A Pocket Guide to The Diagnosis, Evaluation and
Management of von Willebrand Disease
Figure 1. Initial Evaluation For VWD or Other
Bleeding Disorders
Questions to Patient (e.g., an asymptomatic
patient who will undergo surgery or other interventional procedure)
1) Have you or a blood relative ever needed medical
attention for a bleeding problem, or been told you have a bleeding disorder or
problem:
- During /after surgery?
- With dental procedures, extractions?
- With trauma?
- During childbirth or for heavy menses?
- Ever had bruises with lumps?
2) Do you have or have you ever had:
- Liver or kidney disease; a blood or bone marrow
disorder; a high or low platelet count?
3) Do you take aspirin, NSAIDs (provide common names),
clopidogrel (PlavixTM), warfarin, heparin?
No |
Yes |
- No evaluation; usual care
|
- Ask additional questions (see Box 1) and the 3 questions above (if not already asked) AND
obtain history of treatment (e.g., blood transfusion). Examine for bleeding or
underlying disease.
History From Patient
Personal history of VWD
Abnormal laboratory test
Positive family history of a bleeding disorder
or bleeding
Patient is concerned about bleeding; patient who
has unexplained anemia or history of previous DDAVP use
Negative |
Positive |
No further evaluation; usual care
|
Evaluate further: initial laboratory tests
and possible referral (See Figure 2.) |
|
Box 1. Additional Questions to
Screen for a Bleeding Disorder
- Do you have a blood relative who has a bleeding
disorder, such as von Willebrand disease or hemophilia?
- Have you ever had prolonged bleeding from trivial
wounds, lasting more than 15 minutes or recurring spontaneously during the 7
days after the wound?
- Have you ever had heavy, prolonged, or recurrent
bleeding after surgical procedures, such as tonsillectomy?
- Have you ever had bruising, with minimal or no
apparent trauma, especially if you could feel a lump under the bruise?
- Have you ever had a spontaneous nose-bleed that
required more than 10 minutes to stop or needed medical attention?
- Have you ever had heavy, prolonged, or recurrent
bleeding after dental extractions that required medical attention?
- Have you ever had 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?
- Have you ever had anemia requiring treatment or
received a blood transfusion?
- For women, have you ever had heavy menses,
characterized by the presence of clots greater than an inch in diameter and/or
changing a pad or tampon more than hourly, or resulting in anemia or low iron
level?
Figure 2. Laboratory Assessment
for VWD or Other Bleeding Disorders
Initial Evaluation (history and physical examination)
(See Figure 1.)
Positive |
Negative |
Laboratory Evaluation
Initial hemostasis tests
- CBC and platelet count
- PTT
- PT
- Fibrinogen or TT (optional)
If bleeding history is strong, consider
performing initial VWD assays
Other cause identified, e.g.,
↓↓↓platelets*, isolated abnormal PT, low fibrinogen, abnormal
TT
Possible referral for other appropriate
evaluation |
Isolated prolonged PTT that corrects on
1:1 mixing study, or no abnormalities |
Initial VWD assays
1 or more tests abnormal |
No test abnormal |
Referral for selected specialized
VWD studies
Repeat initial VWD assays if
necessary
Ratio of VWF: RCo to VWF: Ag
Multimer distribution
Collagen binding
RIPA or platelet binding
FVIII binding
Platelet VWF studies
DNA sequencing of VWF gene |
Referral for other appropriate
evaluation |
|
|
No further evaluation |
* 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 = Ristocetininduced platelet aggregation; TT
= thrombin time; WVF: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
Making the Diagnosis of vWD
Note: See full guidelines for levels of evidence for
all recommendations (www.nhlbi.nih.gov/guidelines.vwd).
A. Clinical criteriaan increasing number of
positive responses to questions in Fig.1, and abnormal physical findings
increase the likelihood of a bleeding disorder.
AND
B. Laboratory criteria. (See Fig.
2.) The values below represent prototypical cases without additional VWF
(or other disease) abnormalities. Exceptions occur, and repeat testing and
clinical experience may be necessary for interpretation of laboratory
results.
