INTRODUCTION:

Von Will brand disease (VWD) is the most common type of bleeding disorder, affecting up to 1% of the world’s population. Since symptoms are often mild, a significant majority of patients remain undiagnosed. With all forms of VWD, however, bleeding episodes can be severe and may require treatment, particularly during or following surgery or dental work. The diagnosis of VWD is complex and should be made by physicians experienced in the treatment of bleeding disorders. However, the primary care physician can and should play a role in recognizing the signs and symptoms of VWD and in referring patients for proper management Von Willebrand disease (vWD) disease (vWD) discovered by Erik Adolf Von Willebrand, is the most common hereditary blood-clotting disorder in humans.

An acquired form can sometimes result from other medical conditions.It arises from a deficiency in the quality or quantity of Von Willebrand disease (vWD)factor (vWF), a multimeric protein that is required for platelet adhesion. It is known to affect humans and several breeds of dogs. The three forms of vWD are: hereditary, acquired, and pseudo or platelet type. The three types of hereditary vWD are: vWD type 1, vWD type 2, and vWD type 3. Type 2 contains various subtypes. Platelet type vWD is also an inherited condition.^[1]

BIOLOGICAL FUNCTIONS OF VWF:

In contrast to most of the other coagulation factors, VWF functions in hemostasis as an adhesive protein that binds to several ligands that are critical components of the hemostatic process (Figure 1). VWF binds to:

1 Platelets and the subendothelium to promote platelet adhesion.

2 Activated platelets to promote platelet aggregation.

3 FVIII to prevent premature degradation of this coagulation cofactor.

TYPES OF VWD:

The International Society on Thrombosis and Haemostasis last published their official recommendations concerning VWD classification in 2006. In this classification, VWD is considered as either a quantitative (type 1 and type 3) or qualitative (type 2)

TYPE 1 VWD:

This is the most common form of VWD, accounting for ~80% of all cases. The condition is transmitted as an autosomal dominant trait with incomplete penetrance. Type 1 disease is characterized by a mild to moderate (0.05-0.50 U/mL) reduction in plasma levels of VWF. The VWF is functionally normal and the plasma level of factor VIII coagulant activity (FVIII:C) is reduced in proportion to the VWF level. Patients manifest a spectrum of mucocutaneous bleeding symptoms, the severity of which usually correlates with the level of their VWF deficiency.

TYPE 2 VWD:

The current classification of VWD recognizes four distinct qualitative forms of VWD: types 2A, 2B, 2M, and 2N disease. The clinical manifestations of the type 2 variants of VWD are similar to those of type 1 disease. Type 2A VWD This condition represents a loss of the platelet dependent function of VWF through the absence of the high molecular weight forms of the protein. Type 2B VWD This VWD subtype represents a classical gain-of function genetic trait. Type 2B VWD mutations enhance the binding of VWF to the glycoprotein Ib platelet receptor and result in spontaneous VWF platelet interactions in the circulation, a phenomenon that does not occur with normal VWF. As a result of the abnormal platelet interactions, these patients often show mild/moderate thrombocytopenia (low platelet count).

TYPE 3 VWD:

Type 3 disease has a prevalence of between 1 and 3 per million in most populations, although in certain locations where consanguineous marriages are more frequent the prevalence is significantly higher. The condition is inherited as an autosomal recessive trait, with most parents of type 3 patients showing few if any symptoms of bleeding. In type 3 disease, VWF levels are always less than 0.05 U/mL and are often undetectable. The plasma FVIII:C level is reduced to between 0.01 and 0.10 U/mL. These patients manifest severe recurrent mucocutaneous bleeding, as well as frequent soft tissue and musculoskeletal bleeding. Over time, if treatment is inadequate, chronic musculoskeletal damage occurs and type 3 patients may require joint replacement surgery in middle age. ^[2]

The role of Von Willebrand disease (vWD) factor in hemostasis

a. Mediates platelet adhesion to the damaged vessel wall

b. Participates in platelet aggregation

c. Carrier protein for factor VIII

SYMPTOMS:

The clinical assessment of VWD relies heavily upon the acquisition of an objective personal history of excessive mucocutaneous bleeding. Many of the bleeding symptoms seen in VWD also occur frequently in the normal population. Thus, while a standard clinical history may identify patients with an excessive bleeding tendency, relatively brief and validated bleeding scoring questionnaires are now available and may facilitate the identification and classification of “clinical bleeders”. The most frequent symptoms experienced by patients with VWD are:

1) Recurrent Epistaxis

2) Prolonged Bleeding From Lacerations

3) Easy Bruising

4) Gingival Bleeding

5) Menorrhagia

6) Prolonged Post-Procedural Bleeding

7) Heavy or Prolonged Bleeding After Childbirth.

