The absence of large and intermediate multimers in plasma is possibly due to mutation in the vWF gene where a neutral amino acid is replaced by an acidic amino acid, resulting in a conformational change and an abnormally increased susceptiblity to proteolysis in plasma. Combined with gene mutantion in vWD patients, the use of site- directed mutagenesis and expression of vWF will help us understand the function of vWF and give us a model for studying the molecular pathology in other bleeding disorders.

Type 2N vWD patients have a phenotype similar to mild hemophilia A. The FVIII binding domain has been localized to the N-terminal fragment composed of 272 amino acid residues, encoded by exon 18-23 of the vWF gene. Mutations detected in type 2N vWD were all located within exon 18-20 of the vWF gene. We found two novel candidates with missense mutations in this type. One abnormal pattern is in exon 18 of the vWF gene of the type 2N pedigree. DNA sequencing demonstrated a heterozygous G to A transition, substituting glutamic acid to glycine in position 22.[13]This novel missense mutation creates a new restriction site for the enzyme SacI. The family study showed that the mutation originated from the mother. For another candidate, we screened exon 18-20 of the vWF gene from 22 patients with mild phenotypes of hemophilia A by DGGE and found that one fragment of exon 18 showed an abnormal electrophoretic pattern. DNA sequencing demonstrated an A to G transition at nucleotide 2398 in exon 18, substituting Met to Val at position 37 in the mature vWF subunit.

Type 3 vWD represents a severe form of the disease with a nearly complete deficiency of vWF in plasma. Most of the identified mutations in type 3 vWD gene deletions are nonsense mutations. A mutation was detected in a type 3 vWD patient by our lab[14]and was a nonsense mutation of C to A transition at nucleotide 212 in exon 3 of the vWF gene, introducing a stop codon at 71. This mutation created a Xba 1 restriction enzyme site and eliminated a Taq 1 restriction site. The patient was homozygous for the mutation and his parents were heterozygous, whose FVIIIAg, vWFAg and bleeding time were normal.

Polymorphism of von Willebrand factor in Chinese population The vWF gene is one of the most polymorphic genes with more than 40 polymorphic sites having been reported.[15]Wu et al[16]first found the restriction fragment length polymorphism (RFLP) of Xba 1 and BamH 1 in the 5' end of the vWF gene using Southern blot and found that the heterozygous rate is 0.49 and 0.46, respectively. In addition, there are many variable number tandem repeats (VNTR) in intron 40 of the vWF gene, and the heterozygous rate is high. The study of 142 chromosomes in 71 Chinese people in the Suzhou and Kunming area showed that there are ATCT tandem repeated sequences in the vWF gene of Chinese people, with 8 alleles in the area of the nt 1880-1980 in the vWF gene. The total theoretical heterozygous rate is 79.4%.[17]DNA samples from 112 normal people in Shanghai area were also assayed and 7 and 5 types of VNTR were identified on nt 1890-1990 and nt 2215-2380, respectively. The heterozygous rates were 75% and 74%, respectively.[18]

The vWF gene from 52 unrelated individuals of Han Nationality, 44 of the Yi tribe, and 42 of the Dai tribe were amplified by PCR and subsequently analysis with restriction enzyme digestion with Sma I, Hha I, Msp I and Rsa I ( Table 2 ).[19]

The allele frequencies of Sma I, and Hha I of the vWF gene are very different between Chinese and Caucasians, though the theoretical heterozygous rates in the two populations are similar. In the three races of Chinese, allele frequencies and theoretical rates show very little difference. Allele frequencies and theoretical rates of MspI in the vWF gene in Chinese are lower than these of Caucasians. These gene markers are useful for carrier detection and prenatal diagnosis of vWD. As for Ras I RFLP of the vWF gene, the theoretical rate is much lower in Chinese Hans than that in Caucasians, it has a lower diagnostic value in family analysis of vWD in people of Chinese origin.

