Von Willebrand Disease Overview: Causes, Effects and Management Strategies.

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Von Willebrand disease (VWD) is the most common inherited bleeding disorder in humans (Williams & Patel, 2015). The condition is characterised by prolonged mucous membrane and skin bleeds (Green, 2018) and, in more severe forms, by bleeding of the joints (Swedish Council on Health Technology, 2011). These bleeds occur due to inadequate levels or dysfunction of von Willebrand factor (VWF; Swedish Council on Health Technology, 2011), which plays a significant role in platelet adhesion and aggregation during haemostasis (Peyvandi, Garagiola, & Baronciani, 2011). There are three main classifications of VWD: Type 1, Type 2 and Type 3, all of which are based on the quantity and quality of VWF (Green, 2018). The inheritance pattern for most patient types of VWD is autosomal dominant (Green, 2018), affecting both men and women equally (Cameron, Jelinek, Kelly, Brown, & Little, 2015). There are, however, rare cases of Acquired von Willebrand syndrome (AVWS) that can also occur (Nichols et al., 2008). Diagnosis of VWD can be complex (Williams & Patel, 2015), requiring detailed personal and familial history of bleeding symptoms in addition to screening tests and diagnostic tests to confirm diagnosis (Lee, Berntorp, & Hoots, 2014). Several treatments exist for the management of VWD, tailored to the type and severity of the condition (Green, 2018).

Pathophysiology

VWD is a bleeding disorder that causes prolonged mucosal bleeding following vascular injury and is attributable to dysfunction or deficiency of the plasma protein VWF, inhibiting the formation of haemostatic plugs (Green, 2018). VWF is an essential component of haemostasis (Williams & Patel, 2015), with two distinct functions responsible for binding and stabilisation of blood coagulating factor VIII (FVIII) and platelet adhesion to sites of vascular damage (Hassan, Saxena, & Ahmad, 2012). It is synthesised in endothelial cells and megakaryocytes (Lee et al., 2014) and can be found throughout the body in blood plasma and platelets in varying multimeric sizes (Hassan et al., 2012). The larger sizes have been noted to be more effective in the process of haemostasis (Hassan et al., 2012).  VWF carries out its primary functions secondary to vascular injury (Williams & Patel, 2015). This injury leaves subendothelial collagen cells exposed which stimulates release of VWF by several triggers such as histamine, thrombin, fibrin and estrogen (Peyvandi et al., 2011). VWF then goes on to facilitate binding of FVIII and platelets to collagen cells via glycoprotein 1b (GPIb) receptors which are located on the platelet surface (Hassan et al., 2012). Following this adhesion, platelet activation occurs via intracellular signalling (Reininger, 2008). Once activated, platelets undergo a conformational change leading to the activation of platelet glycoprotein 2b3a (GPIIbIIIa) receptor allowing mediation of platelet aggregation via fibrinogen binding and eventual thrombus formation thus completing primary haemostasis (Federici, 2011).

Patients with VWD who possess insufficient VWF to carry out normal haemostasis may present clinically with characteristic symptoms such as contusions, epistaxis, menorrhagia, prolonged bleeds from minor wounds, post tooth extractions, surgery, child birth, and gastrointestinal bleeds (Federici, 2011). Severe symptoms such as musculoskeletal bleeding are more likely to occur in severe classifications (Federici, 2011). Within the 3 types of VWD, an additional four subcategories falling within Type 2, all of which have unique clinical features and significance with regard to diagnosis and treatment (Sadler et al., 2006). Type 1 is the most commonly encountered form of VWD and is defined by decreased VWF activity associated with reduced synthesis, intracellular retention or due to increased clearance (Green, 2018). Type 2 patients are further categorised into four subtypes, Type 2A presents with reduced synthesis or higher than normal proteolysis of high-molecular-weight VWF multimers, Type 2B shows increased affinity of VWF to GPIb platelet receptors and Type 2M show normal measurements of multimers with an inability to bind to collagen or platelet GPIb receptors, while binding site mutations for FVIII characterise Type 2N patients (Green, 2018). Type 3 is rare among patients and presents with complete or near absence of VWF attributed to significant gene deletions that affect synthesis and secretion of VWF (Green, 2018). Acquired von Willebrand syndrome is a rare haemorrhagic condition and presents with symptoms similar to inherited VWD (Mital, 2016). Characteristically, AVWS does not present with previous personal and familial bleeding symptoms and occurs more often in older age groups (Mital, 2016). Development normally occurs as a result of other conditions such as lymphoproliferative, myeloproliferative, cardiovascular and autoimmune disorders but may also present with some non-haematological conditions as well as in the use of some prescription drugs (Mital, 2016). Due to complexity, the pathology of AVWS is not fully understood (Mital, 2016). Deficiency of functioning VWF is thought to occur in the presence of specific antibodies against VWF, its absorption onto surfaces of neoplastic cells, mechanic injury or frequency of clearance (Mital, 2016).

