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Von Willebrand Disease

Von Willebrand Factor Deficiency

Von Willebrand disease (vWD) is a common, inherited hemorrhagic disorder.

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Presentation

  • 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].
Hypoxemia
  • We report a 14 years old white girl, with a history of type 1 von Willebrand disease (vWd), recipient of 2 units' fresh-frozen plasma (FFP) and 1 unit whole blood transfusion who developed an acute respiratory distress with severe hypoxemia and bilateral[ncbi.nlm.nih.gov]
Pseudotumor
  • Pseudotumor (PT) represents a serious complication of hemophilia. Case reports of oral PTs in VWD remain scarce. An 11-year-old Caucasian female presented with an expansile gingival mass of the posterior maxilla.[ncbi.nlm.nih.gov]
Prolonged Bleeding
  • Here, we report the first known case of congenital platelet disorder and von Willebrand disease presenting as prolonged bleeding after cleft lip and palate repair.[ncbi.nlm.nih.gov]
  • Seven abnormalities have been reported to characterize the disease: prolonged bleeding time, capillary abnormality, thrombocytopathy, reduced blood-clotting factor VIII levels in the plasma, overresponse of factor VIII to transfusion, and reduced platelet[jamanetwork.com]
  • Von Willebrand disease is a bleeding disorder that slows the blood clotting process, causing prolonged bleeding after an injury.[ghr.nlm.nih.gov]
Easy Bruising
  • Von Willebrand disease (VWD) is characterized by bleeding symptoms that result in easy bruising, skin bleeding, prolonged bleeding from mucosal surfaces, heavy menstrual bleeding, and serious bleeding from the gastrointestinal tract.[ncbi.nlm.nih.gov]
  • The main symptoms are easy bruising, frequent or prolonged nosebleeds, heavy or prolonged menstrual bleeding and prolonged bleeding following injury, surgery, dental work or childbirth.[nm.org]
  • Symptoms can include easy bruising, nosebleeds, bleeding from the gums after a dental procedure, heavy menstrual bleeding in women, blood in the stool and urine, and excessive bleeding after a cut or other accident or after surgery.[medicinenet.com]
  • bruising Frequent or excessive nosebleeds Heavy menstrual bleeding Heavy and prolonged bleeding after surgery, dental work, injury or childbirth[ilbcdi.org]
Bleeding Gums
  • Signs and symptoms include bruises, nose bleeding, gum bleeding following a dental procedure, heavy menstrual bleeding, and gastrointestinal bleeding Includes true von willebrand disease with mutation at the vwf locus, as well as mimicking disorders with[icd9data.com]
  • Signs and symptoms include bruises, nose bleeding, gum bleeding following a dental procedure, heavy menstrual bleeding, and gastrointestinal bleeding.[fpnotebook.com]
  • gums, and bleeding after dental extraction.[pharmacytimes.com]
Oral Bleeding
  • Can treat oral bleeding with a mouth-wash of TXA! Crush tablets in 10-15ml of water and have patient hold that in their mouth for 5 min before swallowing.[pedemmorsels.com]
Lesion of the Tongue
  • In this article, we report a 21-year-old female who had von Willebrand disease presenting with 1x1 cm lesion of the tongue. The lesion was located at the anterior one-third in midline tongue throughout full-thickness.[ncbi.nlm.nih.gov]
Purpura
  • An infant with presumed maternal immune thrombocytopenic purpura had persistent thrombocytopenia with platelet clumping.[ncbi.nlm.nih.gov]
  • Platelets function well enough that petechiae and purpura rarely occur.[merckmanuals.com]
  • ICD-10-CM Codes › D50-D89 Diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism › D65-D69 Coagulation defects, purpura and other hemorrhagic conditions › D68- Other coagulation defects › Von Willebrand's disease[icd10data.com]
Petechiae
  • Platelets function well enough that petechiae and purpura rarely occur.[merckmanuals.com]
  • The examiner should note the size, location, and distribution of any ecchymoses, hematomas, or petechiae, and should assess for evidence of risks of increased bleeding, such as the following [12] : Jaundice or spider angiomata Splenomegaly Arthropathy[emedicine.medscape.com]
  • The von Willebrand disease… …always presents itself in form of petechiae. …always presents itself in form of sugillations. …always presets itself in form of a purpura. …can often take an asymptomatic course. …always takes an asymptomatic course. 2.[lecturio.com]
  • Physical examination findings that may suggest a bleeding disorder include petechiae, ecchymoses, or other evidence of recent bleeding, although absence of these signs does not exclude the possibility of an underlying bleeding condition (7).[acog.org]
  • […] diameter, bleeding that requires a pad or tampon change more than hourly, and low serum ferritin levels. 13 The physical examination should be directed at detecting signs of bleeding, including size, location, and distribution of ecchymoses, hematomas, and petechiae[aafp.org]
Epistaxis
  • Summary Clinical description The disease manifests as mucocutaneous bleeding anomalies (menorrhagia, epistaxis, gastrointestinal hemorrhage etc. ). Etiology Type 2M VWD is caused by mutations in the VWF gene.[orpha.net]
  • She presented with severe meno-metrorrhagia, which had increased drastically within the past 3 months, associated more recently by gum bleeding and epistaxis. The coagulation screen showed a prolonged bleeding time.[ncbi.nlm.nih.gov]
Vaginal Bleeding
  • It is acknowledged that vaginal bleeding is common during first trimester of pregnancy.[ncbi.nlm.nih.gov]
Dysmenorrhea
  • The proband is a 37-year-old female who suffers from dysmenorrhea and menorrhagia.[ncbi.nlm.nih.gov]

Workup

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].
Bilateral Pulmonary Infiltrate
  • pulmonary infiltrate on chest X-ray within 3 hours of the whole blood transfusion, completely reversible after mechanical ventilation.[ncbi.nlm.nih.gov]

Treatment

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].

Prognosis

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

Etiology

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].

Epidemiology

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].

Sex distribution
Age distribution

Pathophysiology

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].

Prevention

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].

Summary

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].

Patient Information

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.

References

Article

  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

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Last updated: 2019-07-11 20:54