ASH Clinical News ACN_4.5_FULL_ISSUE_DIGITAL - Page 36

TRAINING and EDUCATION
How I Treat In Brief

“ Although type 2B von Willebrand disease is defined by [ a gainof-function defect in von Willebrand factor ], it is a clinically heterogeneous disorder that can be difficult to identify and manage .”

— REBECCA KRUSE-JARRES , MD , MPH , and JILL M . JOHNSEN , MD
Fast Facts
✓✓The diagnosis and management of type 2B vWD requires an understanding of the underlying physiology of vWF-platelet interaction .
✓✓Treatment is similar to other types of vWD , but special consideration should be given to situations that can worsen thrombocytopenia , such as pregnancy .
✓✓The mainstays of type 2B vWD treatment remain vWF replacement and vWD adjunct therapies ( including antifibrinolytics and topical hemostatic agents ).
✓✓Treatment with DDAVP is controversial but may be a convenient option for some patients with minor bleeding .
✓✓For patients with type 2B vWD who are pregnant or considering pregnancy , treatment planning requires close monitoring with a multidisciplinary team consisting of representatives from high-risk obstetrics , anesthesia , hematology , neonatology , pharmacy , blood bank , and the coagulation laboratory .
In type 2B vWD , DDAVP is thought to cause release of higher-molecular-weight , hyperfunctional vWF that provokes transient platelet aggregation and thrombocytopenia . The potential to exacerbate bleeding or thrombocytopenia ( which only appears with type 2B vWD ) resulted in the longstanding practice of avoiding the use of DDAVP in type 2B vWD .
Side effects with DDAVP are common , but most are mild and generally subside after 24 hours . To minimize the risks of serious adverse events such as iatrogenic hyponatremia , fluids should be restricted .
DDAVP offers two advantages over other vWD treatments : It is more economical than factor concentrates and can be self-administered intranasally . And , despite the controversies , DDAVP is occasionally used to treat minor bleeding .
Before considering DDAVP for type 2B vWD , we recommend a monitored study demonstrating the platelet nadir and kinetics of platelet recovery , in addition to vWF responsiveness . A pharmacokinetic study is recommended for all types of vWD .
Case # 2 : Management of Type 2B vWD During Pregnancy
A 23-year-old with type 2B vWD was monitored throughout her pregnancy , labor , and delivery , as well as postpartum . During her pregnancy , vWF : Ag , vWF : RCo , and FVIII : C levels increased , but not to normal pregnancy levels . Thrombocytopenia became apparent and progressively worsened , with platelet counts decreasing from 350,000 /µ L before her pregnancy to 31,000 /µ L at 35 weeks .
Because of changes during pregnancy , laboratory testing at 34 to 36 weeks gestation is recommended to assess vWF levels close to delivery , and platelet counts ( and vWF , when possible ) should be monitored weekly thereafter .
At 38 weeks , the patient went into labor . She received vWF replacement at 60 IU / kg , but no platelet transfusion . She had an uncomplicated vaginal delivery without neuraxial anesthesia and without abnormal bleeding . She was maintained on vWF replacement at 30 IU / kg every 12 hours and started on tranexamic acid 1,300 mg orally three times daily .
During the final stages of labor for a vaginal delivery ( or for bleeding at any time ), we recommend an initial vWF replacement dose of 60 IU / kg to a target vWF : RCo greater than 50 percent .
For thrombocytopenic episodes , if platelet count is less than 50,000 /µ L , we request platelet transfusion within 30 minutes of a procedure , then aim for a platelet count greater than 50,000 /µ L and repeat transfusions as needed . For more severe thrombocytopenia ( platelet counts less than 20,000 /µ L ), we recommend platelet transfusion , frequent platelet-count monitoring , and repeat transfusions as needed .
For the duration of labor and delivery , maintenance vWF dosing starts at half the initial bolus dose every eight to 24 hours , adjusting for vWF : RCo peak and trough levels and monitoring FVIII : C levels .
For caesarean section ( C-section ), we aim for a vWF : RCo close to 80 to 100 percent and continue maintenance therapy as described for vaginal delivery . Goals for maintenance treatment after delivery by C-section are a vWF : RCo greater than 50 percent and platelet count greater than 20,000 /µ L for at least five days .
Neuraxial anesthesia is not recommended in patients with type 2 ( and specifically 2B ) vWD because of safety concerns and lack of evidence . We recommend that if neuraxial anesthesia is performed , it be done within one hour of vWF replacement therapy . If an epidural is placed , we request removal as soon as possible after delivery while drug levels are high .
Post-Partum Prophylaxis Four days postpartum , the patient had experienced no excessive bleeding and vWF replacement dosing was reduced to 30 IU / kg every 24 hours for another three days . She completed two weeks of antifibrinolytic treatment . Four weeks after her last dose of vWF , she complained of heavy vaginal bleeding . She was treated with vWF replacement 60 IU / kg , followed by 30 IU / kg daily for two days . Tranexamic acid was restarted and she achieved good control of her bleeding .