Epidemiology/Prevalence

Prevalence of VWD is often cited as approximately 1% of the general population (Williams & Patel, 2015), however, variances of diagnostic criteria and differences between standardised clinical laboratory methodologies may influence reported incidence rates differently (Federici, 2011). Prevalence of the six VWD types can also vary from study to study (Lee et al., 2014). Summary of data collected from a series of studies places prevalence of Type 1 VWD to occur in approximately 70% of cases, Type 2 in 17% and Type 3 in 13% (Lee et al., 2014). Though VWD affects both men and women equally, women are often higher represented due to tendency to present with menorrhagia, which develops in >80% of women with VWD (Lee et al., 2014). Prevalence of Acquired von Willebrand syndrome is difficult to ascertain due to low rates of detection and common misdiagnoses (Mital, 2016).

Diagnosis

In the diagnosis of VWD, personal and familial history in conjunction with several diagnostic and screening tools are utilised (Lee et al., 2014). Screening tools, though often imprecise, are useful to general practitioners in guiding referral of patients to specialists (Lee et al., 2014). Initial laboratory testing consists of complete blood count, partial thromboplastin time, bleeding time and platelet function analysis (Lee et al., 2014). Definitive diagnosis of VWD relies on diagnostic testing of VWF function in conjunction with consistent clinical history (Lee et al., 2014).

Treatment Aims

Von Willebrand Disease is a lifelong condition with no cure (Castaman, Goodeve & Eikenboom, 2013). Management will therefore continue throughout a patient’s life. Treatment of VWD aims to prevent or stop bleeding episodes (Heijdra, Cnossen & Leebeek, 2017). This is achieved by increasing plasma concentration levels of von Willebrand factor (VWF) and Factor VIII (FVIII) to adequate haemostatic levels (Sadler et al., 2006) (Rodeghiero, 2013). For women, treatment is usually heavily focused on controlling heavy menstrual bleeding and pregnancy related haemorrhage.

Most patients suffering VWD will only require treatment if the patient has experienced trauma, or is having major or minor surgical procedures or dental procedures (Castaman, Goodeve & Eikenboom, 2013). However, more severe forms may require ongoing treatment to maintain Factor levels (Sadler et al., 2006). Treatment options also vary dependent on the type and severity of disease, and patient response to previous treatments (Heijdra, Cnossen & Leebeek, 2017). A variety of therapeutic approaches are used to achieve normal haemostasis, including Desmopressin, Infusion of plasma-concentrates, Anti-fibrinolytic agents, and for women, hormonal contraceptive therapies (Federici et al., 2002). The use of these treatment options are discussed below.

Treatment Options

Desmopressin (DDAVP):

DDAVP is a synthetic hormone which binds to the receptors targeted by vasopressin (Federici et al., 2002). These receptors, when activated, stimulate the release of VWF and FVIII from endogenous stores in the endothelium (James, 2017) (Schneppenheim, 2011) (Schneppenheim, 2011). Factor levels are rapidly increased; often 3-5 fold original levels (Schneppenheim, 2011). DDAVP is the most widely used treatment and is effective for most patients with Type 1 VWD (Heijdra, Cnossen & Leebeek, 2017). Responses of patients with type 2 VWD are difficult to predict. Subtype 2/B are contraindicated against DDAVP due to the risk of severe thrombocytopenia. Type 3 VWD patients are unresponsive to DDAVP as they do not produce any VWF and therefore have no stores to release when receptors are activated (Schneppenheim, 2011).  Patient responses to DDAVP are varied but individual responses are consistent over time (Heijdra, Cnossen & Leebeek, 2017). Therefore a DDAVP test is used establish an individual’s response to the drug, prior to clinical need (Schneppenheim, 2011) (Heijdra, Cnossen & Leebeek, 2017). Response to DDAVP is deemed adequate if levels of plasma VWF increase 3 fold (Schneppenheim, 2011). If the response is deemed adequate, DDAVP is the first choice of management. Mild Side effects of the drug include flushing, transient headache and hypotension (Tiede, 2012). DDAVP is administered intravenously, subcutaneously and intranasal (Heijdra, Cnossen & Leebeek, 2017). Intranasal sprays are often used as home treatments in case of bleeding, but are not as effective at increasing factor levels (Heijdra, Cnossen & Leebeek, 2017). Use of DDAVP is recommended for minor surgeries.

