The diagnosis, evaluation, and management of von Willebrand disease.

Grade

Evidence

Recommendation Level

Ia, Ib

Required-at least one randomized-controlled trial as part of the body of literature of overall good quality and consistency

IIa, IIb, III

Required-availability of well-conducted clinical studies but no randomized clinical trials on the topic of recommendation

Required-evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities; indicates absence of directly applicable clinical studies of good quality

Definitions for the levels of evidence (Ia-IV) and grades of recommendations (A–C) can be found at the end of the "Major Recommendations" field.

Diagnosis and Evaluation

The following recommendations include specific clinical history, physical findings, laboratory assays, and diagnostic criteria that this Panel suggests will allow the most definitive diagnosis of von Willebrand disease (VWD).

Tests such as the bleeding time, platelet function analyzer (PFA-100®), or other automated functional platelet assays have been used but there are conflicting data with regard to sensitivity and specificity for VWD. Therefore, the Panel believes current evidence does not support their routine use as screening tests for VWD.
The Panel believes that platelet-based assays should be used for the ristocetin cofactor method.
The Panel emphasizes the importance of the timing of the phlebotomy for assays, with the patient at his/her optimal baseline as far as possible. (For example, VWF levels may be elevated above baseline during the second and third trimesters of pregnancy or during estrogen replacement, during acute inflammation such as the perioperative period, during infections, and during acute stress.) The careful handling and processing of the sample is also critical, particularly if the sample will be sent out for testing at a distant location.

Evaluation of Bleeding Symptoms and Bleeding Risk by History and Physical Examination
Summarized in Figure 3 and Box 1 in the original guideline document.
1. Ask the following broad questions:
  1. Have you or a blood relative ever needed medical attention for a bleeding problem, or have you been told you had a bleeding problem? (Grade B, level IIb) (Sramek et al., 1995)
    If the answer is "Yes" to either of the broad questions above, ask the additional probes:
    1. Have you needed medical attention for bleeding? After surgery? After dental work? With trauma?
    2. Have you ever had bruises so large they had lumps? (Grade B, level IIb) (Sramek et al., 1995)
  1. Do you have or have you ever had:
    1. Liver or kidney disease?
    2. A blood or bone marrow disorder?
    3. A high or low platelet count?
    If the answer is "Yes" to any of these questions, obtain relevant details. (Grade C level IV)
  1. Are you currently taking, or have you recently taken anticoagulation or antiplatelet medications (warfarin, heparin, aspirin, nonsteroidal anti-inflammatory drugs [NSAIDs], clopidogrel)?
    If the answer is "Yes", obtain relevant details. (Grade C, level IV)
1. If answers to questions I.A.1 are positive, ask if the patient or any blood relatives have had:
  1. A bleeding disorder, such as von Willebrand disease or hemophilia?
  2. Prolonged bleeding, heavy, or recurrent from:
    1. Trivial wounds, lasting more than 15 minutes or recurring spontaneously during the 7 days after the wound?
    2. Surgical procedures, such as tonsillectomy?
  1. Bruising with minimal or no apparent trauma, especially if you could feel a lump?
  2. Spontaneous nosebleeds that required more than 10 minutes to stop or needed medical attention?
  3. Dental extractions leading to heavy, prolonged, or recurrent bleeding?
  4. Blood in your stool, unexplained by a specific anatomic lesion (such as an ulcer in the stomach, or a polyp in the colon), that required medical attention?
  5. Anemia requiring treatment or received a blood transfusion?
  6. For women, heavy menses, characterized by the presence of clots greater than an inch in size and/or changing a pad or tampon more than hourly, or resulting in anemia or low iron level?
  If answers to above questions I.B.1–8 are positive, obtain relevant specific information. (Grade B, level IIb) (Sramek et al., 1995; Drews et al., 2002)
1. Perform a physical examination to include evaluation for:
  1. Evidence for a bleeding disorder, including size, location, and distribution of ecchymoses (e.g., truncal), hematomas, petechiae, and other evidence of recent bleeding and/or anemia. (Grade C, level IV)
  2. Evidence that suggests other causes or risks of increased bleeding, such as jaundice or spider angiomata (liver disease), splenomegaly, arthropathy, joint and skin laxity (e.g., Ehlers-Danlos Syndrome), telangiectasia (e.g., hereditary hemorrhagic telangiectasia), or evidence of anatomic lesions on gynecologic examination. (Grade C, level IV)
Laboratory testing should be guided by the history and physical findings (see section I.) and the initial laboratory evaluation (see II.A., below). For example, findings of liver disease may lead to a different or additional laboratory evaluation rather than an evaluation for VWD (see II.B., below).