Laboratory Values for VWD
Condition |
Description |
VWF:RCo (IU/dL) |
VWF:Ag (IU/dL) |
FVIII |
VWF:RCo/ VWF:Ag |
Type 1 |
Partial quantitative VWF deficiency (75% of
symptomatic VWD patients) |
<30* |
<30* |
↓ or Normal |
>0.50.7 |
Type 2A |
↓ VWF-dependent platelet adhesion with
selective deficiency of high-molecular-weight multimers |
<30* |
<30200* |
↓ or Normal |
<0.50.7 |
Type 2B |
increased affinity for platelet GPIb |
<30* |
<30200* |
↓ or Normal |
Usually <0.50.7 |
Type 2M |
VWF-dependent platelet adhesion without
selective deficiency of high-molecular-weight ↓ multimers |
<30* |
<30200* |
or Normal↓ |
<0.50.7 |
Type 2N |
Markedly decreased binding affinity for FVIII
|
30200 |
30200 |
↓↓ |
>0.50.7 |
Type 3 |
Virtually complete deficiency of VWF (Severe,
rare) |
<3 |
<3 |
↓↓↓ (<10 IU/dL) |
Not applicable |
"Low VWF"** |
|
3050 |
3050 |
Normal |
>0.50.7 |
Normal |
|
50200 |
50200 |
Normal |
>0.50.7 |
↓ 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; some patients with type 1 or type 2 VWD have
levels of VWF:RCo and/or VWF:Ag of 3050 IU/dL.
The VWF:Ag in the majority of individuals with
type 2A, 2B, or 2M VWD is <50 IU/dL.
** This does not preclude the diagnosis of VWD in
patients with VWF:RCo of 3050 IU/dL if there is supporting clinical
and/or family evidence for VWD, nor does this preclude the use of agents to
increase VWF levels in those who have VWF:RCo of 3050 IU/dL and who may
be at risk for bleeding.
Notes:
1. Until more laboratories clearly define a reference
range, the VWF:RCo/VWF:Ag ratio of <0.50.7 is recommended to
distinguish type 1 VWD vs. type 2 VWD variants (A, B, or M). Grade C, level
IV
2. 30 IU/dL is recommended as the "cut-off" level for
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;
- Bleeding symptoms are reported by a significant
proportion of individuals with no disease; and
- 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
Management of VWD
Treatment is aimed at cessation of bleeding or
prophylaxis for surgical procedures. Strategies include:
- increasing plasma concentration of VWF by releasing
endogenous VWF stores through stimulation of endothelial cells with
DDAVP.
- replacing VWF by using human
plasma-derived, viral-inactivated concentrates.
- using agents that promote hemostasis and
wound healing but do not substantially alter the plasma concentration of
VWF.
These strategies are not mutually exclusive, and
patients may receive any one or all three at the same time. The appropriate
therapy depends on the type and severity of VWD, the severity of the hemostatic
challenge, and the nature of the actual or potential bleeding.
Note: the following recommendations are graded
according to level of evidence. See full guidelines for further explanation and
evidence tables. (www.nhlbi.nih.gov/guidelines/vwd)
Testing Prior to Treatment
- Before
treatment (except in urgent situations), persons suspected of having VWD should
have a laboratory-confirmed diagnosis. (C, IV)
- Persons
without a definite diagnosis of VWD but with VWF:RCo levels of 3050 IU/dL
and a bleeding history may benefit from treatment or prophylaxis of bleeding in
certain clinical situations. (B, III)
- Persons with
VWF:RCo >10 IU/dL and FVIII activity >20 IU/dL should undergo a trial of
DDAVP while in a nonbleeding state. Persons with levels below these thresholds
are less likely to respond usefully to DDAVP, but a DDAVP trial should still be
considered. (B, IIa)
General Management of VWD Patients
- Treatment is
aimed at cessation of bleeding or surgical prophylaxis. (C, IV)
- Continued
bleeding, despite adequately replaced VWF:RCo and FVIII activity levels,
requires evaluation for other causes of bleeding. (C, IV)
- Long-term
prophylaxis is rarely required; it is currently under investigation. (C,
IV)
- Patients >
2 years of age should be immunized against hepatitis A and B. (C, IV)
- Patients
should have the opportunity to talk to a knowledgeable genetic counselor. (C,
IV)
- Counsel
patients to avoid aspirin, other NSAIDs, and other platelet-inhibiting drugs.