In some women with VWD, menorrhagia may be the only bleeding manifestation. It is therefore especially important to conduct a detailed assessment of the patient’s menstrual history. Prolonged and excessive bleeding is often documented after oral surgical procedures such as tonsillectomy and wisdom teeth extraction. In contrast, soft tissue bleeds, muscle hematomas, and hemarthroses are rarely encountered in VWD, except in the severe type 3 form of the disease, where very low FVIII levels accompany undetectable levels of VWF. Because the bleeding tendency in VWD is relatively mild in many patients and will only pose problems with provocation of hemostasis (i.e. with surgery or trauma) there may not be an obvious clinical history of spontaneous bleeding problems. This may be especially true in young children and males in who challenges to the hemostatic system may not have been encountered. In patients with the severe form of VWD (type 3), symptoms typical of hemophilia, such as hemarthrosis and muscle hematomas, are the result of concomitantly reduced FVIII levels.

Inheritance patterns of Von Willebrand disease (vWD) disease

· Type 1 VWD Autosomal dominant ~70% penetrance

· Type 2 VWD 2A, 2B, and 2M - Autosomal dominant 2N - Autosomal recessive

· Type 3 VWD Autosomal recessive ^[3]

Fig No.1 Von Willebrand Disease Type-III

CAUSES:

The usual cause of Von Willebrand disease (vWD) disease is an inherited abnormal gene that controls Von Willebrand disease (vWD) factor, a protein that plays a key role in blood-clotting. When you have low levels of this protein or it doesn't work as it should, small blood cells called platelets cannot stick together properly, nor can they attach themselves normally to the blood vessel walls when an injury has occurred. The result is interference with the clotting process, and, sometimes, uncontrolled bleeding.

Von Willebrand disease (vWD) factor carries an additional substance, called factor VIII, that helps stimulate clotting. Many people with Von Willebrand disease (vWD) disease also have low levels of factor VIII. This is also one of the substances involved in another inherited clotting disorder called hemophilia. But unlike hemophilia, which mainly affects males, Von Willebrand disease (vWD)disease affects males and females and is usually milder.

Rarely, Von Willebrand disease (vWD) disease can develop later in life in people who didn't inherit an abnormal gene from a parent. This is known as acquired Von Willebrand disease (vWD) disease, and it's likely caused by another medical condition.

DIAGNOSIS:

Because many people with Von Willebrand disease (vWD) disease have mild signs and symptoms, the condition can be difficult to diagnose. If you have any indication of a bleeding disorder, your doctor may refer you to a blood disorders specialist (hematologist). To evaluate you for Von Willebrand disease (vWD) disease, your doctor will likely ask you detailed questions about your medical history and check for bruises or other signs of recent bleeding.

Your doctor will also likely recommend the following blood tests:

1) Von Willebrand disease (vWD)factor antigen: This test determines the level of Von Willebrand disease (vWD)factor in your blood by measuring a particular protein.

2) Ristocetin cofactor activity: This test measures how well the Von Willebrand disease (vWD)factor works in your clotting process. Ristocetin, which is an antibiotic, is used in this laboratory testing.

3) Factor VIII clotting activity: This test shows whether you have abnormally low levels and activity of factor VIII.

4) Von Willebrand disease (vWD)factor multimers: This test evaluates the specific structure of Von Willebrand disease (vWD)factor in your blood, its protein complexes (multimers) and how its molecules break down. This information helps identify the type of Von Willebrand disease (vWD)disease you have.