Evaluation by Laboratory Testing
1. Initial laboratory evaluation for the etiology of a bleeding disorder should include:
  1. A complete blood count ([CBC] including platelet count), prothrombin time (PT), activated partial thromboplastin time (PTT), and optionally either thrombin time or fibrinogen level.
  2. If laboratory abnormalities besides the PTT are present (the platelet count may also be decreased in type 2B VWD), in conjunction with the history and physical examination findings, consider bleeding disorders other than VWD or additional underlying diseases.
  3. If the mucocutaneous bleeding history is strong, consider performing initial VWD assays at the first visit (See II.B., below).
  4. If there are no abnormalities on initial blood testing, or if there is an isolated prolonged PTT that corrects on the 1:1 mixing study, the following three tests for VWD should be performed (II.B., below), unless another cause for bleeding has been identified and VWD is not likely (see Figure 4 in the original guideline document). For further laboratory evaluation, physicians may consider referral to a hemostasis center because of the special sample handling and testing requirements (see Table 10 in the original guideline document). (Grade C, level IV)
1. Initial tests for diagnosing or excluding VWD include the following three tests:
  1. von Willebrand factor ristocetin cofactor activity (VWF:RCo)
  2. von Willebrand factor antigen (VWF:Ag)
  3. Factor VIII activity
  (Grade B, level III) (Rodeghiero, Castaman & Dini, 1987; Gill et al., 1987; Favaloro et al., "Laboratory diagnosis," 2004; Favaloro et al., "Assessment," 2000)
1. If any one of the above test results is abnormally low, a discussion with or a referral to a hemostasis expert is appropriate. In addition to repeating the initial three tests (in most cases), the specialist may recommend appropriate studies from the following:
  1. The first set of additional tests may include:
    1. Evaluation of the ratio of VWF activity (VWF:RCo and/or von Willebrand factor collagen-binding activity [VWF:CB]) to VWF antigen (only in laboratories that have defined reference ranges for the ratio[s]) (Grade B, level III) (Hillery et al., 1998; Mancuso et al., 1996; Nitu-Whalley et al., "Identification," 2000; Dean et al.,2000; Favaloro et al., "Laboratory diagnosis," 2004; Federici et al., "Ristocetin cofactor," 2000)
    2. VWF multimer study (Grade B, level III) (Studt et al., 2001)
    3. Ristocetin-induced platelet aggregation (Grade B, level III) (Ruggeri et al., 1980)
    4. VWF collagen binding activity (VWF:CB) (Grade B, level IIb) (Favaloro et al., "Laboratory diagnosis," 2004; Favaloro, 2000; Favaloro et al., "Discrimination," 2000)
  1. Studies in selected patients, especially those who have discordantly low FVIII activity compared to VWF levels and who are suspected of having type 2N VWD, should include a FVIII binding assay (VWF:FVIIIB) (Grade B, level IIb) (Mazurier & Meyer, 1996; Schneppenheim et al., 1996; Rodgers et al., 2002)
  2. Additional studies in selected persons may include:
    1. Gene sequencing (Grade C, level IV)
    2. Assays for antibodies to VWF (Grade C, level IV)
    3. Platelet-binding studies (Grade B, level III) (Scott & Montgomery, 1991)

