Managing von Willebrand Disease in Women

WHEC Practice Bulletin and Clinical Management Guidelines for healthcare providers. Educational grant provided by Women's Health and Education Center (WHEC).

Bleeding disorders have serious implications for the practice of obstetrics and gynecology. Women with bleeding disorders are likely to suffer from heavy menstrual bleeding and may experience bleeding complications at the time of childbirth. Furthermore, women with bleeding disorders are disproportionately affected by other gynecologic conditions that manifest with bleeding. The most common inherited bleeding disorder is von Willebrand disease (VWD), which is caused by a deficiency, dysfunction, or absence of von Willebrand factor (VWF). Adequate levels of normally functioning VWF are necessary for platelet adhesion and for protection of clotting factor VIII (FVIII) in the circulation. Inadequate levels of normally functioning VWF result in a bleeding disorder of varying severity. Although men are equally as likely as women to inherit this condition, women are more likely to be symptomatic. In response to a United States House of Representatives conference committee report, the National Heart, Lung, and Blood Institute convened a panel of experts to examine the current science in the area of VWD and to come to consensus regarding clinical final document, The Diagnosis, Evaluation and Management of von Willebrand Disease, in 2008 (1). Ensuring that families have adequate access to healthcare, and encouraging them to the use the medical alert bracelets, are important for prompt and efficient management.

The purpose of this document is to discuss current evaluation and management of von Willebrand Disease (VWD) in obstetrical and gynecological settings. A multidisciplinary approach to management, which involves obstetricians, gynecologists and hematologists, result in optimal treatment outcomes. Women with VWD may be at increased risk for gynecological and obstetrical complications. Many treatments are available for the control of menorrhagia in women with VWD, but the first-line therapy remains combined hormonal contraception. Obstetrical concerns include postpartum hemorrhage (PPH), mode of delivery, operative delivery techniques, spontaneous abortion, and epidural management. It is particularly important to diagnose bleeding disorders early in children and adolescents because accidental trauma is the most common source for the acute bleeding and the treatment in these situations. Because of the importance of these guidelines for the practice of obstetrics and gynecology, the information relevant to women's health is summarized here.


Background

In 1926, Erik von Willebrand first described a familial bleeding disorder in which symptoms were more severe in children and young women. He also noted that the condition had autosomal inheritance and that blood transfusions improved bleeding symptoms. Since then, knowledge of this disease has grown exponentially and it is currently recognized as the most common inherited bleeding disorder (2). Now known as von Willebrand disease (VWD), this disorder is caused by either a quantitative or qualitative defect in von Willebrand factor (VWF). The prevalence of VWD is as high as 1-2% in the general population. VWD is the most common inherited bleeding disorder among American women, with a prevalence of 0.6-1.3%; overall prevalence is even greater among women with chronic heavy menstrual bleeding, and ranges from 5% to 24%. Among women with heavy menstrual bleeding, VWD appears to be more prevalent among Caucasians (15.9%) than African American (1.3%) (3).


Pathogenesis

VWF, a large multimeric glycoprotein, is encoded by a gene that is located in the short arm of chromosome 12 and it is synthesized and released from the endothelium and megakaryocytes (4). As a result of vascular injury, VWF adheres to the sub-endothelial matrix that is exposed; with shear stress, the multimeric VWF uncoils, which leads to platelet adhesion, activation, and aggregation. Besides the predominant role in platelet-induced hemostasis, VWF also binds clotting factor VIII (FVIII) in plasma, thereby preventing its degradation and clearance. The latter action explains the reason that VWD is characterized by both extensive mucosal bleeding, because of platelet dysfunction; and prolonged bleeding after surgery, because of FVIII deficiency. Interestingly, the disease disproportionately symptomatic in women of childbearing age and appears in the form of menorrhagia and/or PPH. Numerous-case series of pregnancies that have been complicated with VWD have been reported in the literature (5). Overall, such women are at a higher risk of bleeding that is associated with invasive procedures, delivery, and both immediate and delayed PPH. Consequently, it is of utmost importance that obstetricians and gynecologists are familiar with this condition. The classification of VWD was updated in 2006 in an attempt to correlate disease subtype and optimal therapy, and it is discussed below (6).


