von Willebrand Disease (vWD, vWF)
1. What every clinician should know
von Willebrand disease (vWD) is the most common genetic bleeding disorder, affecting about 1.3% of the population. This is an inherited disorder of hemostasis caused by a deficiency or an abnormal function of von Willebrand factor (vWF). vWF is a multimeric protein synthesized by endothelial cells and megakaryocytes. It’s essential role in hemostasis involves platelet adhesion to the endothelium, platelet-to-platelet interaction and aggregation, and as a carrier for plasma factor VIII (FVIII).
Subcategories of vWD have been noted, each with varying degrees of bleeding that are proportional to the level of deficiency of the vWF. These subtypes are based on the molecular pathophysiology; three main subtypes are reported.
Type 1, the most common and mildest form, occurs in about 80% of cases. Type 1 results from a partial quantitative deficiency of otherwise normal vWF and is inherited in an autosomal dominant manner. Type 1 vWF platelets fail to aggregate in the presence of ristocetin.
Type 2 occurs in 10-20% of cases. It involves a qualitative deficiency and is associated with more bleeding than type 1 disease. Type 2 vWD is inherited in an autosomal recessive fashion. In addition, type 2 is further subdivided into types 2A, 2B, 2M, and 2N phenotypes.
Type 3 vWD is the rarest and most severe form, occurring in 1 to 2 per million. Type 3 is characterized by a total quantitative deficiency of vWF ( Table I).
2. Diagnosis and differential diagnosis
Three criteria should be considered in making the diagnosis of vWD:
1. Symptoms of bleeding, either spontaneous, after procedures, or in excess of what is expected during menses or after delivery.
These initial screening questions should be used:
Have you or a blood relative needed medical attention for bleeding too much or been told you have a bleeding problem?
Do you have a bleeding, liver, or kidney disease?
At any time, past or current, have you taken medication to thin your blood (anticoagulation) or taken antiplatelet medication?
If answers to the above questions are yes, then additional detailed questions using a standardized assessment tool should be used. Several standardized questionnaires (aka bleeding assessment tools) have been endorsed by the International Society of Thrombosis and Haemostasis and allow for the calculation of a bleeding score (BS). In studies, a BS > 5 in women is considered sensitive and specific for a bleeding disorder and warrants laboratory testing (www.hematology.org/Practical).
2. Reduced vWF activity
Initial tests for hemostasis in women in whom there is a concern of a bleeding abnormality can include complete blood count (CBC), platelets, prothrombin time (PT), partial thromboplastin time (PTT), and fibrinogen.
Additional assays that are more specific to vWD include vWF antigen (vWF:Ag), vWF ristocetin cofactor activity (vWF:RCo), and factor VIII activity (FVIII:C).
If abnormalities in this specific testing for VWD are noted, additional studies are recommended to identify the subtypes: repeat vWD assays, vWF:RCo/vWF:Ag ratio, multimer testing for type distribution, collagen, platelet and FVIII binding, and DNA sequencing of the VWF gene.
A first-degree relative with a confirmed diagnosis of vWD provides strong support for a potential diagnosis of vWD in other family members, especially with a positive BS.
If initial screening tests are abnormal in the presence of normal tests specific for vWD, other bleeding disorders should be considered and include factor IX, XI, and XIII deficiencies, platelet disorders, and Ehlers-Danlos syndrome.
Consultation with hematology and anesthesiology colleagues is suggested, and a multidisciplinary team approach is recommended.
Pregnancy is not contraindicated in women with a diagnosis of vWD. Physiologic changes of hemostasis during pregnancy include increased vWF and FVIII. For type 1 vWD, the vWF and FVIII levels may increase several-fold and support normal hemostasis during pregnancy; however, these levels will be expected to return to the baseline in the postpartum period. Without anti-hemorrhagic prophylaxis, women with vWD have a 30% chance of postpartum hemorrhage compared to 5% in the general population, and the odds ratio for a blood transfusion is 4.7 (95% CI, 3.2-7.0).
Primary treatment of vWD typically includes 1-deamino-8-D-arginine vasopressin (DDAVP), which increases both vWF and FVIII activity. However, the response to DDAVP varies depending on the phenotype of vWD. Types 1 and 2A usually show a positive response after DDAVP administration. DDAVP should be avoided in type 2B because of the minimal response and the risk for worsening thrombocytopenia even though it may be transient and not associated with bleeding or thrombosis. Type 3 VWD rarely responds to DDAVP therapy, and vWF replacement is needed in the form of pooled plasma-derived concentrates: cryoprecipitate, Humate-P, or Alphanate Sd/HT. Although Koate-DVI use for vWD has been suggested by some experts, it is approved by the US Food and Drug Administration for use in hemophilia and its use in vWD is off label ( Table II).
The antepartum period is ideal for identifying the type of vWD as well as its response to DDAVP for type 1 disease. Testing the response to DDAVP can be performed as follows: Administer DDAVP as a single subcutaneous injection (0.3 μg/kg, maximum 20 µg) or intravenous (same dose diluted in 50-100 mL normal saline, infused over 30 minutes) infusion. Ninety minutes after administration, the platelet count and vWF:RCo levels should be measured for a response. Levels of activity greater or equal to 50 IU/dL are desired.
