von Willebrand's Disease, feat. Dr. David Abel
/Today we welcome Dr. David Abel, Assistant Professor in obstetrics and gynecology at the Oregon Health and Sciences University. Dr. Abel’s expertise and interest is in the most commonly encountered bleeding disorder for OB/GYNs: von Willebrand disease.
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Some light reading to accompany today’s podcast:
What is von Willebrand’s disease?
First described in 1926 by Erik von Willebrand, a Finnish pediatrician.
Most common inherited bleeding disorder, accounting for about 80 to 85% of all bleeding disorders.
Prevalence about 1 in 10,000, though possibly as high as 1 to 2% of the general population.
With respect to women with heavy menstrual bleeding, the prevalence appears be greater, ranging from 5 to 24%.
Von Willebrand Factor is a large glycoprotein encoded by a gene on chromosome 12 that is synthesized in endothelial cells and megakaryocytes, the hematopoietic cells that produces platelets.
It is assembled from identical subunits into strings of subunits that vary in size and are referred to as multimers.
Two main functions:
Needed for normal adhesion of platelets to sites of injured endothelium
Serves as a carrier for Factor VIII, which also protects vWF from proteolysis
When vascular injury occurs, this multimeric protein uncoils which results in platelet adhesion, activation and aggregation.
Three main types of disease:
Type I: A partial quantitative deficiency of both von Willebrand factor and Factor VIII. This reduction is usually mild to moderate.
Most common, accounting for 70-80% of cases of vWD
Type II: Quantitative reduction in von Willebrand Factor, with subtypes noted as A, B, M and N.
Accounts for 10 to 30 percent of cases of vWD
Patients with Type 2B vWD may have a moderate to severe bleeding phenotype that may present with thrombocytopenia during pregnancy.
Though uncommon, when you go through your differential for thrombocytopenia during pregnancy, you can keep type 2B von Willebrand disease on your radar!
Type 3 Most severe, characterized by the virtual absence of von Willebrand factor.
Least common type, accounting for only 1-5% of cases.
VWD is usually inherited in an autosomal dominant fashion
Baby generally has a 50% chance of inheriting this condition — obstetric/neonatal implications.
Rarely vWDz is inherited as an autosomal recessive condition, namely in type 3, and some cases of type 2.
How do we establish a diagnosis of von Willebrand’s disease?
Most common bleeding symptoms: bruising, epistaxis, bleeding after injury, surgery or tooth extraction, postpartum bleeding, and menorrhagia (most commonly reported symptom).
In addition to mucocutaneous and soft tissue bleeding, joint and muscle bleeding can also occur.
Severity of bleeding is usually related to the degree of von Willebrand factor and Factor VIII deficiency.
Initial work up typically consists of nonspecific tests such as a CBC, PT, PTT and fibrinogen which are helpful in excluding a clotting factor deficiency.
PTT may be normal in patients with von Willebrand’s.
If thrombocytopenia is detected, type 2B vWDz is in the differential.
Next step are tests that are specific for von Willebrand Disease, three:
von Willebrand factor antigen (vWF:Ag) measures the quantity of von Willebrand Factor protein in the plasma.
Factor VIII assay measures Factor VIII activity which is essentially a surrogate marker for the activity of von Willebrand factor.
von Willebrand factor activity a functional assay that measures the interaction between VWF and platelets.
Historically this was measured by the von Willebrand Factor ristocetin cofactor activity assay (VWF:RCo).
Consultation with hematology will be helpful with diagnostic testing and interpretation of results.
Why does von Willebrand’s disease matter for us in OB/GYN?
Strong association between von Willebrand Disease and heavy menstrual bleeding.
Among women with heavy menstrual bleeding, von Willebrand Dz is found to be the etiology frequently, with a reported prevalence ranging from 5 to 20%.
Many treatment options are available for women with von Willebrand disease and heavy menstrual bleeding, including hormonal and nonhormonal therapies.
Association of VWD with other gynecologic problems, including ovarian cysts, endometriosis, and leiomyomas is unclear.
Prior to procedures as egg retrieval if IVF is planned, or invasive procedure during pregnancy such as CVS and amniocentesis, DDAVP or VWF concentrates can be administered immediately prior to these procedures (more on treatment later).
Antepartum and Intrapartum Management of vWD
Both von Willebrand Factor and Factor VIII levels increase during pregnancy, an increase that usually starts in the second trimester and peaks in the third trimester.