Classification of von Willebrand Disease (VWD):

  • Type 1 VWD: it is the classic and most common form that accounts for nearly 80% of all cases. This subtype is characterized by a partial quantitative deficiency of VWF. Inheritance is autosomal dominant, and the bleeding propensity is mild to moderate. The laboratory evaluation of this disease will typically show a decrease in plasma concentration of both VWF protein (von Willebrand factor antigen [VWF:Ag] and FVIII). Qualitative functional assays of VWF function (von Willebrand factor ristocetin co-factor activity [VWF:RCo]) show a decrease in function that parallels the quantitative deficit of the protein (7).

  • Type 2 VWD: it is mainly a qualitative/functional problem of VWF; plasma concentrations of VWF are normal or near normal. Four variants of type 2 VWD have been described.

    1. Type 2A VWD: it is a variant in which, despite normal (or mildly reduced) plasma concentrations of VWF:Ag and FVIII, VWF-dependent platelet aggregation is compromised. This is demonstrated by a significantly decreased VWF functional test (VWF:RCo). The main problem here is a deficit in the proportion of large VWF multimers. These large multimers are the ones that ultimately interact with platelets to achieve aggregation. This condition may be inherited in either autosomal dominant or recessive fashion.
    2. Type 2B VWD: it is due to a pathologic increase in binding between platelets (through glycoprotein lb) and VWF. Platelets bind to the mutant large multimers, and these complexes are sequestered in the microcirculation and subsequently dissolved by the metalloproteinase ADAMTS 13 (A Disintegrin-like And Metalloprotease domain reprolysin type with ThromboSpondin type 1 motifs). This then leads to a decrease in large multimers and thrombocytopenia. Pregnancy and surgery frequently aggravate thrombocytopenia in these patients (8). Laboratory diagnosis rests on demonstration of patho-physiologically increased ristocetin-induced platelet aggregation. Inheritance is autosomal dominant.
    3. Type 2M VWD: it is characterized by decreased platelet adhesion to VWF due to minimal affinity between VWF and the platelet surface glycoprotein lb. Unlike types 2A and 2B, the concentration of large VWF multimers is normal in this subtype. The diagnosis rests on the demonstration of poor platelet aggregation in-vitro (VWF:RCo) in the presence of a normal amount of large VWF multimers on gel-electrophoresis (7). Inheritance of this subtype may be autosomal dominant or recessive.
    4. Type 2N VWD: it is caused by minimal binding between VWF and FVIII. Quantitative (VWF:Ag) and qualitative (VWF:RCo) testing for VWF are normal; however, the FVIII level is low. The main differential diagnosis in this situation is hemophilia A. Inheritance is autosomal recessive.

  • Type 3 VWD: it is rare. The prevalence has been estimated at 1 per 1,000,000. This is a severe quantitative defect in VWF that is characterized by undetectable levels of VWF:Ag in plasma. Consequently, FVIII levels will also be very low. Bleeding propensity in this subgroup is obviously very high. Inheritance is autosomal recessive.

  • Acquired von Willebrand syndrome (AVWS): it has been described. Autoimmune diseases may lead to increased clearance or inhibition of VWF (mediated by auto-antibodies that cross-react with VWF). Certain conditions (such as ventricular septal defects, aortic stenosis, and pulmonary hypertension) will increase fluid shear stress and may lead to increased proteolysis of VWF by ADAMTS 13 (A Disintegrin-like And Metalloprotease domain reprolysin type with ThromboSpondin type 1 motifs), a plasma metalloprotease that cleaves multimeric VWF. Certain medications (hydroxyethyl starch, valproic acid, ciprofloxacin) may induce AVWS (7).

Evaluation and Diagnosis

The diagnosis of VWD is based on the presence of supportive clinical features and the results of laboratory tests. Bleeding disorder red flags are (9):

  • Patient has a relative with an inherited bleeding condition;
  • Prolonged bleeding, lasting more than 15 minutes, from small injuries or wounds;
  • Heavy prolonged and recurrent bleeding following surgical procedures;
  • Bruising with minimal or no trauma with palpable lump under the bruise;
  • Spontaneous nosebleeds;
  • Prolonged bleeding following dental procedures;
  • Blood in the stool or bleeding ulcer that required urgent medical attention for cessation;
  • History of anemia requiring blood transfusion;
  • Heavy menses resulting in anemia or low iron stores;
  • Passing clots more than 1 inch diameter with menses or soaking more than one pad or tampon hourly;
  • Heavy bleeding during or following childbirth.

