Von Willebrand Disease

Introduction

Von Willebrand disease (VWD) is considered the most common bleeding disorder in humans and some animals such as dogs [1]. VWD is named after the Finnish doctor who described the disease in the 1920s. It is estimated that 1 in 100 to 10,000 people has VWD. Patients with mild VWD symptoms It is rarely diagnosed, resulting in a “100 to 10 000” gap [2]. It is estimated to affect 1% of the total U.S. population [3].

History

In 1926, Finnish physician Erik Von Willebrand described a new bleeding disorder he called “hereditary pseudohemophilia.” He recognized that the new disease was different from hemophilia, but he could not identify the plasma factor responsible for it. many years later; this A factor was also identified and named after him, and it is now called the Von Willebrand factor (VWF)[4].

Von Willebrand Factor

Von Willebrand factor (VWF) is a multifunctional multimeric glycoprotein [5] that is synthesized in endothelial cells [6]. VWF is composed of similar subunits that contain the binding sites for glycoprotein receptors. The adhesive activity of VWF mainly depends on the size of its multimers [7]. Feng Willebrand factor plays an important role in primary and secondary hemostasis as a mediator of adhesion and a carrier of coagulation FVIII. [6] It is also involved in angiogenesis and inflammatory processes. [8] [9]

Definition

Von Willebrand disease can be inherited or acquired.

1. As an autosomal genetic disorder, it is caused by a defect in a protein factor called VWF. Types 1 and 2 are autosomal dominant and type 3 is autosomal recessive. It affects males and females equally as it is an autosomal related disorder [4][10][11].
2. Acquired VWD differs from hereditary VWD because the disease develops later in life rather than as a result of genetic inheritance. Acquired VWD may result from an autoimmune reaction in patients with heart defects; certain forms of cancer; diabetes; autoimmune disease or after use of certain drugs Propionic acid and other drugs [12]

Classification of hereditary von Willebrand disease

There are various classifications of VWD (below). Hereditary VWD is further divided into types 1, 2, and 3, and acquired VWD. The International Society for Thrombosis and Homeostasis further classifies VWD based on the qualitative and quantitative nature of the VWF deficit [13].

Types 1 and 2 are both autosomal dominant (picture): With this pattern of inheritance, affected individuals have 1 copy of the mutated gene and 1 copy of the normal gene on a pair of autosomes. This means that a person with an autosomal dominant disorder has a 50/50 chance of passing on the mutated gene and Bring chaos to each of their children. [14]

Classification of von Willebrand’s disease

Type 1 Von Willebrand Disease

Type 1 VWD is the most common. Approximately 75% of VWD patients are type 1 [15][16]. It is considered the mildest type with partially quantitative VWF deficits [15]. Due to its mild presentation, it is the most difficult to diagnose. Type 1 VWD is inherited in an autosomal dominant manner. most common manifestation Type 1 VWD is dental bleeding and bleeding after surgery or injury. [15][17]

Tooth Bleeding in Von Willebrand Disease

Type 2 Von Willebrand Disease

20-25% of VWD patients are type 2, making it the second most common disease [16]. It is known for its qualitative VWF flaws. For type 2, there is sufficient VWF factor in the blood. But due to mutations in VWF multimers [6][18], VWF factors do not work properly. It is divided into four subtypes Type 2A Type 2B Type 2M and Type 2N[5].

• Type 2A

Type 2A is the most common subtype of type 2. The amount of VWF is normal, but because of a mutation defect in the VWF protein, the platelets cannot bind to each other properly. This can cause problems with the blood clotting process [4]. Type 2A is characterized by postoperative bleeding, menorrhagia, and Bleeding after tooth extraction[5]

• Type 2B

Type 2B is the second most common subtype of type 2. It differs from type 2A in its VWF protein mutation. This defect causes VWF to bind to platelets in the bloodstream rather than at the site of injury. The body then removes the abnormally bound platelets, resulting in Decreased platelet count [16]. Type 2B presents with bruising, prone to prolonged bleeding from minor wounds and epistaxis (epistaxis) [6].

• Type 2M

M stands for multimer. Type 2M is characterized by mutations in the VWF protein multimer, resulting in reduced VWF activity and inability to bind platelets. Type 2M presents with prolonged bleeding from small wounds similar to type 2B [12].

• Type 2N[19]

The “N” refers to Normandy or Normaundie in French, the French town where the subtype was first discovered. [16] It is characterized by failure of factor VIII transport on VMF despite normal platelet binding to VWF. This results in low Factor VIII levels. 2N type is common Misdiagnosed as hemophilia A due to low Factor VIII levels. [16]

Type 3 Von Willebrand Disease

The most severe and rare type of VMD is type 3 VWD. It is characterized by the complete absence of VWF in plasma and platelets. In contrast to types 1 and 2, type 3 is autosomal recessive. Type 3 VWD presents with severe bleeding in the soft tissues, joints, muscles, nose, and bowel [15].