The increase in VWF and FVIII levels usually reduces the likelihood that our patients warrant treatment during the antepartum, intrapartum or even postpartum period.
If a patient was previously undiagnosed, the increase in levels during pregnancy may obscure the diagnosis.
In general, women with baseline levels of VWF and FVIII of >30 U/dL, suggesting type 1 VWD, usually have a high likelihood to achieve normal levels by the end of pregnancy.
In the case of the severe and uncommon type III vWDz, both VWF and FVIII levels do not increase during pregnancy.
Levels of vWF and FVIII fall rapidly after delivery.
Levels start to approach patient’s baseline by one week postpartum and fully reach baseline by three weeks postpartum.
Potential complications of vwD during pregnancy include antepartum bleeding, postpartum hemorrhage and perineal hematoma which are all increased by 2–10-fold.
Importantly the risk of delayed postpartum hemorrhage (bleeding occurring after 24 hours post-delivery) is also increased.
16-29% of women with VWD will have postpartum hemorrhage within the first 24 hours of delivery,
20-29% of women will experience delayed postpartum bleeding.
Bleeding is frequently reported to occur more than 2 to 3 weeks postpartum.
Factor VIII and von Willebrand Factor ristocetin cofactor activity assay are checked early in pregnancy and again in the third trimester.
Consult hematology to decide if any additional testing is needed
Women with type I vwDz with Factor VIII and ristocetin cofactor activity levels less than 50 IU/dL, and no history of severe bleeding, do not require special treatment at the time of delivery.
They can often be cared for by the general obstetrician in a community setting if the provider is comfortable and hematology available if needed.
If levels are less than 50 IU/dl, the patient is at risk of hemorrhagic complications including delayed postpartum hemorrhage. These patients require treatment usually close to delivery or after cord clamping.
The classic teaching is to administer DDAVP.
DDAVP causes release of VWF that has been stored in secretory granules within the endothelium, resulting in FVIII and VWF levels three to five times above basal levels within 30‐60 minutes.
Effective in patients with type 1 VWD with baseline VWF and FVIII levels higher than 10 IU/dL.
The recommended dose of DDAVP is 0.3 μg/kg IV given over 30 minutes or 300 μg given intranasally.
Onset of action of DDAVP is approximately 15-30 minutes.
Usually given at the time of cord clamping, but because the peak effect is 1.5 to two hours after administration, it may be more beneficial if administered during the second stage of labor or immediately before cesarean delivery.
Risks: water retention that can lead to hyponatremia and seizures.
Need fluid restriction to less than 1L in the 24 hours following DDAVP administration.
However, fluid restriction after delivery can be very difficult, and is the reason why many experts do not use DDAVP as a first line treatment.
Alternative: plasma derived VWF concentrates.
Options:
Plasma derived VWF concentration that contains VWF alone without Factor VIII.
Recombinant VWF concentrate that contains only VWF without Factor VIII.
Plasma derived concentrate that contains both VWF and Factor VIII.
The decision regarding which one of these to use will depend upon levels of both VWF and Factor VIII, what is available in your hospital and input from hematology.
Regional anesthesia
No consensus on levels that are safe for regional anesthesia, but if levels are greater than 50 IU/dL and assuming a normal platelet count, regional anesthesia is usually considered reasonable.
Recent ASH guidelines recommend VWF activity levels should be maintained at 50 IU/dL while the epidural is in place and for at least 6 hours after removal.
Mode of Delivery
Fetal status unknown in most cases —> given AD inheritance and 50% risk, best to avoid procedures such as a fetal scalp electrode.
Operative delivery is discouraged due to the potential risk of intracranial hemorrhage - cesarean delivery preferred to operative vaginal delivery.
The pediatrician should be made aware of the mother’s status and male circumcision should be postponed until the baby’s VWDz status can be determined.
Sending cord blood at the time of delivery for a VonWill panel is recommended to determine the status of the newborn.
Postpartum Care
High risk of both primary and delayed postpartum hemorrhage. Perineal hematomas can be seen.
VWF and Factor VIII levels can significantly decrease postpartum, with a return to baseline within 7-21 days postpartum.
These levels are typically checked in the immediate postpartum period and then periodically.
Hematology consultation will be valuable to help work out these details.
NSAIDS should be avoided in the postpartum period.
ASH guidelines recommend the use of oral tranexamic acid in the postpartum period.
Administration of one mg intravenously can be administered prophylactically immediately after delivery and continued PO for 10-14 days postpartum.