Plasma-Concentrates:

Infusions of prepared doses of concentrated VWF and FVIII are used to increase plasma levels and are the treatment of choice when excessive bleeding needs to be prevented (such as major surgery) or when response to DDAVP is inadequate (Schneppenheim, 2011). Infusion therapies can be used for all disease types, but are most commonly used for patients with Type 3 VWD, Type 2/B VWD (due to Contraindication to DDAVP), and patients who are unresponsive to DDAVP (Schneppenheim, 2011) (Heijdra, Cnossen & Leebeek, 2017). Concentrates are most commonly used during surgery or after trauma, but may also be used as prophylaxis for severe forms of the disease (Federici et al., 2002) (Tiede, 2012). Patients with severe forms are usually Type 3 and suffer recurrent spontaneous bleeds, including joint bleeds and Gastrointestinal bleeds in the elderly (Heijdra, Cnossen & Leebeek, 2017). No adverse effects are experienced and the majority of surgical cases are resolved with a single administration (Federici et al., 2002).

Anti-fibrinolytic agents:

These agents inhibit the interaction of plasminogen with fibrin, preventing the degradation of formed fibrin clots (Heijdra, Cnossen & Leebeek, 2017) (Tiede, 2012). Examples include Tranexamic acid and Aminocaproic acid. The drugs are low cost with few side effects and are able to be administered orally or intravenously (Heijdra, Cnossen & Leebeek, 2017). Anti-fibrinolytic medications are often prescribed before and after surgical or dental procedures for patients with bleeding disorders.

Management Strategies for Women

Management strategies for women with VWD are more complex than for men due to the challenges or controlling haemostatic bleeding due to menstruation and child-birth (James, 2017). Women will often experience menorrhagia, a menstrual period with abnormally heavy or prolonged bleeding. If not properly managed, menorrhagia often leads to iron deficiencies, which, if severe, may require blood transfusions (Heijdra, Cnossen & Leebeek, 2017). DDAVP intranasal spray is often used at the beginning of the menstrual cycle to control excessive bleeding (Rodeghiero, 2013) Contraceptives also control heavy bleeding during menstrual periods. Estrogen present in birth control boosts plasma levels of VWF and FVIII activity. Oral contraceptives are recommended for women not wishing to fall pregnant but wanting to maintain fertility (Rodeghiero, 2013) (Heijdra, Cnossen & Leebeek, 2017). Often a combination of hormonal contraceptives and anti-fibrinolytic agents are used during menstruation (Schneppenheim, 2011) (Heijdra, Cnossen & Leebeek, 2017). For Women who do not wish to preserve fertility, Hysterectomies may greatly improve quality of life, though Surgical Complications due to VWD must be considered (James, 2017). VWD in women will also increase the risk of post-partum haemorrhage .Plasma concentrations of VWF rise during pregnancy, but will fall below acceptable levels post-partum (Heijdra, Cnossen & Leebeek, 2017). Anti-fibrinolytic agents and DDAVP are given in combination for at least 7 days post-partum to reduce the risks (Heijdra, Cnossen & Leebeek, 2017).

Outcomes

Although VWD has no cure and will affect the patient for life, it is a disease that is well understood and in most cases easily managed (Sadler et al., 2006). Treatments are highly effective and most patients will only require treatment when undergoing surgery or after experiencing trauma (Sadler et al., 2006). Modern technologies have allowed treatments to become more individually tailored. Plasma-concentrates can be tailored to patients and their individual levels of required VWF and FVIII (Heijdra, Cnossen & Leebeek, 2017) (Heijdra, Cnossen & Leebeek, 2017). Patients with mild presentations of the disease may only require counselling and advice about the use of anti-fibrinolytics for use pre and post invasive procedures (Rodeghiero, 2013).

Paramedic Relevance

VWD is the most common inherited bleeding disorder world-wide (James, 2017). It affects all racial backgrounds, and occurs in both males and females. In Australia the estimated number of cases is over 200 000. Paramedics may therefore encounter cases of VWD, although it is unlikely to be the main presenting issue of the patient. Knowledge of the disease would therefore benefit paramedics, and allow them to recognise the potential complications that a patient with VWD may face. Symptoms that may be present in patients with VWD include muco-cutaneous bleeding, hematomas, excessive bleeding after trauma or surgery, bleeding from minor wounds, oral cavity bleeding, joint and muscle bleeding (rare), and for women post-partum haemorrhage and menorrhagia (Rodeghiero, 2013) (James, 2017) (Schneppenheim, 2011). Medical alert bracelets or cards, a family history of VWD, and the use of medications such as anti-fibrinolytics including Amicar, Cyklokapron, Lysteda and Intra nasal desmopressin, may also alert paramedics to the patients condition.

References

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Tiede, A. (2012). Diagnosis and treatment of acquired von Willebrand syndrome. Thrombosis Research 13052, 52-56.

Williams, M., & Patel, J. (2015). Von Willebrand Disease: diagnosis and management. Paediatrics and Child Health, 25(8), 354-359. doi:10.1016/j.paed.2015.05.005

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