REFERENCES

1. Ginsburg D, Handin RI, Bonthron DT, et al. Human von Willebrand factor (vW F): Isolation of complementary DNA (cDNA) clones and chromosomal localization. Science 1985;228:1401-1406. 2. Verweij CL, Devires CJM, Distel B, et al. Construction of cDNA coding for h uman von Willebrand factor using antibody probes for colony-screening and mappi ng of the chromosomal gene. Nucleic Acids Res 1985;13:4699-4717. 3. Mancuso DJ, Tuley EA, Westfield LA, et al. Structure of the gene for human von Willebrand factor. J Biol Chem 1989;264:19514-19527. 4. Sadler JE, Grainnick HR. Commentary A new classfication for von Willebrand disease. Blood 1994;84:676-679. 5. Holmberg L, Nilsson IM.von Willebrand disease. Clin Haematol 1985;14:461- 488. 6. Rodeghiero F, Castaman G, Dini E. Epidemiological investigation of the prev alence of von Willebrand disease. Blood 1987;69:451-456. 7. Werner EJ, Broxson EH, Tucker EL, et al. Prevalence of von Willebrand disea se in children: A multiethnic study. J Pediatr 1993;123:893-898. 8. Ruan Changgeng, Gu Jianming, Fu Jianxin, et al. Type 2 von Willebrand disea se resulted from an Arg611His mutation within exon 28 of the von Willebrand fact or gene. Chin J Hematol 1996;17:451-454. 9. Wang YC, Zhang JY, Wan HY, et al. Mutation (Ala737Glu) in type 2A von Wil lebrand disease. Chin J Hematol 1999;20:117-119. 10. Hilbert L, Gaucher C, Mazurier C, et al. Identification of two mutations ( Arg611Cys and Arg611His) in the A loop of von Willebrand factor (vWF) responsibl e for type 2 von Willebrand disease decreased platelet-dependent function of vW F. Blood 1995;86:1010-1013. 11. Lyons SE, Baruck ME, Bowie EJW, et al. Impaired intercellular transport pr oduced by a subset of type A von Willebrand disease mutations. J Biol Chem 1992;267:4424-4430. 12. Sadler JE, Ginsburg D. A database of polymorphisms in the von Willebrand f actor gene and pseudogene. Thromb Haemost 1993;69:185-191. 13. J Gu, S Jorieux, JM Lavergene, et al. A patient with 2N von Willebrand dis ease is heterozygous for a new mutation: Gly22Glu. Demonstration of a defective expression of the second allele by the use of monoclonal antibodies. Blood 199 7;89:3263-3269. 14. Li ZY, Wang Y, Wan HY, et al. Detection of gene mutation and genetic analy sis with type 3 von Willebrand disease. Chin J Hematol 1998;19:122-124. 15. Sadler JE, Ginsburg D. A database of polymorphisms in the von Willebrand f actor gene and pseudogene. Thromb Haemost 1993;69:185-191. 16. Wu QY, Pang JL, Gu JM, et al. RFLP analysis of von Willebrand gene in Chin ese people. Chin Sci Bull 1991;12:251-254. 17. Wang YC, Li ZY, Wang Y, et al. Study on the variable number tandem repeats of vWF gene in Chinese Han nationality. J Exp Hematol 1998;6:6293-296. 18. Du LZ, Yu LZ, Wang HL, et al. Linkage analysis of vWD family by mult-PCR assay of microsatellite DNA in vWF gene. Chin J Hematol 1998;19:118-121. 19. Li ZY, Wang Y, Tai H, et al. Sma I, Hha I, Msp I and RsaI restriction frag ment length polymorphisms in the von Willebrand factor gene Chinese population. Chin Med J 1998;111:686-689

von Willebrand disease

DefinitionVon Willebrand disease is caused by a deficiency or an abnormality in a protein called von Willebrand factor and is characterized by prolonged bleeding.

DescriptionThe Finnish physician Erik von Willebrand was the first to describe von Willebrand disease (VWD). In 1926 Dr. von Willebrand noticed that many male and female members of a large family from the Aland Islands had increased bruising (bleeding into the skin) and prolonged episodes of bleeding. The severity of the bleeding varied between family members and ranged from mild to severe and typically involved the mouth, nose, genital and urinary tracts, and occasionally the intestinal tract. Excessive bleeding during the menstrual period was also experience by some of the women in this family. What differentiated this bleeding disorder from classical hemophilia was that it appeared not to be associated with muscle and joint bleeding and affected women and men rather than just men. Dr. von Willebrand named this disorder hereditary pseudohemophilia.

