• 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].

• Inflammation

  Levels of VWF can temporarily increase in response to stress, exercise, pregnancy, inflammation, or infection. [merckmanuals.com]

  Arthritis is the inflammation of joints caused by the gradual degradation of cartilage Pain that is immediately relieved by resting the feet. [tobi-project.eu]

  suggesting that inflammation may be the shared stimulus for release of endothelial cell-derived ULVWF. [ashpublications.org]

• Ecchymosis

  The most common symptoms in people diagnosed with von Willebrand disease include the following: Nose bleeding Abnormal or easy bruising (also known as ecchymosis or hematoma) Bleeding of the gums Bleeding after surgery Gastrointestinal bleeding Heavy [ihtc.org]

  Oral Manifestations[edit] In the case of severe deficiency, there may be spontaneous gingival bleeding, ecchymosis, and epistaxis. [en.wikipedia.org]

  The most common clinical manifestations include: epistaxis 3,4,10, menorrhagia 2-4,10, gingival bleeding 2-10, ecchymosis 2,4,10, hematoma 10, gastrointestinal bleeding 3, hemarthrosis 2,3, and prolonged bleeding after surgeries 4. [scielo.br]

• Pediatric Disease

  All Mental Disorders and Treatment All Mental Disorders and Treatment From A-Z Pediatric Disease and Treatment Pediatric disease and treatment app for childhood diseases and child treatment. [apkamp.com]

• Infertility

  IVF is becoming increasingly popular for women experiencing infertility, and that includes women with VWD. IVF does present risks for bleeding related to procedures such as hormone injections, egg retrieval, and manipulation of the cervix or uterus. [hematologyandoncology.net]

• Easy Bruising

  bruising Frequent or excessive nosebleeds Heavy menstrual bleeding Heavy and prolonged bleeding after surgery, dental work, injury or childbirth [ilbcdi.org]

  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]

  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]

  Von Willebrand Disease - Most common inherited bleeding disorder Clinical • Easy bruising • Skin bleeding • Prolonged bleeding from mucosal surfaces (oropharyngeal, GI. uterine) Laboratory • Normal platelet count (mild thrombocytopenia in type 2B) • Normal [grepmed.com]

• Prolonged Bleeding

  Heavy and prolonged bleeding after surgery, dental work, injury or childbirth [ilbcdi.org]

  […] in 2B) 3. similar to type 1 but a severe autosomal recessive form (1%) CLINICAL FEATURES Presentation asymptomatic epistaxis bruising haemarthrosis haematoma menorrhagia Previous and/or family history of the above INVESTIGATIONS normal platelet count prolonged [lifeinthefastlane.com]

  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]

  Laboratory results usually show a prolonged bleeding time, possibly a prolongation of APPT and a deficiency of factor VIII. However, vWD cannot be ruled out if the APPT and F VIII levels are normal. [lecturio.com]

  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]

• Yawning

  By Richard Klasco, M.D Photo Credit Ask Well Photo Credit Why Do We Yawn? Reading about yawning makes people yawn. You are probably yawning right now. By Roni Caryn Rabin Latest Search Latest Articles Search Articles 13845 results for sorted by [nytimes.com]

  Nichols WL, Rick ME, Ortel TL, Montgomery RR, Sadler JE, Yawn BP, James AH, Hultin MB, Manco-Johnson MJ, Weinstein M. Clinical and laboratory diagnosis of von Willebrand disease: a synopsis of the 2008 NHLBI/NIH guidelines. [ghr.nlm.nih.gov]

  Yawn, B. et. al.(2009 December 1) Diagnosis and Management of Von Willebrand Disease: Guidelines for Primary Care. American Family Physician [On-line information]. [labtestsonline.kr]

  YAWN, von Willebrand disease (VWD): evidence‐based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA), Haemophilia, 14, 2, (171-232), (2008). E. ASATIANI and C. M. [doi.org]

  Fonti utilizzate nelle precedenti revisioni Yawn, B. et. al.(2009 December 1) Diagnosis and Management of Von Willebrand Disease: Guidelines for Primary Care. American Family Physician [On-line information]. [labtestsonline.it]

• 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]

  gums, and bleeding after dental extraction. [pharmacytimes.com]

  Signs and symptoms include bruises, nose bleeding, gum bleeding following a dental procedure, heavy menstrual bleeding, and gastrointestinal bleeding. [fpnotebook.com]

