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Von Willebrand Disease (VWD)
Part 1: NHLBI Diagnosis Guidelines

Introduction & Clinical Assessment Recommendations

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Published: May 2011

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Von Willebrand disease (VWD) is a commonly encountered inherited bleeding disorder that affects both males and females. It may also occur less frequently as an acquired disorder (acquired von Willebrand syndrome: AVWS).  A published evidence-based guideline from the National Heart, Lung, and Blood Institute (NHLBI) expert panel outlines recommendations for the evaluation and management of VWD, including suggesting an approach for clinical and laboratory evaluation of individuals with bleeding symptoms, history of bleeding or conditions associated with increased bleeding risk.

This is the first in a four-part series on von Willebrand disease.

Presenter: Dr. William L. Nichols

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Transcript

Introduction

Welcome to Mayo Medical Laboratories' Hot Topics. These presentations provide short discussions of current topics and may be helpful to you in your practice.

Our presenter for this program is William L. Nichols, MD, consultant in the Special Coagulation Laboratory and Hemophilia Center at Mayo Clinic in Rochester, Minnesota. In Part 1 of this 2-part presentation, Dr. Nichols will provide a brief overview of von Willebrand disease (VWD) and summarize recommendations for clinical assessment for VWD, primarily based on guidelines from the National Heart, Lung, and Blood Institute expert panel.

Thank you for tuning in for Mayo Medical Laboratories' Hot Topics series on von Willebrand disease (VWD). For this first of two short presentations on VWD Diagnosis Guidelines, I will initially provide an introduction about von Willebrand factor (VWF) and hereditary VWD, as well as a summary about acquired von Willebrand syndrome (AVWS). Since VWD diagnosis involves synthesizing both clinical and laboratory assessments, I will then focus on discussing guidelines for the clinical evaluation for VWD. My discussion will be mainly based on the evidence-based guidelines from the National Heart, Lung, and Blood Institute (NHLBI) expert panel report in 2008. In the subsequent presentation (Part 2) I will focus on a discussion of guidelines for the laboratory evaluation for VWD.

Objectives — Part 1

Part 1 will sequentially briefly cover these 4 objectives: the biology of von Willebrand factor (VWF), the classification of hereditary VWD, acquired von Willebrand syndrome (AVWS), and a survey discussion of VWD clinical diagnostic guidelines, primarily based on the 2008 NHLBI VWD Guidelines.

VWF Biology

I will review key points about the biology of von Willebrand factor (VWF), because this information is important for understanding von Willebrand disease (VWD). Von Willebrand factor is mainly synthesized in vascular endothelium, but also in bone marrow megakaryocytes (which produce blood platelets). During its synthesis, VWF is multimerized into an extremely large polymeric glycoprotein with molecular weight up to 20 million Daltons. Endothelial cells secrete VWF multimers into the blood, and they also package it into storage organelles called Weibel-Palade bodies — from which VWF can be secreted by endothelial stimulation such as by desmopressin (DDAVP), vasopressin, or epinephrine. Platelet VWF is stored in alpha (a) granules from which it is secreted with platelet activation, and by which platelet adhesion and aggregation are enhanced. VWF has important hemostatic functions including: (1) VWF is the principal protein mediating platelet adhesion to injured blood vessels, and it thereby initiates and localizes platelet accumulation at vascular injury sites, resulting in primary hemostasis, which is the process for initial cessation of blood loss. (2) VWF binds and stabilizes coagulation factor VIII, abbreviated FVIII, the anti-hemophilic procoagulant cofactor that is synthesized from its X-chromosome gene (rather than from the VWF gene on chromosome 12). Factor VIII bound to VWF is protected from proteolytic inactivation that shortens its survival. Also, the factor VIII bound to VWF accelerates thrombin generation within primary hemostatic plugs; this process is called secondary hemostasis. (3) Lastly, recent research identifies that VWF plays a role in down-regulating angiogenesis — the process of generating new blood vessels in tissues. This evolving information may help us better understand why some VWD patients develop microvascular arterio-venous malformations or AVMs,that can cause gastrointestinal mucosal bleeding.

VWF and Normal Hemostasis

This cartoon about VWF and normal hemostasis illustrates some of the VWF biology we just reviewed, and demonstrates key roles for VWF in hemostasis and vascular biology.