Pseudohemophilia, or von Willebrand disease (VWD) as it is now called, is caused when the body does not produce enough of a protein called von Willebrand factor(vWF) or produces abnormal vWF. vWF is involved in the process of blood clotting (coagulation). Blood clotting is necessary to heal an injury to a blood vessel. When a blood vessel is injured, vWF enables blood cells called platelets to bind to the injured area and form a temporary plug to seal the hole and stop the bleeding. vWF is secreted by platelets and by the cells that line the inner wall of the blood vessels (endothelial cells). The platelets release other chemicals, called factors, in response to a blood vessel injury, which are involved in forming a strong permanent clot. vWF binds to and stabilizes factor VIII, one of the factors involved in forming the permanent clot.

A deficiency or abnormality in vWF can interfere with the formation of the temporary platelet plug and also affect the normal survival of factor VIII, which can indirectly interfere with the production of the permanent clot. Individuals with VWD, therefore, have difficulty in forming blood clots and as a result they may bleed for longer periods of time. In most cases the bleeding is due to an obvious injury, although it can sometimes occur spontaneously.

VWD is classified into three basic types: type 1, 2, and 3 based on the amount and type of vWF that is produced. Type 1 is the most common and mildest form and results when the body produces slightly decreased amounts of typically normal vWF. Type 2 can be classified into five subtypes (A,B,M,N) and results when the body produces an abnormal type of vWF. Type 3 is the rarest and most severe form and results when the body does not produce any detectable vWF.

Approximately one out of 100 people are affected with VWD, making it the most common inherited bleeding disorder (hemophilia). VWD affects people of all ethnic backgrounds. Approximately 70-80% of people with VWD have type 1 and close to 20-30% have type 2. Type 3 is very rare and occurs in less than one percent of people with VWD.

Causes and symptomsThe genetics of VWD are complex and involve a gene that produces vWF and is found on chromosome 12. Since we inherit two of each type of chromosome we inherit two vWF genes. There are different types of changes in the vWF gene that can affect the production of vWF. Some types of changes can cause the vWF gene to produce decreased amounts of normal vWF, while other changes can cause the gene to produce abnormal vWF. Most of the gene changes are significant enough that a change in only one vWF gene is sufficient to cause VWD. Some gene changes only cause VWD if both genes are changed, which often leads to more severe symptoms. Type 1 VWD is called an autosomal dominant condition since it is caused by a change in only one vWF gene. Since type 1 VWD results in only a slight decrease in the amount of vWF produced, the symptoms are often mild and even non-existent in some patients. Most cases of Type 2 VWD are autosomal dominant since they are caused by a change in only one vWF gene that results in the production of an abnormal protein. An autosomal dominant form of VWD can be inherited from either parent or can occur spontaneously in the embryo that is formed when the egg and sperm cells come together during fertilization.

Some cases of type 2 VWD and all cases of type 3 VWD are autosomal recessive since they are caused by changes in both vWF genes. A person with an autosomal recessive form of VWD has inherited a changed gene from his or her mother and a changed gene from his or her father. Parents who have a child with an autosomal recessive form of VWD are called carriers, since they each possess one changed vWF gene and one unchanged vWF gene. Many carriers for the autosomal recessive forms of type 2 VWD and type 3 VWD do not have any symptoms, although some people with type 3 VWD are born to parents who have type 1 VWD and may have symptoms. Each child born to parents who are both carriers for VWD has a 25% chance of having VWD, a 50% chance of being a carrier, and a 25% chance of being neither a carrier nor affected with VWD disease. A person with an autosomal dominant form of VWD has a 50% chance of passing the changed gene on to his or her children who may or may not have symptoms.

VWD is usually a relatively mild disorder characterized by easy bruising, recurrent nosebleeds, heavy menstrual periods, and extended bleeding after surgeries and invasive dental work. There is a great deal of variability in the severity of symptoms, which can range from clinically insignificant to life threatening. Even people within the same family who are affected with the same type of VWD may exhibit different symptoms. An individual with VWD may exhibit a range of symptoms over the course of his or her lifetime and may experience an improvement in symptoms with age. The severity of the disease is partially related to the amount and type of vWF that the body produces, but is also influenced by other genetic and non-genetic factors.