Making the Diagnosis
1. Clinical criteria. These criteria include personal and/or family history and/or physical evidence of mucocutaneous bleeding. Until further validation of scoring systems and criteria for assessing bleeding history and the probability of VWD, especially type 1 VWD, the Expert Panel suggests that an increasing number of positive responses to the questions about bleeding (see Figure 3 and Box 1 in the original guideline document) and abnormal findings on physical examination increase the likelihood that an individual has a bleeding disorder, including possible VWD.
  AND
2. Laboratory criteria. The values in the following table represent prototypical cases without additional VWF (or other disease) abnormalities in the patient. In practice, exceptions occur, and repeat testing and clinical experience are important and may be necessary for interpretation of laboratory results.
  1. Although published evidence is limited, for defining the ratio of VWF:RCo/VWF:Ag to use for distinguishing type 1 VWD versus type 2 VWD variants (A, B, or M), the Expert Panel recommends a ratio of <0.5–0.7 until more laboratories clearly define a reference range using large numbers of normal subjects and persons who have type 1 VWD and type 2 VWD variants. (Grade C, level IV) (Hillery et al., 1998; Mancuso et al., 1996; Nitu-Whalley et al., "Identification," 2000; Dean et al.,2000; Favaloro et al., "von Willebrand disease," 2004; Federici et al., "Ristocetin cofactor," 2000)
  2. The panel currently recommends that 30 IU/dL be used as the "cut-off" level for supporting the definite diagnosis of VWD for the following reasons:
    - There is a high frequency of blood type O in the United States, and it is associated with "low" VWF levels (Gill et al., 1987)
    - Bleeding symptoms are reported by a significant proportion of normal individuals (Silwer, 1973; Sramek et al., 1995; Drews et al., 2002; Mauser Bunschoten et al., 1988)
    - No abnormality in the VWF gene has been identified in many individuals who have mildly to moderately low VWF:RCo levels (Grade C, level IV) (Casana et al., 2001; Castaman et al, 1999; Miller et al., 1979)
This recommendation does not preclude the diagnosis of VWD in individuals with VWF:RCo of 30–50 IU/dL if there is supporting clinical and/or family evidence for VWD. This recommendation also does not preclude the use of agents to increase VWF levels in those who have VWF:RCo of 30–50 IU/dL and may be at risk for bleeding.

Condition	VWF:RCo (IU/dL)	VWF:Ag (IU/dL)	FVIII	Ratio of VWF:RCo/VWF:Ag
Type 1	<30*	<30*	v or Normal	>0.5–0.7
Type 2A	<30*	<30–200*+	v or Normal	<0.5–0.7
Type 2B	<30*	<30–200*+	v or Normal	Usually <0.5–0.7
Type 2M	<30*	<30–200*+	v or Normal	<0.5–0.7
Type 2N	30–200	30–200	vv	>0.5–0.7
Type 3	<3	<3	vvv (<10 IU/dL)	Not applicable
"Low VWF"	30–50	30–50	Normal	>0.5–0.7
Normal	50–200	50–200	Normal	>0.5–0.7

v refers to a decrease in the test result compared to the laboratory reference range.

*<30 IU/dL is designated as the level for a definitive diagnosis of VWD; there are some patients with type 1 or type 2 VWD who have levels of VWF:RCo and/or VWF:Ag of 30–50 IU/dL.

+The VWF:Ag in the majority of individuals with type 2A, 2B, or 2M VWD is <50 IU/dL.

Management Recommendations

Testing Prior to Treatment
1. Before treatment, all persons suspected of having VWD should have a laboratory-confirmed diagnosis of type and severity of VWD. This recommendation does not preclude treatment that may be indicated for urgent or emergency situations, despite the absence of confirmatory laboratory data. (Grade C, level IV) (Lak, Peyvandi, & Mannucci, 2000; Federici, 2004; Silwer, 1973; Sramek et al., 1995; Drews et al., 2002; Mauser Bunschoten et al., 1988; Woods et al., 2001; Ziv & Ragni, 2004)
2. Persons who do not have a definite diagnosis of VWD but who have VWF:RCo levels of 30–50 IU/dL and have a bleeding phenotype may merit treatment or prophylaxis of bleeding in certain clinical situations. (Grade B, level III) (Nitu-Whalley et al., "Type 1," 2000)
3. Persons with >10 IU/dL VWF:RCo and >20 IU/dL FVIII activity levels should undergo a trial of desmopressin: 1-desamino-8-D-argnine vasopressin (DDAVP) while in a nonbleeding state. Persons with levels below these thresholds are less likely to demonstrate clinical or laboratory responses to DDAVP, but a DDAVP trial should still be considered in these individuals. (Grade B, level IIa) (Mannucci et al 1985; de la Fuente et al., 1985; Federici et al., 2004; Mannucci et al., 1981; Rodeghiero et al., 1989)