Broad questions to ask in evaluating a woman for a bleeding disorder:

  1. "Have you or a blood relative ever needed medical attention for a bleeding problem or have you been told you had a bleeding disorder or problem?" With these questions, the practitioner is advised to ask the additional probes:
    • During or after surgery?
    • After dental procedures or extractions?
    • With trauma?
    • During childbirth or for heavy menses?
    • Bruises so large they had 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. "Are you currently taking, or have you recently taken anticoagulation or antiplatelet medications (warfarin, heparin, aspirin, non-steroidal anti-inflammatory drugs, clopidogrel)?"

Laboratory Work-up

The initial evaluation should include a complete blood count (CBC) to assess hemoglobin level and evaluate for thrombocytopenia, and prothrombin time (PT), activated partial thromboplastin time (PTT), and optionally fibrinogen level (or thrombin clotting time), to evaluate for clotting factor deficiency. Although these tests are useful for detecting or excluding clotting factor deficiencies, the PTT will be normal in patients with platelet dysfunction and may be normal in patients with VWD. If bleeding history is strong, consider performing initial VWD assays (stated below) in conjunction with hematologist. Other causes identified (e.g. decreased platelets, isolated abnormal PT, low fibrinogen, and abnormal thrombin clotting time) referral to a hematologist for other appropriate evaluation is recommended. Isolated prolonged PTT that corrects on 1:1 mixing study, or no abnormalities advised to do specific tests for VWD (1).

The next series of tests includes specific tests for VWD. Because there are several forms of VWD and because existing laboratory assays have limitations, no single diagnostic test reliably identifies the condition. The recommended initial three specific blood (plasma) tests for VWD include:

  1. VWF ristocetin co-factor activity (VWF:RCo);
  2. VWF antigen (VWF:Ag); and
  3. Clotting factor VIII activity (FVIII).

The levels of VWF and FVIII may vary depending on multiple factors, including age, race, genetic factors, blood type, stress, inflammation, hormones, sample processing, and quality of the laboratory. Sometimes, such as when test results are low normal or minimally decreased, repeated analyses over several months may be required. In some instances, only one of several tests in the panel may be abnormally low. Further testing to determine the type of VWD includes, among other studies, VWF multimer analysis. If VWD is excluded, other categories of bleeding disorders should be considered. The expert panel recommended a "cutoff" level of less than 30 international units (IU)/dL for VWF:RCo to support the definite diagnosis of VWD. This recommendation does not preclude the diagnosis of VWD in individuals with VWF:RCo levels of 30-50 IU/dL if there is supporting clinical or family history, nor does this recommendation preclude the use of agents to raise VWF levels in patients with VWF:RCo levels of 30-50 IU/dL who are at risk for bleeding (10).


Management of von Willebrand Disease (VWD)

The treatment of VWD depends on the type of VWD and how severe it is. Most cases of VWD are mild and may only require treatment at the time of surgery, dental procedures, injury, or childbirth. When treatment is required VWD is treated by controlling bleeding symptoms where they occur, by using medications to reduce the risk of bleeding, and by raising VWF and clotting factor VIII. Once a diagnosis of VWD has been established, a multidisciplinary approach to management, which involves obstetricians-gynecologists and hematologists, results in optimal treatment outcomes. Hematologic consultation can guide decisions related to VWF replacement, optimization of hematologic parameters for epidural anesthesia, the use of VWF or factor VIII if necessary for the control of bleeding. Patients should be reminded that products that prevent platelet adhesion, such as aspirin or non-steroidal anti-inflammatory drugs, should be avoided once VWD is diagnosed (1).


Hemostatic Therapies for von Willebrand Disease (VWD)

There are two strategies for raising VWF. One is to administer 1-desamino-8-D-arginine vasopressin also known as desmopressin (DDAVP), which causes VWF to be released from endothelial cells. DDAVP is a synthetic derivative of the antidiuretic hormone vasopressin. It acts mainly on V2 receptors that are located in the renal collecting ducts that favor water retention. V2 receptors are also located in the endothelial cells where DDAVP will induce release of preformed VWF. The typical dose is 0.3 μg/kg intravenously (maximum dose, 25-30 μg) given over 30 minutes. The observed peak increment in FVIII and VWF levels usually occurs 30-90 minutes after the infusion. Alternatively, DDAVP may be administered intranasally at a dose of 300 μg. Intravenous administration is the preferred route for prophylaxis of surgical bleeding (7). Because the elevation of factors lasts only 8-10 hours after administration, DDAVP should be administered every 12-24 hours. The main problem with this approach is tachyphylaxis (decreased responses with repeated use). The latter may be avoided by monitoring FVIII response after each dose and tailoring repeated treatments accordingly. In general, if treatment is required for >3 days, VWF concentrates should be used as a supplement to therapy with DDAVP (11).