In the upper panel, showing blood flowing in a small arteriole lined by endothelium, VWF multimers bind factor VIII molecules; however, the blood platelets do not interact with VWF — because the platelet-binding domains in VWF are hidden internally in the globular VWF polymer.

In the middle left panel, blood vessel damage allows exposure of the sub-endothelial tissues — that contain collagen and other adhesive proteins — then VWF adheres via its collagen-binding domains. In the middle right panel, high blood flow shear stress in the microvasculature uncoils and stretches VWF multimers, exposing binding sites for platelets that become activated during this process. The larger the VWF multimer, the more attractive it is for capturing platelets from the flowing blood to form a primary (1°) hemostatic plug.

In the bottom left panel, adherent activated platelets expose negatively-charged phospholipids such as phosphatidylserine which, in turn, binds and coordinates interactions of plasma coagulation factors (including factor VIII) to accelerate thrombin generation. In the bottom right panel, secondary hemostasis strengthens the hemostatic plug by creating a fibrin meshwork around platelets. Subsequently, fibrinolysis is activated and the processes of blood vessel repair and healing evolve, leading to restoration of blood flow.

VWF Structure and Domains

The VWF protein amino acid sequence, shown at the top of this diagram, is aligned with the VWF gene cDNA at the bottom, and domains of VWF are shown in the middle.

The VWF protein has a propeptide, at the top left, that is cleaved during multimerization of the protomer. Near the middle of the mature protomer is the cleavage site for ADAMTS13, the plasma protease that degrades circulating VWF multimers to down-regulate VWF activity. Deficiency of ADAMTS13 causes thrombotic thrombocytopenic purpura, known as TTP. Domains of the mature VWF protomer include binding sites for ligands including factor VIII, the platelet surface glycoprotein Ib (GP Ib) complex in the A1 domain, collagen, and platelet GP IIb/IIIa. Also shown are the locations of disulfide bonds near the carboxyl terminus (at the right), and near the amino terminus (at the left), by which VWF is first dimerized then multimerized during its synthesis. Mutations causing dysfunctional or Type 2 VWD variants generally correspond to the functional domains as shown in the bottom diagram of VWF cDNA. Type 2A mutations either impair VWF multimerization (Type 2A1) or enhance multimer proteolysis (Type 2A2), whereas Types 2B or 2M mutations affect platelet GP Ib interactions, and Type 2N mutations impair FVIII binding.

VWD Classification — ISTH

VWD is classified on the basis of criteria developed by the VWF Subcommittee of the International Society on Thrombosis and Haemostasis (ISTH) in 1994 and revised in 2006. VWD is classified into 3 major categories: Type 1 VWD reflecting partial quantitative VWF deficiency; Type 2 VWD reflecting qualitative VWF deficiency; and Type 3 VWD defined as total VWF deficiency. Type 1 VWD is the most common form and is of variable severity, whereas type 3 VWD is rare. Type 2 VWD has 4 variants or subtypes: Type 2A VWD, the most common, has decreased VWF-dependent platelet adhesion caused by deficiency of the high molecular weight multimers (HMWM) of VWF; Type 2B VWD reflects increased affinity of VWF for platelet GP Ib, resulting in deficiency of high molecular weight multimers of VWF and is often accompanied by thrombocytopenia; Type 2M VWD has decreased VWF-dependent platelet adhesion NOT caused by deficiency of high molecular weight multimers; and Type 2N VWD reflects markedly decreased VWF binding affinity for factor VIII. Laboratory features of these VWD subtypes will be discussed in more detail later in Part 2 of this presentation.

VWD: Prevalence, Inheritance, Symptoms

VWD is the most common inherited bleeding disorder worldwide, with estimates of prevalence up to 1% (or 1 in 100 persons); but this depends on definitions, so the clinical prevalence is probably somewhat lower, such as 1 in 500 or 1 in 1000 (0.1%). About 75% of clinically affected persons have Type 1 VWD of variable severity, whereas almost all the remainder have Type 2 variants, and Type 3 VWD is rare (approximately 1 in 1 million).

