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Evaluation of Bleeding Symptoms, Disorders, and Risks, Including Evaluation for von Willebrand Disease (VWD):

The 2008 NHLBI/NIH Guidelines


October 2008

Appropriate clinical and laboratory evaluation of bleeding symptoms, disorders, and risks is challenging. Bleeding symptoms or concerns are relatively frequent in adults as well as children and can occur in normal persons or those with certain anatomic or pathological conditions. Bleeding also occurs in persons with hereditary or acquired bleeding disorders. However, diagnosed bleeding disorders are less common than are bleeding symptoms or the presence of conditions associated with increased bleeding risk.

Common bleeding symptoms
       Nosebleeds
       Bruising
       Gingival bleeding
       Bleeding from small wounds
       Menorrhagia
       Postpartum bleeding
Postoperative and invasive procedures
       Dental extractions
Other bleeding symptoms
       Gastrointestinal bleeding
       Urinary bleeding
       Hematomas
       Hemarthroses
       Hemoptysis
       Central nervous system bleeding

Congenital (Hereditary) von Willebrand Disease

von Willebrand disease (VWD) is the most common inherited bleeding condition, affecting males and females in approximately equal proportions in up to 1% of the United States and world populations. The cause is a deficiency in or dysfunction of von Willebrand factor (VWF), a plasma glycoprotein that enables platelets to adhere to sites of vascular injury and that also acts as a stabilizing protein for blood clotting factor VIII (FVIII) in the circulation.

There are 3 main types of VWD: type 1 (partial quantitative deficiency), type 2 (qualitative deficiency) and type 3 (total quantitative deficiency). Type 2 VWD is further classified into 4 variants (2A, 2B, 2M, 2N). The most commonly diagnosed VWD is type 1; accounting for approximately 75% of symptomatic persons. Nearly all the remaining affected persons have type 2 variants. Type 3 VWD is the least common, affecting approximately 1 person in 1 million. People with VWD may experience easy bruising, nosebleeds, or heavy menstrual bleeding in women, and may be at risk of bleeding following surgery, traumatic injury, or childbirth. Symptoms can range from mild bleeding in type 1, to severe, life-threatening bleeding in type 3.

Acquired von Willebrand Syndrome

Acquired von Willebrand syndrome (AVWS) is less common than congenital (hereditary) VWD and is usually etiologically associated with an underlying medical disorder (see published guidelines1,2), which should be considered in persons found to have abnormal VWF test results without a personal or family history consistent with congenital VWD. The following medical conditions are associated with AVWS:

  • Monoclonal gammopathies (monoclonal gammopathy of unknown significance [MGUS], myeloma, macroglobulinemia, amyloidosis)
  • Lymphoproliferative disorders (chronic lymphocytic leukemia, lymphoma [non-Hodgkin], hairy cell leukemia)
  • Myeloproliferative disorders, especially those with marked thrombocytosis (essential thrombocythemia, polycythemia vera, agnogenic myeloid metaplasia with myelofibrosis, etc)
  • Certain cardiovascular disorders (aortic stenosis, hypertrophic obstructive cardiomyopathy, left ventricular assist device, ventricular septal defect)
  • Certain drugs (valproic acid, ciprofloxacin, griseofulvin, hydroxyethyl starch)
  • Other (autoimmune disorders, hypothyroidism, Wilms tumor, etc)

Although VWF:RCo values are typically decreased (with variably decreased VWF:Ag and/or FVIII) in AVWS, sometimes only VWF multimer analysis is abnormal, with mild reduction or loss of the highest molecular weight multimers. Evolving information suggests this latter situation is more likely for AVWS associated with enhanced VWF proteolysis reflecting the following possible clinical situations:

  • Severe aortic valvular stenosis with clinical bleeding
  • Hypertrophic obstructive cardiomyopathy with clinical bleeding
  • Left ventricular assist device with clinical bleeding
  • Certain congenital heart disorders such as ventricular septal defect
  • Gastrointestinal arteriovenous malformations with clinical bleeding