(C, IV)
- Restriction
of fluids to maintenance levels should be considered in persons receiving DDAVP
(especially young children and in surgical settings) to avoid hyponatremia and
seizures. (C, IV)
Treatment for Minor Bleeding and Prophylaxis for
Surgery
- Epistaxis and
oropharyngeal, soft tissue, or minor bleeding should be treated with
intravenous or nasal DDAVP, if supported by results of a DDAVP trial. (B,
IIa)
- 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. (C, IV)
- For minor
surgery, initial prophylactic treatment should achieve VWF:RCo and FVIII
activity levels ≥30 IU/dL and preferably >50 IU/dL, and should be
maintained for 1-5 days. (B, III)
- Management of
minor bleeding (e.g., epistaxis, simple dental extraction, or menorrhagia) with
DDAVP and proper fluid restriction can be performed without monitoring of
electrolytes unless Stimate® or DDAVP is used more than three times within
72 hours. (C, IV)
- For persons
with 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.
(B, IIb)
- Topical
agents, such as fibrin sealant or bovine thrombin, may be useful adjuncts for
oral surgery. Careful attention to hemostasis of a tooth extraction socket and
to suturing of sockets is also important. (C, IV)
Treatment of Major Bleeding and Prophylaxis for
Surgery
- 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. (B,
IIb)
- Whenever
possible, all major surgeries and bleeding events should be treated in
hospitals with a 24-hour/day laboratory and with clinical monitoring by a team
including a hematologist and a surgeon skilled in the management of bleeding
disorders. (C, IV)
- For severe
bleeding (e.g., intracranial, retroperitoneal) or prophylaxis of major surgery,
initial target VWF:RCo and FVIII activity levels should be ≥100 IU/dL.
Subsequent dosing should maintain VWF:RCo and FVIII levels above a trough of 50
IU/dL for at least 710 days. (B, III)
- To decrease
risk of perioperative thrombosis, VWF:RCo levels should not exceed 200 IU/dL,
and FVIII activity should not exceed 250 IU/dL. (C, IV)
- For major surgical procedures in selected patients
with type 3 VWD or AVWS who are at risk for poor VWF recovery because of
inhibitors, a preoperative trial infusion of VWF concentrate with
pharmacokinetic laboratory monitoring should be considered. (C, IV)
Management of Menorrhagia and Hemorrhagic Ovarian
Cysts
- Women with
menorrhagia or abnormal vaginal bleeding should have a full gynecological
evaluation before therapy. (C, IV)
- In the
adolescent or adult woman who does not desire pregnancy, but may desire future
childbearing, the first choice of therapy for either menorrhagia or to prevent
hemorrhagic ovarian cysts should be combined oral contraceptives. (B, III and
C, IV, respectively)
- 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. (B, IIb)
- For the woman
who desires pregnancy, DDAVP, antifibrinolytics, or VWF concentrate may be
tried to control menorrhagia. (C, IV)
- Dilation and
curettage is not usually effective to manage excessive uterine bleeding in
women who have VWD. (C, IV)
Management of Pregnancy and Childbirth
- Women planning
for pregnancy should have, before conception, an evaluation by a hematologist
and a high-risk obstetrician who are skilled in the management of VWD. (C,
IV)
- For 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:
- refer 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. (C, IV)
- administer prophylaxis with DDAVP or VWF
concentrate before invasive procedures. (C, IV)
- achieve VWF:RCo and FVIII levels of at least 50
IU/dL before delivery and maintain those levels for at least 35 days
afterward. (C, IV)
- 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. (C, IV)
- Because
coagulation factors return to prepregnancy levels within 1421 days after
delivery, health care providers should be in close contact with women during
the postpartum period. (C, IV)
Acquired von
Willebrand Syndrome (AVWS)
- AVWS patients
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. (C, IV)
- For AVWS
patients who bleed excessively despite therapy with DDAVP and VWF concentrate,
treatment with high-dose IGIV should be considered, especially in IgG isotype
MGUS. (B, IIa)
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