VWD inheritance is generally autosomal dominant, except for autosomal recessive inheritance for Type 3 VWD. Bleeding symptoms in VWD are usually mild to moderate in severity (ie, the bleeding does not require physician visits or blood transfusions), but can sometimes be more serious (or life-threatening), especially in more severe VWD such as with Type 3 or some Type 2 VWD variants. Bleeding in VWD mainly involves mucous membranes or skin sites (mucocutaneous bleeding) such as: nosebleeds (epistaxis), excessive skin bruising (ecchymosis), menorrhagia in women, or gastrointestinal (GI) bleeding. Provoked bleeding, such as with or following surgery or other invasive procedures, or with trauma or childbirth (obstetrical bleeding), can be troublesome, partly depending on the underlying VWD subtype and severity.

As a group, women with VWD are more clinically affected than men with VWD, because of the hemostatic challenges of menstruation and childbirth, as well as ovulation (eg, the risk of hemorrhagic ovarian cysts is increased in women with VWD). Hemarthroses (intra-articular joint bleeds) and tissue hematomas are uncommon in VWD, except for Type 3 (severe) VWD, in contrast to their frequency in Hemophilias A or B (hereditary X chromosome-linked deficiencies of coagulation factors VIII or IX).

Disorders Pathophysiologically Associated with Acquired von Willebrand Syndrome (AVWS)

Acquired von Willebrand syndrome (AVWS) refers to defects in VWF quantity, structure, or function that are not inherited directly, but are consequences of other medical disorders. Bleeding symptoms in AVWS are similar to those in VWD, and are mainly muco-cutaneous or surgical. However, in contrast to VWD, there is no antecedent personal or family history of VWD. Acquired VWF abnormalities, but without recognized clinical bleeding, may be referred to as "AVWA;" however this abbreviation is not standardized, and the risks of future bleeding associated with AVWA are currently not well understood.

This Table summarizes etiologic (pathophysiologic) categories and disease associations for AVWS and AVWA. Antibodies to VWF can rarely occur in autoimmune disorders such as lupus (SLE); however, monoclonal IgG or IgM antibodies such as in MGUS (monoclonal gammopathy of undetermined significance) or other dysproteinemias (eg, myeloma, macroglobulinemia, amyloidosis, etc) are relatively common causes of AVWS. Shear-induced VWF proteolysis (believed to be mediated by ADAMTS13) is an increasingly recognized cause of AVWS and AVWA, and can occur in association with severe aortic valvular stenosis (AS), ventricular septal defect (VSD), hypertrophic obstructive cardiomyopathy (HOCM), certain left ventricular assist devices (LVADs), or primary pulmonary hypertension (PPH). Marked thrombocytosis (blood platelets of 1 million or more per microliter) can cause AVWS or AVWA, and mainly occurs in association with essential thrombocythemia (ET) and other myeloproliferative disorders such as polycythemia vera (PV) or AMM (agnogenic myeloid metaplasia with myelofibrosis). Other listed conditions and pathophysiologies of AVWS are relatively rare, but should be considered in the etiologic differential diagnosis of AVWS. Laboratory findings in AVWS and AVWA are similar to those in VWD subtypes, especially Types 1, 2A, or 3. However, laboratory testing results currently cannot readily distinguish between VWD and AVWS (or AVWA); therefore, clinical assessment is essential for this important distinction.

AVWS, and disorders causing it, should be considered in persons found to have abnormal VWD test results and clinical bleeding, but without an antecedent personal or family history consistent with VWD. Conversely, when bleeding occurs in association with one of the causative medical conditions, AVWS should be considered and initial VWD testing performed if indicated.

VWD NHLBI Guidelines — Background

In 2004 the National Heart, Lung, and Blood Institute (NHLBI) convened an expert panel to develop evidence-based guidelines for VWD diagnosis and management. The panel consisted of 10 physicians and scientists with expertise in adult and pediatric hematology, gynecology, family medicine, public health and epidemiology, laboratory medicine, and basic science. The NHLBI VWD Guidelines project was the first one undertaken for a blood disorder, and required about 4 years for completion.