Diagnosis and Evaluation

In March 2008, the National Heart, Lung, and Blood Institute (NHLBI), a branch of the National Institutes of Health, published evidence-based guidelines for evaluating and managing the most common hereditary bleeding disorder, von Willebrand disease (VWD). These new guidelines—the first from NHLBI for any blood disorder—also provide recommendations for the initial clinical and laboratory evaluation of patients with bleeding symptoms, history, or medical conditions associated with increased bleeding risk with invasive procedures. An expert panel, chaired by William L. Nichols, MD at Mayo Clinic in Rochester, MN, developed the guidelines for the diagnosis, evaluation, and management of VWD. The full guidelines are available online at the NHLBI Web site,1 as is a Pocket Guide synopsis for practitioners and a patient education brochure. An edited version of the guidelines also was published in the March 2008 issue of Haemophilia.2

Figure 1 (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; 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 Fig. 1 provides 3 recommended questions for preoperative screening of asymptomatic persons for bleeding risks or disorders. Box 1 provides 9 questions 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 that are based on limited published research, except for questions 2 and 3 in the left upper box that primarily reflect expert opinion (grade C recommendations). Persons answering positively to 1 or more questions should be considered for further evaluation such as hemostasis consultation and focused laboratory testing.

Figure 1

Figure 1. Initial clinical evaluation for VWD or other bleeding disorders. Initial clinical evaluation strategy to determine which patients would most benefit from further diagnostic evaluation for von Willebrand disease (VWD) or other bleeding disorders. “An increasing number of positive responses to the questions about bleeding (the initial 3 questions, and the 9 additional questions), and abnormal findings on physical examination, increase the likelihood that an individual has a bleeding disorder.”1 Source: originally Figure 3 from The Diagnosis, Evaluation and Management of von Willebrand Disease, National Heart, Lung, and Blood Institute, National Institutes of Health (December 2007).

Physical examination, directed to assess evidence for a bleeding disorder, should also be performed, such as identifying ecchymoses, hematomas, petechiae, and other evidence of recent bleeding. The examination should also focus on findings that may suggest other causes of increased bleeding such as evidence of liver disease (eg, jaundice), splenomegaly, joint and skin laxity (eg, Ehlers-Danlos syndrome), telangiectasia (eg, hereditary hemorrhagic telangiectasia), signs of anemia, or anatomic lesions on gynecologic examination.

Figure 2 (from the NHLBI VWD Guidelines) provides an algorithm for initial laboratory evaluation for VWD or other bleeding disorders. If the initial clinical evaluation suggests a bleeding disorder, the “initial hemostasis tests” (box on the left) should be ordered. This testing does not evaluate for VWD, but it can suggest whether coagulation factor deficiency or thrombocytopenia (or thrombocytosis) might be the potential cause of clinical bleeding. If the mucocutaneous bleeding history is strong, consider performing initial VWD assays (box on the right) with the initial visit. The initial hemostasis tests, which include a complete blood count (CBC), prothrombin time (PT) and activated partial thromboplastin time (PTT), reflect grade C recommendations, whereas the initial VWD assays (VWF antigen [VWF:Ag], VWF ristocetin cofactor activity [VWF:RCo] and factor VIII coagulant activity [FVIII]) and the specialized VWD assays generally are grade B recommendations. This laboratory evaluation algorithm does not address additional considerations such as evaluation for platelet hypofunction or for certain other bleeding disorders, acquired or hereditary.

Figure 2

Figure 2. Laboratory assessment algorithm for VWD or other bleeding disorders. If the initial clinical hemostasis evaluation (Fig. 1) suggests a bleeding disorder, the initial hemostasis tests should be ordered, followed by or along with the next tests (initial VWD assays) indicated in the laboratory algorithm. Referral to a hemostasis specialist is appropriate for help in interpretation, repeat testing, and specialized tests. Source: originally Figure 4 from The Diagnosis, Evaluation and Management of von Willebrand Disease, National Heart, Lung, and Blood Institute, National Institutes of Health, (December 2007).

* Isolated decreased platelets may occur in VWD type 2B.
† Correction in the PTT mixing study immediately and after 2-hour incubation removes a factor VIII (FVIII) inhibitor from consideration. Investigation of other intrinsic factors and lupus anticoagulant also may be indicated.
CBC=complete blood count; PT=prothrombin time; PTT=partial thromboplastin time; RIPA=Ristocetin induced platelet aggregation; TT=thrombin time; VWF:Ag=VWF antigen; VWF:RCo=VWF Ristocetin cofactor activity. Referral to a hemostasis specialist is appropriate for help in interpretation, repeat testing, and specialized tests.
See full guidelines for levels of evidence for each recommendation www.nhlbi.nih.gov/guidelines/vwd

Following initial assessment, consultation or discussion with a hemostasis specialist may be useful for further evaluation of a suspected or diagnosed bleeding disorder. Initial laboratory evaluation should begin with CBC testing and screening PT and PTT testing from the local hospital laboratory. Some centers add a bleeding time (BT) or a platelet function analyzer (PFA-100) assay to their initial laboratory tests, but there are conflicting data with regard to sensitivity and specificity for VWD. Therefore, current evidence does not support the routine use of the BT or PFA-100 as screening tests for VWD.