Patients with type 1 disease respond to DDAVP, but patients with type 3 do not. In type 2 disease, the main problem is that, despite an increase in secretion of VWF after DDAVP, the VWF secreted will retain its intrinsic molecular dysfunction. Consequently, the preferred therapy for type 2 disease is the use of VWF concentrates (12). However, small subset of patients with type 2 VWD responds to desmopressin. Identification of those individuals requires a test dose of DDAVP and subsequent measurement of VWF:RCo four hours after the dose. If the VWF:RCo corrects after the dose, DDAVP is an acceptable treatment for those particular patients. In the past type 2B disease was considered to be a contraindication for DDAVP use because the secretion of multimers with high affinity for platelets leads to thrombocytopenia. However, such an effect has been noted to be transient and not associated with bleeding or thrombosis (13). Recent data indicate that some individuals with type 1 disease have accelerated clearance of VWF; therefore, even patients with type 1 disease may benefit from a test dose of DDVP and subsequent measurement of VWF:RCo to document treatment efficacy.

Minor side effects of DDAVP include flushing, headache, gastrointestinal complaints and transient hypo- and hypertension. Repeated dosing may lead to water retention and hyponatremia. It is of paramount importance to limit fluid intake and to follow sodium plasma levels during prolonged therapy (14). Myocardial infarction has been reported in elderly patients with coronary artery disease after the use of DDAVP. In general, the drug should not be used in people with unstable coronary artery disease because the large VWF multimers that are secreted will aggregate platelets and could lead to myocardial infarction (12).

The other strategy for raising VWF is to administer human plasma-derived, virally inactivated clotting factor concentrates. VWF concentrates may be required perioperatively, peripartum, at the time of serious injury, and in episodes of severe, acute bleeding, including severe, acute bleeding, including severe, acute menorrhagia. VWF concentrates that undergo viral inactivation should be administered instead of fresh frozen plasma or cryoprecipitate in acute cases. It may carry a very low risk of viral transmission.

Tranexamic acid is an antifibrinolytic agent that helps to prevent dissolution of hemostatic fibrin clots. Although currently available only for intravenous use in the United States, an oral preparation of tranexamic acid is already approved in Europe and Canada, may soon be approved for use in the United States. Tranexamic acid has equivalent or superior hemostatic efficacy and generally is better tolerated as compared with another antifibrinolytic, epsilon aminocaproic acid, but intravenous and oral preparations of epsilon aminocaproic acid are currently available in the United States (15).


- GYNECOLOGIC CONSIDERATIONS -

Adolescent Considerations

The onset of heavy menses at menarche is often the first sign of VWD. Retrospective analysis of a cohort of 38 women with type 1 VWD revealed that heavy menstrual bleeding at menarche was the most common initial bleeding symptom, which occurred in 53% of women (16). However, adolescence is a time when bleeding patterns can be highly variable. If the heavy bleeding is attributed solely to immaturity of the hypothalamic-pituitary axis, an underlying bleeding disorder may be overlooked. Adolescents may have both immaturity of hypothalamic-pituitary axis and heavy menses, further complicating the presentation. Careful screening is necessary to avoid delay in diagnosis. We recommend that an initial reproductive health visit occur between the ages of 13 years and 15 years, which provide clinicians with an opportunity to inquire about menstrual history and screen for bleeding disorders (17). It is particularly important to diagnose bleeding disorders early in children and adolescents because accidental trauma is the most common source of morbidity and mortality in this age group.

Specific questions can help one gain a better understanding of how heavy an adolescent is bleeding, including the following:

  1. How many pads or tampons do you use in a day?
  2. How frequently do you need to change your pad or tampon?
  3. Do you have flooding?
  4. Do you miss school because of your period?