This Table summarizes etiologic (pathophysiologic) categories and disease associations for AVWS and AVWA. Antibodies to VWF can rarely occur in autoimmune disorders such as lupus (SLE); however, monoclonal IgG or IgM antibodies such as in MGUS (monoclonal gammopathy of undetermined significance) or other dysproteinemias (eg, myeloma, macroglobulinemia, amyloidosis, etc) are relatively common causes of AVWS. Shear-induced VWF proteolysis (believed to be mediated by ADAMTS13) is an increasingly recognized cause of AVWS and AVWA, and can occur in association with severe aortic valvular stenosis (AS), ventricular septal defect (VSD), hypertrophic obstructive cardiomyopathy (HOCM), certain left ventricular assist devices (LVADs), or primary pulmonary hypertension (PPH). Marked thrombocytosis (blood platelets of 1 million or more per microliter) can cause AVWS or AVWA, and mainly occurs in association with essential thrombocythemia (ET) and other myeloproliferative disorders such as polycythemia vera (PV) or AMM (agnogenic myeloid metaplasia with myelofibrosis). Other listed conditions and pathophysiologies of AVWS are relatively rare, but should be considered in the etiologic differential diagnosis of AVWS. Laboratory findings in AVWS and AVWA are similar to those in VWD subtypes, especially Types 1, 2A, or 3. However, laboratory testing results currently cannot readily distinguish between VWD and AVWS (or AVWA); therefore, clinical assessment is essential for this important distinction.

AVWS, and disorders causing it, should be considered in persons found to have abnormal VWD test results and clinical bleeding, but without an antecedent personal or family history consistent with VWD. Conversely, when bleeding occurs in association with one of the causative medical conditions, AVWS should be considered and initial VWD testing performed if indicated.

NHLBI VWD Expert Panel

The NHLBI VWD expert panel included, in the back row in this portrait, Drs. Margaret Rick, Barbara Yawn, Mark Weinstein, Andra James, Mae Hultin and Marilyn Manco-Johnson, and in the front row, Drs. Thomas Ortel, William Nichols, Evan Sadler, and Robert Montgomery.

Methodology

VWD and VWF published literature and studies were identified and categorized into hierarchical categories for level of evidence, with randomized controlled trials (and meta-analyses of them) ranked the highest (levels Ia and Ib), whereas information reflecting the opinions of experts was ranked lowest (evidence level IV).

Evidence-based recommendations were graded based on assessment of the strength of the evidence. Grade A was reserved for recommendations based on the highest level of evidence; grade B denoted recommendations supported by intermediate levels of evidence; and grade C was used for recommendations based on expert opinions and/or clinical experience of respected authorities.

Overall Outcome / Results

The final NHLBI VWD Guidelines document cited about 400 selected references. It included sections on scientific background and overview, clinical and laboratory diagnosis, treatment and management, and opportunities and needs. The document has 17 Tables, 6 Figures, and 13 Evidence Tables (for Grade B recommendations with 2 or more published studies). There are approximately 54 evidence-based graded recommendations, for diagnosis or for management, but none are grade A recommendations (reflecting a paucity of evidence from randomized controlled trials). The evidence-based recommendations are approximately equally divided into those of grade B (based on published evidence at levels II and III) and grade C (mainly based on expert opinions at level IV). There are many additional "soft" (un-numbered) recommendations throughout the document, based primarily on expert opinions and/or limited evidence.

The NHLBI VWD Guidelines include a caveat that these guidelines and recommendations do not abrogate professional judgment in individual cases.

Initial Clinical Evaluation for VWD or Other Bleeding Disorders

This Figure from the NHLBI VWD Guidelines provides an algorithm for initial clinical evaluation for VWD, or other bleeding disorders. Two main scenarios are envisioned: 1) Asymptomatic persons who will undergo a surgical or invasive procedure and who should be assessed for bleeding risk (on the left side of the Figure); or 2) Persons presenting with a personal and/or family history of bleeding symptoms or bleeding disorder, abnormal hemostasis laboratory tests, or concerns about bleeding symptoms.

The left upper box in the Figure provides 3 recommended questions for pre-operative screening of asymptomatic persons for bleeding risks or disorders. "Box 1" at the lower right provides 9 questions (selected for sensitivity and specificity for VWD) that are recommended for further evaluation of persons answering positively to the initial 3 questions, or for evaluation of persons who have specific hemostasis issues. All questions are grade B recommendations based on limited published research, except questions 2 and 3 in the left upper box that reflect expert opinion (grade C). These latter 2 questions provide screening for acquired conditions that can increase bleeding risk, such as cirrhosis or renal failure, or bone marrow or platelet disorders, as well as the use of medications that impair hemostasis such as aspirin and other platelet-inhibitory drugs, or anticoagulants such as warfarin or heparin. Focused physical examination is also recommended (grade C) to detect signs of bleeding (ecchymoses, hematomas, petechiae, or other bleeding) or to detect other causes of bleeding risk such as liver disease (eg, jaundice, splenomegaly), telangiectasia (eg, HHT: hereditary hemorrhagic telangiectasia), joint and skin laxity (eg, Ehlers-Danlos syndrome), signs of anemia, or anatomic lesions on gynecologic examination. If the initial clinical assessment raises significant suspicion or probability that a bleeding disorder may be present, including VWD, then initial laboratory testing may be indicated (lower central box in the Figure). Laboratory testing is discussed in Part 2 of this presentation.