Coagulation Consultations

If there is strong suspicion of a bleeding disorder (hereditary or acquired), #551 Coagulation Consultation, Bleeding Diathesis, Plasma is available from Mayo Medical Laboratories. The panel is performed using frozen-thawed plasma samples; therefore, assessment for platelet hypofunction is not included. This test panel includes PT and PTT (with reflexive mixing studies and coagulation factor assays, if indicated), as well as the initial VWD assays (with reflexive VWF multimer analysis, if indicated). Additional tests performed include thrombin time (TT), fibrinogen, D-dimer (to screen for hyperfibrinolytic bleeding disorders, including intravascular coagulation and fibrinolyis [ICF] or disseminated intravascular coagulation [DIC]) and screening for factor XIII deficiency. In addition to measuring coagulation factor VIII activity, which also evaluates for hemophilia A, factor IX activity is measured to evaluate for hemophilia B (males only, unless test results and available clinical information suggest females should be tested). Results of all tests are reviewed by a coagulation consultant and an interpretive report is provided.

For diagnosis or exclusion of VWD, #554 Coagulation Consultation, von Willebrand Disease, Plasma is available. This consult includes the 3 initial tests ([VWF:Ag], [VWF:RCo], and [FVIII], using frozen-thawed plasma for testing), with reflexive VWF multimer analysis if:

  • VWF is decreased
  • The ratio of VWF:RCo to VWF:Ag substantially discordant
  • Available clinical information suggests a need for VWF multimer analysis

All abnormal test results are reviewed by a coagulation consultant and an interpretive report is provided.

The provision of the following information is very important for optimizing the evaluation and interpretation of test results when ordering a VWD panel, bleeding diathesis panel, or individually ordered VWF multimer analysis:

  • Results of locally obtained laboratory test results (ie, VWF:RCo, VWF:Ag, FVIII), if recently performed
  • The name and office telephone number of the ordering clinician
  • Focused clinical information (briefly describe the bleeding concern or history, including whether the patient has recently received desmopressin [DDAVP] or infusion of VWF concentrate)

VWF multimer analysis visualizes the distribution of plasma VWF multimers, requires several days to perform and is technically very complex. The analysis is qualitatively interpreted in conjunction with results of the initial 3 tests and available clinical information, and is used to help subtype von Willebrand disease. This assay is generally not useful if initial VWD tests are normal (and if the VWF:RCo to VWF:Ag ratio is 0.6–0.7). Nonetheless, requests are often received to perform only VWF multimer analyses without accompanying test results or clinical information to support the diagnosis of VWD. In this situation, the multimer analysis is often found to be normal. This approach may result in unnecessary testing and expense for the patient. For these reasons, and in accordance with the published guidelines,1,2 we recommend utilization of the VWF multimer assay only when initial VWD testing identifies an abnormal result, or clinical information suggests a high likelihood of abnormal VWF multimer analysis.

Summary

Laboratory evaluation for VWD or AVWS is relatively complex and, unfortunately, there is no single laboratory screening test. Thus, the newly published NHLBI guidelines suggest an algorithmic approach to the diagnosis of these conditions. Mayo Medical Laboratories approach to the testing and diagnosis of VWD is consistent with the NHLBI guidelines.

Authored by Nichols WL, Plumhoff EA

References

1. The National Heart, Lung, and Blood Institute: The Diagnosis, Evaluation and Management of Von Willebrand Disease. Bethesda, MD: National Heart, Lung, and Blood Institute, National Institutes of Health, December 2007.
Available at: http://www.nhlbi.nih.gov/guidelines/vwd (last accessed 07.15.2008)

2. Nichols WL, Hultin MB, James AH, et al: von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia March 2008;14:171–232


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