Recommended Screening Tool for Adolescent Patients who Report Heavy Menstrual Bleeding

If patient meets one or more of the following criteria, it indicates a positive screen result and warrants further evaluation (18):

  1. Menses greater than 7 days and "flooding" or "gushing" sensation or bleeding through pad or tampon in 2 hours;
  2. History of anemia;
  3. Family history of bleeding disorder;
  4. History of bleeding disorder after hemostatic challenge (i.e., tooth extraction, surgery, delivery).

If screening results are positive, laboratory evaluation is indicated (as discussed above). Screening for disorders of hemostasis before starting hormonal treatment is recommended because treatment may interfere with the results and combined oral contraceptive treatment should be interrupted for accurate VWD testing. Although recent studies have suggested that interrupting combined hormonal contraceptive therapy for VWD testing may be unnecessary (19). Given emerging controversy surrounding VWD testing, consultation with a hematologist may be helpful for the management of patients already taking combined hormonal contraceptives. Available treatment options for adolescents are similar to those for other women. In adolescents, fertility preservation is paramount; therefore, medical options should be used rather than surgical procedures. Antifibrinolytic agents, such as tranexamic acid and aminocaproic acid, can be effective non-hormonal treatment options for adolescents; however, their use in individuals younger than 18 years is considered "off-label". As with the adult patient, a multidisciplinary approach to management, which involves both obstetricians and gynecologists and hematologists, results in optimal treatment outcomes.


Hormonal Treatments

Limited studies have been conducted on the treatment of heavy menstrual bleeding specifically for women with VWD or other disorders of hemostasis; the following treatments are based on this evidence and expert opinion. Studies in women with VWD and heavy menstrual bleeding suggest that the levonorgestrel-releasing intrauterine system may be effective for this population (20). Use of progestin-only contraceptives, such as depot-medroxyprogesterone acetate; progestin-only pills; and the progestin implant, also may reduce menstrual flow in the setting of bleeding disorders (21). For women without bleeding disorders, use of combined oral contraceptives or the levonorgestrel-releasing intrauterine system reduce menstrual bleeding. Limited studies in women with VWD and heavy menstrual bleeding suggest these treatments also may be effective for this population (20). Although oral progestins (taken for 21 days of the cycle) and depot-medroxyprogesterone acetate are effective for women with heavy menstrual bleeding without bleeding disorders and may be effective for women with bleeding disorders as well, few studies have focused on their use in this specific population.


Non-Hormonal Treatments

Non-hormonal treatment options include antifibrinolytic agents, such as tranexamic acid and aminocaproic acid, and treatments that increase endogenous plasma concentration of VWF, replace VWF, or promote hemostasis without affecting VWF. Antifibrinolytics inhibit the conversion of plasminogen to plasmin, which inhibits fibrinolysis, and thereby, help stabilize clots. Tranexamic acid was approved for the treatment of heavy menstrual bleeding by the U.S. Food and Drug Administration (FDA) in 2009. Studies in women without bleeding disorders demonstrate that tranexamic acid reduce menstrual bleeding by 30-55% in women with heavy menstrual bleeding (15),(22). Theoretically, tranexamic acid also should work in women with VWD because it stabilizes clots that have already formed, and clot formation is an essential step in limiting menstrual bleeding. Therapies generally prescribed in conjunction with a hematologist once a diagnosis of VWD is established include desmopressin acetate, recombinant factor VIII, and VWF complex infusion (23). Desmopressin acetate is a synthetic derivative of the antidiuretic hormone vasopressin and works by stimulating the release of VWF from endothelial cells (7). Recombinant factor VIII and VWF complex infusion are plasma-derived concentrates used to replace factor VIII and VWF, respectively. One study demonstrated that women with bleeding disorders had reduced menstrual flow with the use of either intranasal desmopressin or tranexamic acid (24).


- OBSTETRIC CONSIDERATIONS -

Ideally, planning for pregnancy begins before conception. Women contemplating a pregnancy should be aware that they may be at an increased risk of bleeding complications during pregnancy, and are definitely at an increased risk of PPH, particularly delayed PPH. Before conception or during pregnancy, women should be offered the opportunity to speak with a genetic counselor regarding the inheritance of VWD and with a pediatric hematologist regarding the evaluation of the infant after delivery. Because of the possible need for transfusion, women with VWD who have not already been vaccinated should be immunized against hepatitis A and hepatitis B. During pregnancy, levels of VWF and clotting factor VIII increase, frequently obviating the need for hemostatic therapy at the time of delivery.