Type 1Type 1, the mildest form of VWD, is usually associated with easy bruising, recurrent nosebleeds, heavy menstrual periods, and prolonged bleeding after surgeries and invasive work. Many people with type 1 VWD do not have any noticeable symptoms or only have prolonged bleeding after surgery or significant trauma. The amount of vWF produced by the body increases during pregnancy, so prolonged bleeding during delivery is uncommon in people with type 1 VWD.

Type 2People with type 2 VWD usually have symptoms from early childhood and symptoms may even be present at birth. They usually experience prolonged bleeding from cuts, easy bruising, nose bleeds, skin hematomas, and prolonged bleeding from the gums following teeth extraction and minor trauma. More than 50% of women with type 2 VWD experience heavy periods that may require a blood transfusion. Gastrointestinal bleeding is rare but can be life-threatening. Some women with type 2 VWD exhibit prolonged bleeding during delivery.

Type 3Type 3 VWD can be quite severe and is associated with bruising and bleeding from the mouth, nose, intestinal, genital and urinary tracts. Type 3 is also associated with spontaneous bleeding into the muscles and joints, which can result in joint deformities. Some women with type 3 VWD experience prolonged bleeding during delivery.

DiagnosisDiagnostic testingMany people with VWD have mild symptoms or symptoms that can be confused with other bleeding disorders making it difficult to diagnose VWD on the basis of clinical symptoms. VWD should be suspected in any person with a normal number of platelets in their blood and bleeding from the mucous membranes such as the nose, gums and gastrointestinal tract. Testing for an individual with suspected VWD often includes the measurement of:

how long it takes for the bleeding to stop after a tiny cut is made in the skin (the bleeding time)

the amount of vWF (vWF antigen measurement)

the activity of vWF (ristocetin co-factor activity)

the amount of factor VIII (factor VIII antigen measurement)

activity of factor VIII

People with type 1 VWD usually have an increased bleeding time but they may have an intermittently normal bleeding time. They also have a decreased amount of vWF, and decreased vWF activity and usually have slightly decreased factor VIII levels and activity. People with type 2 VWD have a prolonged bleeding time, decreased activity of vWF and may have decreased amounts of vWF and factor VIII, and may have decreased factor VIII activity. Type 3 individuals have undetectable amounts of vWF, negligible vWF activity, factor VIII levels of less than 5-10%, and significantly reduced factor VIII activity. The activity of vWF is reduced for all types of VWD, making it the most sensitive means of identifying all three types of VWD. Patients with borderline results should be tested two to three times over a three month period.

Once a patient is diagnosed with VWD, further testing such as vWF multimer analysis and ristocetin-induced platelet aggregation (RIPA) may need to be performed to determine the subtype. Multimer analysis evaluates the structure of the vWF, and RIPA measures how much ristocetin is required to cause the clumping of platelets in a blood sample. The vWF multimer analysis is able to differentiate people with a structurally normal vWF (type 1) from people with a structurally abnormal vWF (type 2) and is often able to identify the subtype of patients with type 2 VWD. People with type 1 VWD usually have normal to decreased RIPA concentrations. Depending on the subtype, patients with type 2 VWD either have increased or decreased RIPA. RIPA is usually absent and the multimer analysis shows undetectable vWF in people with type 3 VWD.

In some cases DNA testing can be a valuable adjunct to biochemical testing. The detection of gene alteration(s) can confirm a diagnosis and can determine the type and subtype of VWD. It can also help to facilitate prenatal testing and testing of other family members. Unfortunately, as of 2001, many people with VWD possess DNA changes that are not detectable through DNA testing. A person who has a mother, father, or sibling diagnosed with VWD should undergo biochemical testing for VWD. If the relative with VWD possesses a detectable gene change, then DNA testing should also be considered.