Delayed postpartum hemorrhage ( bleeding between 24 hours and 6 weeks postpartum ) is common in women with vWD . For type 2B vWD , we recommend monitoring with vWF replacement for five to seven days , platelet transfusion as needed , and antifibrinolytic therapy for at least two weeks postpartum . If bleeding continues or recurs , additional treatment and other causes of bleeding should be considered .
Diagnosis of Type 2B vWD in the Newborn Laboratory diagnosis in newborns is challenging , but screening may be done on cordblood sampling . Cord blood vWF : Ag and FVIII : C may be normal , but the vWF : RCo can be decreased . Infants with type 2B vWD can have thrombocytopenia and plateletclumping on peripheral smear . Genetic testing for a familial 2B vWD variant also can confirm or exclude the diagnosis .
Infants ’ bleeding risk is not known , but potential causes of hemorrhage should be avoided when possible . In cases of thrombocytopenia with bleeding or for invasive procedures , platelet transfusions should be given . In bleeding patients , both vWF replacement therapy and platelet transfusions should be considered .
Final Considerations
Recently , development and use of bleedingassessment tools have allowed for improved stratification of which patients require further testing and which are most likely to require treatment for their bleeding disorders .
New options for laboratory assessments of vWF activity under investigation include new platelet-binding assays that may offer more stable results than the vWF : RCo assay and provide insight into different functions of vWF . ●
34 ASH Clinical News April 2018
TRAINING and EDUCATION How I Treat In Brief Fast Facts “Although type 2B von Willebrand disease is defined by [a gain- of-function defect in von Willebrand factor], it is a clinically heterogeneous disorder that can be difficult to identify and manage.” —REBECCA KRUSE-JARRES, MD, MPH, and JILL M. JOHNSEN, MD In type 2B vWD, DDAVP is thought to cause release of higher-molecular-weight, hyperfunctional vWF that provokes transient platelet aggregation and thrombocytopenia. The potential to exacerbate bleeding or thrombocytopenia (which only appears with type 2B vWD) resulted in the longstanding practice of avoiding the use of DDAVP in type 2B vWD. Side effects with DDAVP are common, but most are mild and generally subside after 24 hours. To minimize the risks of serious adverse events such as iatrogenic hyponatremia, fluids should be restricted. DDAVP offers two advantages over other vWD treatments: It is more economical than factor concentrates and can be self-administered intranasally. And, despite the controversies, DDAVP is occasionally used to treat minor bleeding. Before considering DDAVP for type 2B vWD, we recommend a monitored study demonstrating the platelet nadir and kinetics of platelet recovery, in addition to vWF respon- siveness. A pharmacokinetic study is recom- mended for all types of vWD. Case #2: Management of Type 2B vWD During Pregnancy A 23-year-old with type 2B vWD was moni- tored throughout her pregnancy, labor, and delivery, as well as postpartum. During her pregnancy, vWF:Ag, vWF:RCo, and FVIII:C levels increased, but not to normal pregnancy levels. Thrombocytopenia became apparent and progressively worsened, with platelet counts decreasing from 350,000/µL before her pregnancy to 31,000/µL at 35 weeks. Because of changes during pregnancy, laboratory testing at 34 to 36 weeks gestation is recommended to assess vWF levels close to delivery, and platelet counts (and vWF, when possible) should be monitored weekly thereafter. At 38 weeks, the patient went into labor. She received vWF replacement at 60 IU/kg, but no platelet transfusion. She had an uncom- plicated vaginal delivery without neuraxial anesthesia and without abnormal bleeding. She was maintained on vWF replacement at 30 IU/kg every 12 hours and started on tranexamic acid 1,300 mg orally three times daily. 34 ASH Clinical News During the final stages of labor for a vaginal delivery (or for bleeding at any time), we recommend an initial vWF replacement dose of 60 IU/kg to a target vWF:RCo greater than 50 percent. For thrombocytopenic epi- sodes, if platelet count is less than 50,000/µL, we request platelet transfusion within 30 minutes of a procedure, then aim for a platelet count greater than 50,000/µL and repeat transfusions as needed. For more severe thrombocytopenia (platelet counts less than 20,000/µL), we recommend platelet transfusion, frequent platelet-count monitoring, and repeat transfusions as needed. For the duration of labor and delivery, maintenance vWF dosing starts at half the initial bolus dose every eight to 24 hours, adjusting for vWF:RCo peak and trough levels and monitoring FVIII:C levels. For caesarean section (C-section), we aim for a vWF:RCo close to 80 to 100 percent and continue maintenance therapy as described for vaginal delivery. Goals for maintenance treatment after delivery by C-section are a vWF:RCo greater than 50 percent and platelet count greater than 20,000/µL for at least five days. Neuraxial anesthesia is not recommended in patients with type 2 (and specifically 2B) vWD because of safety concerns and lack of evidence. We recommend that if neuraxial anesthesia is performed, it be done within one hour of vWF replacement therapy. If an epidural is placed, we request removal as soon as possible after delivery while drug levels are high. 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