General Management
1. Treatment of persons who have VWD is aimed at cessation of bleeding or prophylaxis for surgical procedures. (Grade C, level IV) (Sadler et al., 2000; Federici, Castaman, & Mannucci, 2002; Pasi et al., 2004)
2. Continued bleeding, despite adequately replaced VWF:RCo and FVIII activity levels, requires evaluation of the person for other bleeding etiologies, including anatomic. (Grade C, level IV)
3. Long-term prophylaxis is currently under investigation in an international cooperative study, and the long-term risks and benefits should be considered carefully. (Grade C, level IV) (Berntorp & Petrini, 2005; Sumner & Williams, 2004)
4. Individuals who are more than 2 years of age, who have VWD and have not already been vaccinated, should be immunized against hepatitis A and B. (Grade C, level IV) (National Hemophilia Foundation [NHF], 2001)
5. Persons who have VWD should have the opportunity to talk to a knowledgeable genetic counselor. (Grade C, level IV) (Kadir, 1999)
6. At diagnosis, persons who have VWD should be counseled to avoid aspirin, other NSAIDs, and other platelet-inhibiting drugs. (Grade C, level IV) (Barbui, Rodeghiero, & Dini, 1977; Rosentein & Zacharski, 1979; Stuart et al., 1979)
7. Restriction of fluids to maintenance levels should be considered in persons receiving DDAVP (especially for young children and in surgical settings) to avoid the occurrence of hyponatremia and seizures. (Grade C, level IV) (Bertholini & Butler, 2000; Das, Carcao, & Hitzler, 2005; Smith et al., 1989)

Treatment of Minor Bleeding and Prophylaxis for Minor Surgery
1. Epistaxis and oropharyngeal, soft tissue, or minor bleeding should be treated with intravenous or nasal DDAVP, if appropriate, based on trial testing. (Grade B, level IIa) (Castaman et al., 1995; Castaman & Rodeghiero, 1996; de la Fuenta et al., 1985; Revel-Vilk et al., 2003; Mariana et al., 1984)
2. If elevation of VWF is necessary and response to DDAVP is inadequate, VWF concentrate should be used, with dosing primarily based on VWF:RCo units and secondarily on FVIII units. (Grade C, level IV) (Nitu-Whalley et al., 2001; Lillicrap et al., 2002)
3. For prophylaxis for minor surgery, initial treatment should be expected to achieve VWF:RCo and FVIII activity levels of at least 30 IU/dL and preferably >50 IU/dL. (Grade B, level III) (de la Fuenta et al., 1985; Revel-Vilk et al., 2003; Federici et al., "Optimising local therapy," 2000; Nitu-Whalley et al., 2001)
4. For minor surgery, VWF:RCo and FVIII activity levels of at least 30 IU/dL and preferably >50 IU/dL should be maintained for 1–5 days. (Grade B, level III) (Jimenez-Yuste et al., 2002; Kreuz et al., 1994; Nitu-Whalley et al., 2001; Thompson et al., 2004)
5. For persons who have VWD, management of minor bleeding (e.g., epistaxis, simple dental extraction, or menorrhagia) with DDAVP and proper fluid restriction can be performed without laboratory monitoring unless Stimate® or DDAVP is used more than three times within 72 hours. (Grade C, level IV) (Lethagen, Frick, & Sterner, 1998; Amesse et al., 2005)
6. For persons who have mild to moderate VWD, antifibrinolytics combined with DDAVP are generally effective for oral surgery. VWF concentrate should be available for persons who cannot receive DDAVP or who bleed excessively despite this combined therapy. (Grade B, level IIb) (Castaman et al., 1995; de la Fuenta et al., 1985; Rodeghiero et al., 1988; Federici et al., "Optimising local therapy," 2000; Mariana et al., 1984; Nitu-Whalley et al., 2001; Saulnier et al.,1994)
7. Topical agents, such as fibrin sealant or bovine thrombin, may be useful adjuncts for oral surgery in persons who have VWD. Careful attention to hemostasis of an extraction socket and to suturing of sockets is also important in oral surgery in persons who have VWD. (Grade C, level IV) (Federici et al., "Optimising local therapy," 2000; Rakocz et al., 1993)