Prenatal testingIf one parent has been diagnosed with an autosomal dominant form of VWD or both parents are carriers for an autosomal recessive form of VWD, then prenatal testing can be considered. If the parent with an autosomal dominant form of VWD possesses a detectable gene change or both parents who are carriers for an autosomal recessive form of VWD possess detectable mutations, then DNA testing of their fetus would be available. DNA testing can be performed through amniocentesis or chorionic villus sampling. If the DNA change in the parent(s) is unknown then prenatal testing can sometimes be performed through biochemical testing of blood obtained from the fetal umbilical cord, which is less accurate and is associated with a higher risk of pregnancy loss.

TreatmentVWD is most commonly treated by replacement of vWF through the administration of blood products that contain vWF or through treatment with desmopressin (DDAVP, 1-deamino-8-D-arginine vasopressin). DDAVP functions by increasing the amount of factor VIII and vWF in the bloodstream. Treatment with blood products or DDAVP may be started in response to uncontrollable bleeding or may be administered prior to procedures such as surgeries or dental work. The type of treatment chosen depends on the type of VWD and a patient's response to a preliminary treatment trial.

Treatment with desmopressinDDAVP is the most common treatment for people with type 1 VWD. About 80% of people with type 1 VWD respond to DDAVP therapy. Treatment with DDAVP can also be used to treat some people with type 2 VWD. Patients with Type 2B VWD should not be treated with this medication since DDAVP can induce dangerous platelet clumping. Type 3 VWD should not be treated with DDAVP since this medication does not increase the level of vWF in type 3 patients. DDAVP should only be used in people who have been shown to be responsive through a pre-treatment trial transfusion with this medication.

DDAVP can be administered intravenously or through a nasal inhaler. DDAVP has relatively few side effects although some people may experience facial flushing, tingling sensations, and headaches after treatment with this medication. Often treatment with this medication is only required prior to invasive surgeries or dental procedures.

Treatment with blood productsPatients who are unable to tolerate or are unresponsive to drug-based treatments are treated with concentrated factor VIII obtained from blood products. Not all factor VIII concentrates can be used since some do not contain enough vWF. The concentrate is treated to kill most viruses, although caution should be used since not all types of viruses are destroyed. If the factor VIII concentrates are unable to manage a severe bleeding episode, then blood products called cryoprecipitates, which contain concentrated amounts of vWF, or platelet concentrates should be considered. Caution should be used when treating with these blood products since they are not treated to kill viruses.

Other treatments and precautionsMedications called fibrinolytic inhibitors can be helpful in the control of intestinal, mouth, and nose bleeding. Estrogens such as are found in oral contraceptives increase the synthesis of vWF and can sometimes be used in the long-term treatment of women with mild to moderate VWD. Estrogens are also sometimes used prior to surgery in women with type 1 VWD. Some topical agents are available to treat nose and mouth bleeds. Patients with VWD should avoid taking aspirin, which can increase their susceptibility to bleeding and people with severe forms of VWD should avoid activities that increase their risk of injury such as contact sports.

PrognosisThe prognosis for VWD disease is generally fairly good and most individuals have a normal lifespan. The prognosis can depend, however on accurate diagnosis and appropriate medical treatment.

Key TermsAmniocentesisA procedure performed at 16-18 weeks of pregnancy in which a needle is inserted through a woman's abdomen into her uterus to draw out a small sample of the amniotic fluid from around the baby. Either the fluid itself or cells from the fluid can be used for a variety of tests to obtain information about genetic disorders and other medical conditions in the fetus.

Autosomal dominantA pattern of genetic inheritance where only one abnormal gene is needed to display the trait or disease.

Autosomal recessiveA pattern of genetic inheritance where two abnormal genes are needed to display the trait or disease.

Biochemical testingMeasuring the amount or activity of a particular enzyme or protein in a sample of blood or urine or other tissue from the body.

CarrierA person who possesses a gene for an abnormal trait without showing signs of the disorder. The person may pass the abnormal gene on to offspring.

Chorionic villus sampling (CVS)A procedure used for prenatal diagnosis at 10-12 weeks gestation. Under ultrasound guidance a needle is inserted either through the mother's vagina or abdominal wall and a sample of cells is collected from around the early embryo. These cells are then tested for chromosome abnormalities or other genetic diseases.