  The main symptoms are: bruising easily or getting large bruises frequent or long-lasting nosebleeds bleeding gums heavy or long-lasting bleeding from cuts in women, heavy periods and bleeding during or after labour heavy or long-lasting bleeding after [nhs.uk]

• 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]

  Deposition of hemosiderin and other blood degradation products on the tooth surfaces and turn them brown can occur if continuous oral bleeding over long periods.[31] The location of oral bleeds was as follows: labial frenum, 60%; tongue, 23%; buccal mucosa [en.wikipedia.org]

  Biting on a tea bag can help stop oral bleeding because tannin in tea promotes local vasoconstriction and clotting. Topical adrenaline promotes vasoconstriction and stimulates the release of stored vWF and factor VIII. [journals.lww.com]

  The following treatment options can be employed in treating a bleeding patient with vWD 64 : Local measures: Minor bleeding from nasal or oral bleeding may be managed with prolonged local pressure to the injury site or with the use of certain topical [doi.org]

  The aim is to determine the responsiveness to prophylaxis in patients with clinical manifestations of joint, gastrointestinal and/or nasal/oral bleeding, or menorrhagia, and the dose and intervals of treatment required to control bleeding episodes. [karger.com]

• Purpura

  혈전성 혈소판감소성 자반증(thrombotic thrombocytopenic purpura)(M31.1) D69.0 알레르기성 자반증(Allergic purpura) 아나필락토이드 자반증(Anaphylactoid purpura) 헤노흐(-쇤라인) 자반증(Henoch(-Schonlein purpura) 출혈성 비혈소판감소성 자반증(Haemorrhagic nonthrombocytopenic purpura) 특발성 비혈소판감소성 자반증(Idiopathic [dic.impact.pe.kr]

  An infant with presumed maternal immune thrombocytopenic purpura had persistent thrombocytopenia with platelet clumping. [ncbi.nlm.nih.gov]

  Von Willebrand Diseases Idiopathic Thrombocytenic Purpura Diseases of Plasma Include: Deep Vain Thrombosis Disseminated Intravascular Coagulation Hypercogulable State Van Willebrand Diseases [play.google.com]

  Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. [citeseerx.ist.psu.edu]

• Petechiae

  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]

  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]

  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]

• Contusion

  As in adults, acute lung injury (ALI) in children occurs as a consequence of various direct (e.g., infectious pneumonia, bronchiolitis, aspiration, traumatic lung contusion) or indirect (e.g., sepsis, shock, massive blood transfusion, non-pulmonary trauma [frontiersin.org]

• Epistaxis

  Summary Clinical description The disease manifests as mucocutaneous bleeding anomalies (menorrhagia, epistaxis, gastrointestinal hemorrhage etc. ). [orpha.net]

  Epistaxis 1. Three or more bleeding episodes in a six-month period that required treatment with VWD concentrates or red cell transfusions. [clinicaltrials.gov]

  Presentation This varies according to the extent of the deficiency: Bleeding tendency from mucosa - eg, epistaxis, menorrhagia (consider in women with no other obvious cause). [patient.info]

  […] quantitative reduction in von Willebrand factor (vWF) (90% of cases) 2. qualitative abnormality in vWF (9%) – 5 subtypes (DDAVP contraindicated in 2B) 3. similar to type 1 but a severe autosomal recessive form (1%) CLINICAL FEATURES Presentation asymptomatic epistaxis [lifeinthefastlane.com]

• Intracranial Hemorrhage

  Operative vaginal deliveries, in which there may be an increased risk of trauma to the newborn, should be avoided because of the potential risk of intracranial hemorrhage (15). [acog.org]

  hemorrhages Postnatal disorders associated with infantile spasms include the following: Pyridoxine dependency Inborn errors of metabolism such as nonketotic hyperglycinemia, maple syrup urine disease, phenylketonuria, biotinidase deficiency, lysosomal [emedicine.medscape.com]

• Vaginal Bleeding

  No serious bleeding episodes were noticed during delivery or postpartum period. Two healthy babies were delivered from the cases Nos. 2 and 3. It is acknowledged that vaginal bleeding is common during first trimester of pregnancy. [ncbi.nlm.nih.gov]

  In type 3 VWD women, VWF and FVIII do not increase during pregnancy and thus VWF/FVIII concentrates may be required during pregnancy to control intermittent vaginal bleeding and at delivery or for Cesarean section. [haematologica.org]

• Dysmenorrhea

  The proband is a 37-year-old female who suffers from dysmenorrhea and menorrhagia. [ncbi.nlm.nih.gov]

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.
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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.
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