Clinical Manifestations

The clinical manifestations of VWD vary according to the type of VWD [15].

The most common presentations include:[20][21]

• Nasal haemorrhage
• Dental and oral cavity haemorrhage
• Prolonged wound healing
• menorrhagia is menorrhagia
• Gastrointestinal bleeding (severe)

Some common presentations in the pediatric population include: [22]

• Umbilical stump haemorrhage
• Cephalic haematoma
• Cheek haematoma
• Conjunctival haemorrhage
• After circumcision haemorrhage
• After venipuncture haemorrhage

Diagnostic Tools

Von Willebrand disease is the most common bleeding disorder, but it is also the most difficult to diagnose. [23] Unfortunately, common blood clotting screening laboratory tests such as CBC activated partial thromboplastin time (APTT) test prothrombin time (PT) test and fibrinogen test in Patients with VWD, especially those with mild to moderate VWD [24]

To diagnose VWD, screening and diagnostic laboratory tests are available. [25]

• VWD Screening Tests
• VWF antigen (VWF:Ag)

VWF antigen is a quantitative and reliable assessment tool for plasma VWF protein levels24. This method is effective in detecting VWD quantitative defect types. The normal range for VWF:Ag is 50 to 200IU/dl. Any value below 50 may indicate VWD. [26]

• VWF ristocetin cofactor activity (VWF:RCo)

VWF: RCo is the most commonly used test to assess the binding capacity of VMF24. The normal range for VWF:RCo is between 50 and 200 IU/dL. [26]

• Factor VIII activity (FVIII: C)

Measurement of FVIII:C is included in the screening laboratory test for VWD. VWF is the carrier protein of FVIII. The normal range for the FVIII:C/VWF:Ag ratio is about 1. In type 2N, the ratio is lower, and in type 3 VWD, FVIII:C is less than 10 IU/dL [26].

• VWF:RCo/VWF:Ag Ratio

The VWF:RCo/VWF:Ag ratio is used to diagnose the type of VWD. In type 1 VWD, the levels of both VWF:RCo and VWF:Ag are reduced so that the ratio between them remains around 1. In type 2 VWD, VWF:RCo is reduced compared to VWD:Ag levels, so that VWF:RCo/VWF:Ag is approximately 0.6.[26]

• VWD Confirmatory Tests

Once VWD is diagnosed, a number of confirmatory tests are run to indicate the type of VWD, such as [26]:

• Types 2A and 2B were found to have abnormal VWF multimer distribution
• VWF: CB is abnormal in types 2A and 2B and 2M.
• VWF: PB increases in type 2
• LD-RIPA increases in type 2B.
• VWF: FVIIIB decreases in type 2
• VWFpp/VWF: Ag ratio increases in type 1
• VWF gene sequencing most helpful in distinguishing type 2 variants

Medical Management

Treatment of VWD is based on the severity of symptoms and the amount of bleeding. Since most VWD patients are type 1 (mild); they do not require regular treatment. The goals of treatment are to increase circulating VWF activity and reduce bleeding. [27]

Some medicines are used to treat and reduce the symptoms of VWD, such as:

• Desmopressin

Desmopressin can be given as a nasal spray intravenously or subcutaneously. It can be easily managed at home for Type 1 VWD. Recommended dose is 0.3 mcg/kg IV or subcutaneous injection or 2 intranasal sprays (for patients over 50 kg) or 1 intranasal spray (for patients less than 50 kg) [28]

• Plasma-Derived VWF and FVIII Concentrates

Plasma-derived VWF and FVIII concentrates such as Humate P (VWF:RCo:FVIII ratio = 2.4:1) Wilate (VWF:RCo:FVIII ratio = 1:1) and Alphanate plasma-derived VWF and FVIII concentrates (VWF: RCo:FVIII ratio 1:3) is an intravenous drug used as an acute treatment for severe forms of VWD. them It can also be used as a drug to prevent bleeding. The recommended dose for major surgery is 50-60 ristocetin cofactor activity units/kg, depending on baseline VWF levels and desired target levels. [28]

• Antifibrinolytics

Antifibrinolytic drugs such as aminocaproic acid and tranexamic acid inhibit fibrinolysis. They are used as active and prophylactic therapy, especially for mucosal surfaces. They are given orally or intravenously. The recommended dose of aminocaproic acid is 100 mg/kg followed by 50 mg/kg every 6 doses Hour. In cases of menorrhagia, the dose of tranexamic acid is 1500 mg 3 times a day for 5 days. [27][28]

• Hormonal therapy

Hormone therapy is also an option for treating menorrhagia. [29]

Physical Therapy Management

Physical therapy has an important role in promoting functional skills in pediatrics and adults with VWD; that is why the National Hemophilia Foundation established a Physical Therapy Task Force to create best physical therapy practices for bleeding disorders such as VWD. [30]

The Medical and Scientific Advisory Committee (MASAC) developed guidelines and a framework for the management of physical therapy for bleeding disorders. Physiotherapy is essential for joint and muscle rehabilitation after soft tissue injury and hemarthrosis, says MASAC These clinical presentations Most occur in more severe types of VWD.