Before any invasive procedure (CVS, amniocentesis, cervical cerclage), laboratory assays to determine FVIII:C and vWF:RCo levels are necessary and prophylaxis should be administered as needed.
Levels of circulating vWF:RCo can be monitored in the third trimester and, when less than 50 IU/dL, are indicative of decreased levels at the time of delivery. Treatment with DDAVP or replacement of clotting factors will be needed to achieve this level at the time of delivery.
If a response to DDAVP was noted during earlier testing, a single dose may be sufficient in type1 vWD; however, for the other types or if a single DDAVP dose is not sufficient, the vWF concentrates are preferred. Humate-P is a lyophilized concentrate primarily of vWF and FVIII. One milliliter of reconstituted Humate-P = 50-100 IU/mL vWF:RCo and 20-40 IU/mL FVIII:C, and the median half-life is approximately 10.5 hours. Humate-P is approved by the FDA for use in vWD. A dosing strategy (package insert) for Humate-P is provided at www.humate-p.com/Professional/Resources-and-Tools/Dosing-Calculator-Table.aspx.
Cryoprecipitate concentrates do not list the vWF or FVIII levels but on average contains 80 IU FVIII per donor unit. However, Cryoprecipitate is not the first choice for therapy. Platelets contain 10-15% total blood vWF and are recommended as an adjunct source of vWF, especially in type 3 vWD.
As listed earlier, vWF plasma concentrate replacement products are usually labeled with the functional activity of vWF (VWF:Ac) and one can expect 1 IU/kg of vWF:RCo to increase the plasma level by 2.0 IU/kg. Prophylactic treatment with DDAVP or replacement factors can be administered either 60 minutes before the anticipated delivery or after the umbilical cord has been clamped. vWF:RCo for a vaginal delivery is recommended at 50 IU/mL, while for a cesarean section, 100 IU/mL is recommended.
Epidural or spinal anesthesia has been used in the setting of vWD but primarily in those with type 1 disease and a vWF:RCo greater than or equal to 50 IU/dL. This should be a decision considered in advance of delivery with the participation of a multidisciplinary team. Epidural or spinal anesthesia is not typically considered for those with type 2 or 3 disease.
Cesarean delivery has been advised by some with the intent to avoid bleeding for the infant; however, there is no evidence to support this practice. Vacuum and rotational forceps should be avoided.
FVIII:C or vWF:RCo should be maintained at 50 IU/dL or greater for 3-5 days after a vaginal delivery. The most conservative postsurgical recommendations include maintaining vWF:RCo activity at no less than 50 IU/mL for 7-14 days after a cesarean section. NSAIDs should not be used postpartum. Infants should be tested after birth to determine vWF status and circumcision withheld until the status of the infant is known. Prolonged or intermittent postpartum bleeding has been documented several weeks after delivery; thus, it is important to monitor patients several weeks after the delivery. The use of tranexamic acid has proved useful in controlling bleeding in type 1 disease postpartum and remote from delivery.
Complications of DDAVP include thrombocytopenia, especially in the setting of type 2B vWD. Serious adverse effects include hyponatremia and fluid overload. Myocardial infarction, although rare, has been noted after DDAVP administration to patients with hemophilia A. Minor adverse effects include headache, flushing, and changes in blood pressure.
Fluid restriction of 1 liter per day for 24 hours after the administration of DDAVP can help avoid the serious adverse effects.
Complications of vWF concentrate replacement include thrombosis, particularly in those in a high thrombosis risk category; thus, thromboprophylaxis strategies are recommended.
5. Prognosis and outcome
With a high degree of suspicion for a diagnosis of VWD, timelytesting, and appropriate planning by a multidisciplinaryteam, the prognosis and outcome for VWD during pregnancy are favorable.
6. What is the evidence for specific management and treatment recommendations?
Creasy, RK, Resnik, R, Iams, JD. “Maternal-Fetal Medicine. Principles and Practice”. 2014.
Lee, CA, Chi, C, Pavord, SR. “The obstetric and gynaecological management of women with inherited bleeding disorders: review with guidelines produced by a taskforce of UK Haemophilia Centre Doctors Organization”. Haemophilia. vol. 12. 2006. pp. 301-336. (2012 Clinical Practice Guideline on the Evaluation and Management of von Willebrand Disease (VWD) Presented by the American Society of Hematology, adapted from: The Diagnosis, Evaluation, and Management of von Willebrand Disease. National Heart, Lung, and Blood Institute, NIH Pub. No 08-5832. December 2007. www.hematology.org/Practical.
“Diagnosis, evaluation and management of von Willebrand disease”. 2007.
Rodeghiero, F. “Von Willebrand disease: Pathogenesis and management”. Thrombosis Research. vol. 131. 2013. pp. S47-S50.
Castaman, G, Tosetto, A, Rodeghiero, F. “Pregnancy and delivery in women with von Willebrand's disease and different von Willebrand factor mutations”. Haematologica. vol. 95. 2010. pp. 963
Castaman, G, Rodeghiero, F. “Advances in the diagnosis and management of Type 1 von Willebrand disease”. Expert Review of Hematology. vol. 95. 2011.
Pacheco, LD, Costantine, MM, Saade, GR, Mucowski, S, Hankins, GD, Scicione, AC. “von Willebrand disease and pregnancy: a practical approach for the diagnosis and treatment”. Am J Obstet Gynecol. vol. 203. 2010. pp. 194-200.
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