ChromosomeA microscopic thread-like structure found within each cell of the body and consists of a complex of proteins and DNA. Humans have 46 chromosomes arranged into 23 pairs. Changes in either the total number of chromosomes or their shape and size (structure) may lead to physical or mental abnormalities.

Deoxyribonucleic acid (DNA)The genetic material in cells that holds the inherited instructions for growth, development, and cellular functioning.

Desmopressin (DDAVP)A drug used in the treatment of von Willebrand's disease.

Diagnostic testingTesting performed to determine if someone is affected with a particular disease.

DNA testingAnalysis of DNA (the genetic component of cells) in order to determine changes in genes that may indicate a specific disorder.

Endothelial cellsThe cells lining the inner walls of the blood vessels.

Factor VIIIA protein involved in blood clotting that requires vWF for stability and long-term survival in the bloodstream.

GeneA building block of inheritance, which contains the instructions for the production of a particular protein, and is made up of a molecular sequence found on a section of DNA. Each gene is found on a precise location on a chromosome.

MutationA permanent change in the genetic material that may alter a trait or characteristic of an individual, or manifest as disease, and can be transmitted to offspring.

PlateletsSmall disc-shaped structures that circulate in the blood stream and participate in blood clotting.

Prenatal testingTesting for a disease such as a genetic condition in an unborn baby.

ProteinImportant building blocks of the body, composed of amino acids, involved in the formation of body structures and controlling the basic functions of the human body.

Skin hematomaBlood from a broken blood vessel that has accumulated under the skin.

von Willebrand factor (vWF)A protein found in the blood that is involved in the process of blood clotting.

For Your InformationBooks Handin, Robert I. "Disorders of the Platelet and Vessel Wall." In Harrison's Principles of Internal Medicine, edited by Anthony S. Fauci, et al. New York: McGraw-Hill, 1998.

Sadler, J.E. "Von Willebrand Disease." In The Metabolic and Molecular Basis of Inherited Disease, edited by C.R. Scriver, et al. New York: McGraw Hill, 1995.

Periodicals Ginsburg, David. "Molecular Genetics of von Willebrand Disease." Thrombosis and Haemostasis 82, no. 2 (1999): 585-591.

Nichols, William C., and David Ginsburg. "Von Willebrand's Disease." Medicine 76 (Jan. 1997): 1.

Voelker, Rebecca. "New Focus on von Willebrand's Disease." Journal of the American Medical Association 278 (October 8, 1997): 1137.

Organizations National Hemophilia Foundation. Soho Building, 110 Greene Street, Suite 406, New York, NY 10012. (212) 219-8180. http://www.hemophilia.org/home.htm.

Other Mannucci, Pier "Desmopressin (DDAVP) in the Treatment of Bleeding Disorders: The First Twenty Years." The Treatment of Hemophilia Monograph Series. No. 11 (1998).

Paper, Renee. "Gynecological Complications in Women with Bleeding Disorders." The Treatment of Hemophilia Monograph Series. No. 5 (1996).

World Federation of Hemophilia. "Protocols for the Treatment of Hemophilia and von Willebrand Disease." No. 14 (1998).

Source: Gale Encyclopedia of Medicine, Published December, 2002 by the Gale Group

The Essay Author is Lisa Maria Andres MS, CGC.

Von Willebrand Disease

by Laurie Rosenblum, MPHEn Espaol (Spanish Version)Definition

Von Willebrand disease (VWD) is an inherited blood disorder. It decreases the bloods ability to clot. As a result, bleeding lasts longer than usual. V

Von Willebrand's disease is the most common hereditary bleeding disorder affecting at least 1% of the population. It affects both sexes approximately equally. There are no racial or ethnic associations with this disorder.

Causes

VWD is caused by a reduced amount of a protein called von Willebrand Factor (vWF) or an abnormality in this protein. This protein helps blood to clot. When a person is bleeding, blood cells called platelets form a plug to stop the bleeding. Normally, vWF allows platelets to adhere to the cells that line the inside of the blood vessels (endothelium), a process necessary for successful clotting. If there is not enough vWF or if it is defective, platelets cannot properly grip onto the injured area and bleeding does not stop as quickly as it should.