Treatment of Major Bleeding and Prophylaxis for Major Surgery
1. All treatment plans should be based on objective laboratory determination of response of VWF:RCo and FVIII activity levels to DDAVP or to VWF concentrate infusion. (Grade B, level IIb). (Federici, 2004; Rodeghiero et al., 1989; Allen et al., 1999; Derkay, Werner, & Plotnick, 1996; Kreuz et al., 1994; Manno et al., 1998; Nitu-Whalley et al., 2001; Shah, Lalwani, & Koerper, 1998; Dobrkovska, Krzensk, & Chediak, 1998; Hanna et al., 1994; Lillicrap et al., 2002; Lubetsky et al., 1999; Michiels et al., 2004; Thompson et al., 2004; Scharrer, Vigh, & Aygoren-Pursun, 1994; Gill et al., 2003)
2. Whenever possible, all major surgeries and bleeding events should be treated in hospitals with a 24-hour/day laboratory capability and with clinical monitoring by a team including a hematologist and a surgeon skilled in the management of bleeding disorders. (Grade C, level IV)
3. For severe bleeding (e.g., intracranial, retroperitoneal) or for prophylaxis of major surgery, initial target VWF:RCo and FVIII activity levels should be at least 100 IU/dL. Subsequent dosing should maintain VWF:RCo and FVIII levels above a trough of 50 IU/dL for at least 7–10 days. (Grade B, level III) (Kreuz et al., 1994; Nitu-Whalley et al., 2001; Dobrkovska, Krzensk, & Chediak 1998; Hanna et al., 1994; Lillicrap et al., 2002; Lubetsky et al., 1999; Michiels et al., 2004; Thompson et al., 2004; Scharrer, Vigh, & Aygoren-Pursun, 1994; Gill et al., 2003)
4. To decrease risk of perioperative thrombosis, VWF:RCo levels should not exceed 200 IU/dL, and FVIII activity should not exceed 250 IU/dL. (Grade C, level IV) (Makris et al., 2002; Mannucci, 2002; Mannucci et al., 2002)
5. For major surgical procedures in selected patients with type 3 VWD or acquired von Willebrand syndrome (AVWS) who are at risk for poor VWF recovery because of inhibitors, a pre-operative trial infusion of VWF concentrate with pharmacokinetic laboratory monitoring should be considered. (Grade C, level IV)

Management of Menorrhagia and Hemorrhagic Ovarian Cysts in Women Who Have VWD
1. Women who have menorrhagia or abnormal vaginal bleeding should have a full gynecological evaluation before therapy. (Grade C, level IV) (Chuong & Brenner, 1996)
2. In the adolescent or adult woman who does not desire pregnancy, but may desire future childbearing, the first choice of therapy for menorrhagia should be combined oral contraceptives. (Grade B, level III) (Foster, 1995)
3. In the adolescent or adult woman who does not desire pregnancy, but may desire future childbearing, the first choice of therapy to prevent hemorrhagic ovarian cysts should be combined oral contraceptives. (Grade C, level IV) (Bottini et al., 1991; Ghosh et al., 1998; Jarvis & Olsen, 2002)
4. If a woman would otherwise be a suitable candidate for an intrauterine device, the second choice of therapy for menorrhagia should be the levonorgestrel intrauterine system. (Grade B, level IIb) (Kingman et al., 2004)
5. For the woman who desires pregnancy, DDAVP, antifibrinolytics, or VWF concentrate may be tried to control menorrhagia. (Grade C, level IV) (Foster, 1995)
6. Dilation and curettage is not usually effective to manage excessive uterine bleeding in women who have VWD. (Grade C level IV) (Greer et al., 1991; Kadir et al., 1999)