The results of these tests can fluctuate in the same person over time due to factors such as stress, exercise, infection, pregnancy and medications. So you may need to repeat some tests. If you have Von Willebrand disease (vWD)disease, your doctor may recommend that family members undergo the same or similar tests to determine if this condition runs in your family.

TREATMENT:

Even though Von Willebrand disease (vWD)disease is a lifelong condition with no cure, treatment can help prevent or stop bleeding episodes. Your treatment depends on:

1) The type and severity of your condition

2) How you've responded to previous therapy

3) Your other medications and conditions

Your doctor may suggest one or more of the following treatments to increase your Von Willebrand disease (vWD)factor, strengthen blood clots or, in women, control heavy menstrual bleeding:

1) Desmopressin:

This medication is available as an injection (DDAVP) or nasal spray (Stimate). It's a synthetic hormone, similar to the natural hormone vasopressin. It controls bleeding by stimulating your body to release more Von Willebrand disease (vWD)factor already stored in the lining of your blood vessels. DDAVP is usually effective in people with type 1 and some subtypes of type 2 disease.

Many doctors consider DDAVP the first treatment to use in the management of Von Willebrand disease (vWD)disease. Some women use the nasal spray (Stimate) at the beginning of their menstrual periods to control excessive bleeding. It can also be effective when used before a minor surgical procedure.

1) Replacement therapies:

These include infusions of prepared doses of concentrated blood-clotting factors containing Von Willebrand disease (vWD)factor and factor VIII (Humate-P, others). These therapies can be useful in all disease types. Your doctor may recommend them if DDAVP isn't an option for you or was ineffective.

Another replacement therapy approved by the FDA for treating adults 18 and older is a genetically engineered (recombinant) Von Willebrand disease (vWD)factor product (Vonvendi). Because recombinant factor is made without plasma, it may reduce the risk of a viral infection or allergic reaction.

1) Contraceptives: For women, these can be useful for controlling heavy bleeding during menstrual periods. The estrogen hormones present in birth control pills can boost levels of Von Willebrand disease (vWD)factor and factor VIII activity. This effect is likely available with birth control patches, though further study is needed to confirm it.

2) Clot-stabilizing medications: These anti-fibrinolytic medications — such as aminocaproic acid (Amicar) and tranexamic acid (Cyklokapron, Lysteda, others) — can help stop bleeding by slowing the breakdown of blood clots. Doctors often prescribe these drugs before or after a surgical procedure or tooth extraction.

3) Drugs applied to cuts: A fibrin sealant (Tisseel VHSD) placed directly on a cut helps curtail bleeding. These substances are applied like a glue using syringes.^[4]

If your condition is mild, your doctor might recommend treatment only when you're undergoing surgery or dental work or when you've experienced trauma.

CONCLUSION:

In conclusion, a good medical history and family history must be obtained from the patient in order to make an early diagnosis and prevent complications in subclinical cases of vWD, which is the most common hemorrhagic diathesis. The importance of a detailed medical history is emphasized. Further tests are recommended in patients who have a history of prolonged bleeding as bleeding time and other routine coagulation tests done preoperatively cannot always make a definite diagnosis.

REFERENCES:

1. https://www.mayoclinic.org/diseases-conditions/von-willebrand-disease/symptoms-causes/syc-20354978

2. https://www.google.co.in/search?rlz=1C1CHZL_enIN736IN737&tbm=isch&q=von+willebrand+disease&chips=q:von+willebrand+disease,online_chips:symptoms&sa=X&ved=0ahUKEwiL77yM4OvXAhULvo8KHTsLCpsQ4lYIJygC&biw=1280&bih=869&dpr=1

3. http://ir.uiowa.edu/pog/vol3/iss2/9/

4. https://www.google.co.in/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwiCk_vf5uvXAhXJtY8KHcQrByAQjRwIBw&url=http%3A%2F%2Fmedifitbiologicals.com%2Fvon-willebrand-disease%2F&psig=AOvVaw2A6vsLgKAlkOWA5_aJr7ok&ust=1512318641991723

Received on 24.12.2017 Modified on 15.01.2018

Asian J. Res. Pharm. Sci. 2018; 8(1):41-44.

DOI: 10.5958/2231-5659.2018.00009.7