VWF has a separate function of protecting against the break down of another protein involved in clottingfactor VIII:C. The relative absence of functioning vWF, therefore, can lead to minor clotting problems through this mechanism as well.

Von Willebrand disease can often be traced through several generations in a family. Some have symptoms while others just carry the gene. Most people with VWD inherit only one gene with the VWD defect. They have one of the milder forms of the disordereither type 1 or type 2. This means they have some blood clotting ability. The small percent of people who inherit two defective genestype 3 VWDhave little clotting ability and experience severe bleeding episodes.

Types 1 and 2 are usually inherited in what is known as a "dominant" pattern. A man or woman with the disease has a 50% chance of passing the gene on to his or her child. This means that if even one parent has the gene and passes it onto a child, the child gets the disease. Whether the child has no symptoms, mild symptoms, or, less commonly, severe symptoms, he or she definitely has the disease. Regardless of severity of the symptoms, the child can still pass the gene on to his or her own offspring.

Type III von Willebrand disease, however, is usually inherited in a "recessive" pattern. This type occurs when the child inherits the gene from both parents. Even if both parents have mild or asymptomatic disease, their children are likely to be severely affected.

Risk Factors

A risk factor is something that increases your chances of getting a disease or condition. The only risk factor for VWD is having family members with this disease.

Symptoms

Many people with the VWD gene have very mild symptoms or none at all. When symptoms do occur, the severity varies from person to person. Many people only notice symptoms after taking aspirin or similar medications that interfere with clotting. Symptoms usually begin in childhood and fluctuate throughout life. Common symptoms include:

Easy bruising

Frequent or prolonged nosebleeds

Prolonged bleeding from the gums and minor cuts

Heavy or prolonged bleeding during menstrual periods

Bleeding in the digestive system

Prolonged bleeding after injury, childbirth, surgery, or invasive dental procedures

Diagnosis

Your doctor will ask about your symptoms and medical history, and perform a physical exam. Blood tests may be done to check the following:

Bleeding time in VWD it will be prolonged, particularly after the administration of aspirin

Factor VIII antigen indirectly measures levels of vWF in your blood; in VWD it will be reduced

Ristocetin cofactor activity shows how well your vWF works; in VWD it will be decreased

von Willebrand factor multimer examines the different structural types of vWF in the blood; in VWD it will be reduced

Treatment

Many people with VWD do not need treatment. If you do, your treatment will depend on the type and severity of your VWD. In many cases, treatment is only necessary if you are having a surgical or dental procedure that is likely to cause bleeding.

Treatment may include:

Desmopressin a medicine that usually controls bleeding in mild cases of type I VWD by raising the level of vWF in the blood. It can be taken as:

Nasal spray (Stimate)

Injection (DDAVP)

Intravenous infusions to control your bleeding these infusions are concentrates that contain:

Factor VIII

von Willebrand Factor

Birth control pills may be used to control heavy menstrual periods in women with type 1 VWD.

Antifibrinolytic medicine (often, Amicar) can be used for bleeding in the nose or mouth. It helps keep a clot that has already formed from being dissolved.

Prevention

There are no guidelines for preventing VWD. Genetic counseling can be helpful to review a detailed family history and discuss risks and tests available for von Willibrand disease.

RESOURCES:

National Heart, Lung, and Blood Institute

http://www.nhlbi.nih.govNational Hemophilia Foundation

http://www.hemophilia.orgReferences:

Bleeding Disorders. MedlinePlus website. Available at: http://www.nlm.nih.gov/medlineplus/bleedingdisorders.html. Accessed October 7, 2005.

Longe JL and Blanchfield DS. The Gale Encyclopedia of Medicine, 2nd ed. Farmington Hills, MI: Gale Research Company; 2001.

Von Willebrand Disease. National Hemophilia Foundation website. Available at: http://www.hemophilia.org/bdi/bdi_types3.htm. Accessed October 7, 2005.

Von Willebrands disease: what you need to know about this inherited disorder. American Journal of Nursing. 2000 Feb.

Last reviewed September 2005 by Mark A. Best, MD, MPH, MBA, FCAP, FASCP