Physical Therapy Evaluation

According to MASAC; physical therapy assessment is an important part of VWD management. This assessment is designed to detect musculoskeletal and other limitations caused by bleeding disorders that affect functional activities and activities of daily living (ADL). [31]

History and Interview[31]

It includes interviewing the patient or caregiver and documenting the following:

• Personal history
• Family history
• Bleeding history
• Medical and surgical history
• Pain history
• ADL concerns   
• Occupational concerns

Joints with recurrent bleeding disorders are referred to as “target joints.” The most common target joints are the knees, elbows, ankles, and shoulders. [30]

Subjective Assessment

• Palpate joints at rest and in range of motion to detect crepitus synovitis edema or temperature.
• Circumference measurement (measurement of circumference with tape measure) to assess for edema/muscle atrophy.
• Atypical joint end sensory detection via passive range of motion.
• Manual muscle testing to assess muscle strength.
• Muscle Flexibility test.
• Sensation and proprioception.

Objective Assessment

• Balance and fall assessment
• Posture and alignment assessment
• Assessment of functional activities
• Gait analysis
• Neuromotor assessment
• Musculoskeletal Ultrasound

Physical Therapy Treatment

MASAC recommends a physical therapy program for muscle and joint bleeding in different stages of recovery (acute subacute and chronic). With the exception of the iliopsoas, all muscles follow the same guidelines, and all physiotherapy-recommended protocols are performed post-factor Alternative medicines are as follows:[32]

Acute Phase Subacute Phase Chronic Other Treatment Considerations Preventive Measures Bleeding in muscles other than iliopsoas Major Problem: Pain at rest and with exercise Primary Problem: ADL limited but no increase from baseline Pain Major Problem: ADL limited but not Electrical Pain Stimulation – Work Close collaboration with Hematologist – Patient taught to avoid overstretching – Activity Modification Education – Kinesiotape® – Treatment duration will vary based on individual needs – Blood Absorption Ultrasound can be used with caution. Monitoring for neurovascular damage during splinting – Be careful when using pressure on the affected muscle. – Use heating modalities, including ultrasound and preventive measures Physiotherapy program: – Do not compress in case of neuromuscular symptoms. – Do not actively exercise or bear weight until the bleeding has stopped. – Splints. – RICE: rest ice Compression and Elevation – TENS Physiotherapy Program: – Splints and Assistive Devices to Limit Motion – Toe Contact Weight Bearing – Isometric Contraction – Active Range of Motion – Positioning – Painless AAROM – TENS Physiotherapy Program: – Full Weight Bearing Without Assistive Devices – Postural Stretching – Range of Motion Exercises – Unrestricted Lifting – Reassessment. Iliopsoas bleeding Primary issue: Pain at rest and with exercise Primary issue: ADL restricted but no increase from baseline Pain Primary issue: ADL restricted but not Pain electrical stimulation to prevent femoral nerve paralysis/atrophy. – Carefully stretch the hip flexors. – Teach patient to avoid hyperextension – Duration of treatment varies – Monitor femoral nerve palsy Physiotherapy program: – Bed rest – Toe contact weight bearing For Home Activities – Rest – Contralateral Limb ROM Ankle Pump Involves Lower Extremity, Avoids Pain Physical Therapy Program: – Toe Contact Weight Bearing Without Added Pain – Isometric Contractions – Active Range of Motion Exercises Involves Lower Extremity Without Added Pain – Positioning on supine and prone pillows to increase range of motion in hip extension did not increase pain. – Therapeutic exercises of the unaffected extremity Range of Motion Exercises – Reassess Joint Bleeding Primary Issue: Pain at rest and with exercise Primary Issue: ADL limitation but no pain increase from baseline Primary Issue: ADL limitation but no pain – TENS – Relaxation Technique – Kinesiology Tape – Cryotherapy – Resilience stockinette – myofascial release – in collaboration with a hematologist. -Further MRI to determine if chronic synovitis is present)-Duration of treatment will vary according to individual needs. – avoid premature strenuous exercise – monitor for nerve compression – use heat therapy, including Ultrasound with precautions – do not return to sport or activity until pain free full ROM and strength Physiotherapy program: – RICE (10-20 minutes on ice every 1-2 hours) – Splint – Non-weight bearing physical therapy program with assistive devices: – Continue RICE for pain and Post-exercise splint – Night rest with splint protection – Initiation of progressive weight bearing – Mobility modifications to avoid pain – Pain-free gentle movement Range of motion – Pain-free progressive strengthening Physiotherapy program: – Dynamic splints increase ROM – Mobility Range of motion Progressive – As open chain closed chain and resistance band strengthening – Proprioceptive training – Gentle joint mobilization – Modified functional mobility – Orthotics – Reassessment

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