Von Willebrand Disease

• Hematomas and nose bleeds are the most common manifestations of the disease.
• Excessive menstrual bleeding among women.
• Excessive bleeding even with trivial wounds or oral cavity bleeding.
• There is a rare chance of gastrointestinal bleeding.
• Heavy bleeding after tooth extraction or any other oral surgery.
• In patients with vWD, bleeding is prolonged.
• After surgery, severe hemorrhage is observed.
• In patients with vWD, the common physical findings are normal, though the patients may show physical sequele including bleeding or bruises [7] [8].

The laboratory studies have revealed that there is a deficiency or a qualitative defect of vWF in patients with vWD. The levels of vWF vary with physiologic stress. The plasma levels of vWF may be normal intermittently in patients with vWD; hence repeating the tests after more than 2 weeks becomes important in order to confirm abnormal results. Tests for vWD must be avoided during pregnancy, infections or strenuous exercise as the results may not be correct.

• Screening tests: Prothrombin time (PT), FVIII coagulant activity, activated partial thromboplastin time (aPTT), are some of the important tests that must be performed to confirm vWD.
• Ristocetin cofactor (RCoF) activity: This test is an excellent tool to evaluate vWF function. In the test, ristocetin is added to the suspension of the washed formalin fixed platelets in the presence of patient’s plasma. Following this, the rate of aggregation is measured with the help of aggregometer.
• ABO-Blood groups and its impact: There exists the importance of blood group determination in patients with vWD. Individuals with O-blood group have around 50-75% of vWF levels as found in patients with other blood types.
• PT and aPTT: aPTT is mildly prolonged in half-of the patients with vWD. Low levels of FVIII cause this prolongation as one of the important functions of vWF is preventing the degradation of FVIII [7] [8].

Treatment options for patients with vWD are as follows:

• Use of Desmopressin (DDAVP)
• Transfusion therapy: The transfusion therapy is beneficial in patients with vWD where the disease is refractory to the other therapies. The fresh frozen plasma has functional vWF, but must be avoided due to possible transmission of the viral disease common with such transfusion. 
• Prophylaxis in major surgery/serious bleeding episodes: In such situations, vWF containing FVIII concentrates are beneficial. 
• Pregnancy: During pregnancy, the levels of vWF increase in most of the patients with vWD. In functionally normal vWF, the labor and delivery usually proceed normally; however, in patients with type II disease may have an increased chance of hemorrhagic problems. Hence, all patients must be monitored closely during pregnancy [9].

Though bleeding in most of the patient with vWD is manageable; there can be significant variability in the symptoms even among the family members. Patients with type II and type III vWD, the episodes of bleeding may be severe and life-threatening. Individuals with low levels of FVIII may also develop anthropathies [5].

Complications

• Iron deficiency anemia is common among women who experience heavy bleeding.
• Swelling and severe pain occurs when the bleeding occurs in the joints. 
• Death may also result in some cases due to abnormal bleeding, which cannot be controlled [6].

vWD is an inherited disease due to the mutation of genes, except, for the rare acquired form which is caused by the antibodies to vWF. There are three categories of vWD:

1. Type I is also called partial quantitative deficiency.
2. Type II or qualitative deficiency: This type of disease is further categorized based on the characteristics of functional vWF: II (A, B, N, M).
3. Type III also called total deficiency [2] [3].

The estimates suggest that clinically significant vWD is seen in 125 persons per million populations. Only about 0.5-5 persons per million populations are affected by the severe form of the disease.

Though both males and females have equal probability of having this disease, the phenotypic visibility is more among women owing to the menorrhagia. Since vWD is an inherited condition, the symptoms related to bleeding can occur even at a young age. Recent reports suggest that there is a decrease in the bleeding tendency as the patient age [4].

Chromosome 12 contains the vWF gene, which is located near the tip of the short arm of the said chromosome. This gene has 52 exons, similar to the size to FVIII gene. The expression of this gene is not allowed in the megakaryocytes, and endothelial cells. It is interesting to note here that there exists a pseudogene (partial, nonfunctional duplication of the gene 12) on chromosome 22.