Common Bleeding Symptoms of Healthy Persons vs. VWD Patients

This slide, based on Table 7 from the NHLBI VWD Guidelines, illustrates a variety of bleeding symptoms (eg, epistaxis, menorrhagia, ecchymoses, bleeding from wounds or dental extractions or surgical procedures, etc) — and demonstrates that, individually such bleeding symptoms commonly occur in apparently normal persons, with prevalences up to 50% or higher. However, the prevalences and types and numbers of episodes of these symptoms are typically increased in persons with VWD — who may also have a family history suggesting a hereditary bleeding disorder.

VWD NHLBI Guidelines (2008)1Initial Patient Evaluation — History

Which bleeding history questions are the most useful for identifying persons with a bleeding disorder? This Table is excerpted from a larger Table in the NHLBI VWD Guidelines, and summarizes part of the information from one of the few published studies4 — that helps identify which bleeding history questions are the most informative for identifying persons with a possible bleeding disorder. The most informative questions are: 1) Family history of a bleeding disorder, especially a diagnosed bleeding disorder, demonstrating odds ratios (OR) of 50-98 vs. those without a bleeding disorder; and 2) History of abnormal bleeding with surgery or wounds or dental extractions, demonstrating OR of 6-67 for those with a bleeding disorder. Mucocutaneous bleeding symptoms, such as easy bruising (ecchymoses) or nosebleeds (epistaxis) have lower predictive power for a bleeding disorder (eg, OR 4-10), however mucocutaneous bleeding symptoms are prevalent in persons with VWD. Other bleeding symptoms such as a history of menorrhagia have limited predictive power (OR) for a bleeding disorder, however menorrhagia is a frequent manifestation of a bleeding disorder such as VWD, but may often have other causes. Information from this study, and 2 others, was used to develop the 9 recommended bleeding history questions (previous slide 16, Box 1).

Summarizing and synthesizing the clinical bleeding history assessment, persons with VWD (or other bleeding disorders) are likely to have more than 1, or several of these bleeding symptoms or a history of them — especially abnormal bleeding with surgical or invasive challenges, along with a history of mucocutaneous bleeding, as well as a family history of a bleeding disorder — and the history and types of abnormal bleeding symptoms are partially age-dependent (eg, adults vs children).

VWD NHLBI Guidelines (2008) Initial Patient Evaluation — History

Scoring systems for quantifying the bleeding history, and analyzing the probability of having a bleeding disorder such as VWD, are evolving as research tools, and this slide identifies several recent studies. However, these bleeding history scoring studies were mainly of defined populations such as persons with an identified bleeding condition like VWD. Studies of more general populations are evolving.

Initial Patient Evaluation — History

Recommendation III.A. from the NHLBI VWD Guidelines states: "Until further evaluation of scoring systems and criteria for assessing bleeding history and the probability of VWD, the Expert Panel suggests that an increasing number of positive responses to the questions about bleeding, and abnormal findings on physical examination, increase the likelihood that an individual has a bleeding disorder, including possible VWD."

VWD NHLBI Guidelines (2008)

In summary, the patient history assessment and focused physical examination are the first steps in the evaluation of bleeding symptoms and risk, and for the evaluation of the possible presence of a bleeding disorder such as VWD. Physical examination should include evaluation for evidence of a bleeding disorder, or other causes or risks of increased bleeding. Increasing numbers of positive responses to questions about bleeding, and abnormal findings on physical examination, increase the probability of a bleeding disorder, including possible VWD.

References

This slide lists most of the references discussed in this presentation. The NHLBI VWD Guidelines full document1, as well as summaries for practitioners and patients, can be found at the NHLBI/NIH website shown. An edited version of the full guidelines was published in the journal, Haemophilia5, and a diagnostic synopsis was published in the American Journal of Hematology3.

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