Management of Pregnancy and Childbirth in Women Who Have VWD
1. Women planning for pregnancy should have, before conception, an evaluation with a hematologist and a high-risk obstetrician, both of whom are skilled in the management of VWD. (Grade C, level IV) (Kadir, 1999)
2. Women who have type 1, type 2, or type 3 VWD, with FVIII or VWF:RCo levels <50 IU/dL or a history of severe bleeding:
  1. Should be referred to a center that has high-risk obstetrics capabilities and with expertise in hemostasis for prenatal care, delivery, termination of pregnancy, or management of miscarriage. (Grade C, level IV)
  2. Should receive prophylaxis with DDAVP or VWF concentrate before invasive procedures. (Grade C, level IV) (Kadir, 1999; Kouides 2001)
  3. Should achieve VWF:RCo and FVIII levels of at least 50 IU/dL before delivery and maintain that level for at least 3–5 days afterward. (Grade C, level IV) (Pasi et al., 2004; Mannucci, 2004; Greer et al., 1991; Kadir et al., 1998; Kouides, 2001)
1. If VWF:RCo and FVIII levels can be monitored and maintained above 50 IU/dL during labor and delivery, and no other coagulation defects are present, then regional anesthesia may be considered. (Grade C, level IV) (Kadir et al., 1998)
2. Because coagulation factors return to prepregnancy levels within 14–21 days after delivery, health care providers should be in close contact with women during the postpartum period. (Grade C, level IV) (Kouides, 2001)

Acquired von Willebrand Syndrome
1. Individuals who have AVWS and who require surgery should be considered for a pharmacokinetic trial of therapy with DDAVP and/or VWF concentrate, with monitoring of VWF:RCo and FVIII levels, to evaluate for possible accelerated clearance of VWF. (Grade C, level IV) (Federici et al., "Acquired von Willebrand syndrome," 2000; Kumar, Pruthi, & Nichols, 2003)
2. For persons who have AVWS and who bleed excessively despite therapy with DDAVP and VWF concentrate, treatment with high-dose immune globulin intravenous (IGIV) should be considered, especially in immunoglobulin G (IgG) isotype monoclonal gammopathy of uncertain significance (MGUS) (See page 47 in the original guideline document for a discussion of this non-U.S. Food and Drug Administration [FDA]-approved use). (Grade B, level IIa) (Federici et al., "Acquired von Willebrand syndrome," 2000; Federici et al., 1998; Arkel, Lynch, & Kamiyama, 1994; Macik et al., 1988; van Genderen, et al., 1995)

Definitions:

Grade of Recommendation*

Grade	Evidence	Recommendation Level
A	Ia, Ib	Required-at least one randomized-controlled trial as part of the body of literature of overall good quality and consistency
B	IIa, IIb, III	Required-availability of well-conducted clinical studies but no randomized clinical trials on the topic of recommendation
C	IV	Required-evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities; indicates absence of directly applicable clinical studies of good quality

*Source: Laffan M, Brown SA, Collins PW, Cumming AM, Hill FG, Keeling D, Peake IR, Pasi KJ. The diagnosis of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors' Organization. Haemophilia. 2004 May;10(3):199-217.

Level of Evidence*

Ia Evidence obtained from meta-analysis of randomized controlled trials

Ib Evidence obtained from at least one randomized controlled trial

IIa Evidence obtained from at least one well-designed controlled study without randomization

Ib Evidence obtained from at least one other type of well-designed quasi-experimental study

III Evidence obtained from well-designed nonexperimental studies, such as comparative studies, correlational studies, and case studies

IV Evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities

* Source: Acute pain management: operative or medical procedures and trauma. (Clinical practice guideline.) Publication No. AHCPR 92-0032. Rockville, MD: Agency for Health Care Policy and Research, Public Health Service, U.S. Department of Health and Human Services, February 1992.

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