• vWD type I: This type of disease is caused by quantitative deficiency (mild/moderate) of vWF.(less by 20-50% of normal levels).
• vWD type II: When the disease occurs due to the qualitative abnormalities of vWF, it is categorized as the type II vWD. The most common abnormality is the selective loss of large or medium sized multimers.
• vWD type III: When the patient inherits a mutant vWF gene from both the parents, this rare type of vWD is seen. In this type of vWD there is a severe deficiency of the plasma or platelet vWF, thus causing profound bleeding disorder. This type of disease is very rare (1 in every one-million persons) [3].

Patients with known vWD must be wary of the physical activity which increases their chances of hemorrhage. Use of aspirin-containing compounds must be avoided [10].

Von Willebrand disease (vWD) is a hemorrhagic disorder. The disease is genetically inherited and is clinically heterogeneous in nature. vWD is caused by the deficiency or the dysfunction of a glycoprotein, von Willebrand factor (vWF). vWF is a large glycoprotein which is released from the storage granules located in platelets and endothelial cells in response to the stimuli. The interaction between defective protein and platelets and vessel wall causes primary hemostatis.

The primary functions of the protein are as follows:

1. To facilitate the adhesion of the platelets at the site of injury.
2. To stabilize FVIII present in the coagulation cascade [1].

Von Willebrand disease (vWD) is the most common genetic coagulation disorder caused by missing or defective von Willebrand factor (VWF), a clotting protein.

Patients must be informed about their condition so that they can avoid any situation that can aggravate their coagulation disorder. Patients are advised to avoid drugs containing aspirin. When undergoing any surgery or dental procedures, the patient must seek the opinion of a hematologist.

1. Keeney S, Bowen D, Cumming A, et al. The molecular analysis of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors’ Organization Haemophilia Genetics Laboratory Network. Haemophilia. 2008;14:1099-1111.
2. Udvardy ML, Szekeres-Csiki K, Hársfalvi J. Novel evaluation method for densitometric curves of von Willebrand factor multimers and a new parameter (M(MW)) to describe the degree of multimersation.Thromb Haemost. Aug 2009;102(2):412-7.
3. Sutherland MS, Cumming AM, Bowman M, et al. A novel deletion mutation is recurrent in von Willebrand disease types 1 and 3. Blood. Jul 30 2009;114(5):1091-8.
4. Byams VR, Kouides PA, Kulkarni R, et al. Surveillance of female patients with inherited bleeding disorders in United States Haemophilia Treatment Centres. Haemophilia. Jul 2011;17 Suppl 1:6-13
5. Sadler JE, Budde U, Eikenboom JC, et al. Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. J Thromb Haemost. 2006;4:2103-2114.
6. Gallinaro L, Cattini MG, Sztukowska M, et al. A shorter von Willebrand factor survival in O blood group subjects explains how ABO determinants influence plasma von Willebrand factor. Blood. 2008;111:3540-3545.
7. Nichols WL, Hultin MB, James AH, et al, and the NHLBI von Willebrand Disease Expert Panel. The Diagnosis, Evaluation, and Management of von Willebrand Disease. Bethesda, Md: National Heart, Lung, and Blood Institute. NIH publication no. 08-5832. December 2007.
8. Rodeghiero F, Castaman G, Tosetto A. How I treat von Willebrand disease. Blood. Aug 6 2009;114(6):1158-65.
9. Franchini M, Targher G, Montagnana M, Lippi G. Antithrombotic prophylaxis in patients with von Willebrand disease undergoing major surgery: when is it necessary?. J Thromb Thrombolysis. Aug 2009;28(2):215-9.
10. Cumming AM, Bowman M, et al. A novel deletion mutation is recurrent in von Willebrand disease types 1 and 3. Blood. Jul 30 2009;114(5):1091-8