Symptoms usually involve mild-to-moderate mucocutaneous bleeds, such as epistaxis, menorrhagia, bleeding after dental-extractions, ecchymoses, gingival-bleeding, and prolonged bleeding from minor cuts. Patients with rare type 3 disease may have life-threatening bleeding episodes, such as intracranial and gastrointestinal hemorrhages. Once the clinical suspicion is present, the next step is laboratory confirmation (discussed above). Other specialized tests may follow to further classify the disease. Gel-electrophoresis may provide information on the abundance of different-sized VWF multimers, which would aid in the diagnosis of subtypes 2A and 2 B, where large multimers are decreased. A binding assay is available to evaluate interaction between VWF and FVIII. Minimal interaction will point towards type 2N VWD (25). The low-dose ristocetin-induced platelet aggregation test is valuable in diagnosing type 2 B VWD. In this test, low doses of the antibiotic ristocetin are added to the patient's sample. In type 2B disease, because of the high affinity of VWF and platelets, even such low concentrations of ristocetin will induce platelet aggregation. This test will be negative in all other subtypes of the disease. Reference laboratories frequently will perform a ratio to compare the amount of qualitative-to-quantitative dysfunction present (VWF:RCo/VWF:Ag). This will be useful in the differentiation of type 1 and type 2 VWD variants.

If the ratio is <0.5-0.7, the patient is most likely affected with type 2 disease, because such a low ratio is consistent with dysfunctional VWF (a higher ratio is consistent with type 1 disease because the VWF:Ag will be lower). Both the VWF:Ag and VWF:RCo assays are reported in IU per deciliters (dL). A value <30 IU/dL is diagnostic for VWD; however, some patients with VWD may have values between 30 and 50 IU/dL (7). This subgroup of patients should be treated in the same fashion as other patients with VWD before any invasive procedure during pregnancy. Occasionally, repeated testing for VWD is needed because conditions such as pregnancy, stress, surgery, and inflammation will increase levels of VWF and mask lower baseline values.


Peripartum Management of von Willebrand Disease (VWD):

It should ideally include obstetricians, hematologists and blood bank personnel. Clinical pearls for the management of VWD during pregnancy are suggested below (26):

  1. Consider diagnosis in patients with mild-to-moderate mucocutaneous bleeds, such as epistaxis, menorrhagia, delayed PPH, bleeding after dental-extractions, ecchymoses, gingival-bleeding, and prolonged bleeding from minor cuts. Patients with menorrhagia and no documented pelvic anomalies should be screened for VWD;
  2. Detailed laboratory testing is basic to identify correctly the subtype of the disease. Treatment is tailored according to subtype.
  3. Once diagnosed, follow-up factor VIII levels should be monitored at least once every trimester.
  4. Offer genetic counseling.
  5. Maintain factor VIII levels at >50 IU/dL before any invasive procedures, at the time of delivery, and during the postpartum period. Ideally, maintain such levels for up to 2 weeks after delivery.
  6. If possible, avoid procedures such as pudendal blocks, episiotomies, and operative vaginal deliveries.

Overall, 16-29% of women will experience delayed postpartum bleeding (27). Vaginal delivery is considered safe for women VWD types 1 and 2. In patients with type 3 disease, a prolonged second stage of labor should be avoided, and early cesarean delivery may be considered in such cases (28). Summary of the peripartum management is discussed below:

  1. Check CBC, aPTT, PT, FVIII, VWF:RCo assay and type and cross-match packed red blood cells as needed. Operative vaginal delivery only if necessary. Avoid pudendal blocks and episiotomies if possible.
  2. Type 1 VWD:
    DDAVP if FVIII or VWF:RCo <50 IU/dL. Follow FVIII and VWF:RCo daily (titrate infusions accordingly). Maintain levels of both >50 IU/dL during labor, delivery, and up to 5 days postpartum. If prolonged treatment with DDAVP, consider adding VWF concentrates. Continue close follow-up of FVIII and VWF:RCo levels for up to 2 weeks postpartum (especially if cesarean section) and provide prophylaxis accordingly to avoid late postpartum hemorrhage.
  3. Type 2 VWD:
    DDAVP if response documented on test dose (mainly 2A). VWF concentrates (if FVIII or VWF:RCo <50 IU/dL. Follow FVIII and VWF:RCo daily (titrate infusions accordingly). Maintain levels of both >50 IU/dL during labor, delivery, and up to 5 days postpartum. Continue close follow-up of FVIII and VWF:RCo levels for up to 2 weeks postpartum (especially if cesarean section) and provide prophylaxis accordingly to avoid late postpartum hemorrhage.
  4. Type 3 VWD:
    VWF concentrates (if FVIII or VWF:RCo <50 IU/dL). Follow FVIII and VWF:RCo daily (titrate infusions accordingly). Maintain levels of both >50 IU/dL during labor, delivery, and up to 5 days postpartum. Continue close follow-up of FVIII and VWF:RCo levels for up to 2 weeks postpartum (especially if cesarean section) and provide prophylaxis accordingly to avoid late postpartum hemorrhage.
  5. If prolonged treatment with DDAVP, consider adding VWF concentrates.
  6. Avoid hypotonic solutions at time of delivery if using DDAVP in order to prevent hyponatremia.
  7. Continue close follow-up of FVIII and VWF:RCo levels up to 2 weeks postpartum (especially if cesarean section) and provide prophylaxis accordingly to avoid late PPH.

[Abbreviations: CBC: complete blood count; aPTT: activated partial thromboplastin time; PT: prothrombin time; DDAVP: desmopressin; FVIII: clotting factor VIII; VWF:RCo: von Willebrand factor ristocetin cofactor assay.]

DDAVP is safe for the fetus because it does not cross the placenta in detectable amounts and has little-to-no oxytocic effect (12). DDAVP is a pregnancy category B medicine. VWF concentrates include Humate-P and Alphanate. These are plasma-derived concentrates of VWF and FVIII that are available in the United States for treatment of patients with VWD who are not candidates for DDAVP treatment. Adverse reactions to Humate-P and Alphanate are rare but may include rash, pruritis, and urticaria. When used for several days, one should follow levels of VWF:RCo (do not exceed 200 IU/dL) and FVIII (do not exceed 250-300 IU/dL) because high levels of FVIII have been associated with venous thromboembolism (30). Thromboembolic prophylaxis in patients who undergo surgery with VWD should be used in the same fashion as in patients without the disease. The usual loading dose for these products is 40-60 IU/kg. VWF concentrates are dosed primarily on the basis of FVIII units. Infusions ideally should start daily before delivery until levels of 50 IU/dL are achieved for both VWF:RCo and FVIII. Such levels should be maintained for at least 3-5 days after delivery. Levels should be followed daily, and the need for repeated doses should be tailored accordingly. Maintenance doses usually range between 20 and 40 IU/kg every 12-48 hours. As stated before, because of delayed postpartum hemorrhage, laboratory monitoring may be needed for more than 2 weeks after delivery to correctly identify those patients who will require prolonged prophylaxis with either VWF concentrates or DDAVP.

In acute bleeding cases, hemostasis may be achieved in VWD with 10 bags of cryoprecipitate. However, this blood product does not undergo viral inactivation, which poses a significant risk of disease transmission. Fresh frozen plasma may also be used to correct VWD; however, large amounts of volume will be needed to achieve hemostasis. Platelet concentrates contain 15% of total blood VWF; consequently, platelet transfusions are considered to be an adjunctive therapy in cases in which bleeding is not controlled, despite adequate FVIII levels (31). Antifibrinolytics are considered second-line therapy for patients with VWD. They are mostly used to treat mild mucocutaneous bleeding in VWD because mucosal tracts typically have rich fibrinolytic activity (7). Aminocaproic acid is administered as a loading dose of 5 g, starting 1 hour before an invasive procedures followed by a drip of 1 g/hr until bleeding is controlled. Side effects include nausea, vomiting, and rarely, thrombotic complications. Antifibrinolytics should be avoided in patients with gross hematuria, because renovascular thrombi may fail to lyse and cause urinary tract obstructions (7). An algorithm for the treatment of VWD in the peripartum period is discussed above.


- NEWBORN CARE -

Intracranial hemorrhage of term neonates with severe VWD type 3 and near normal delivery have not been published to the date. The occurrence of central nervous system bleedings in neonates with VWD (including the most severe form, type 3) is extremely rare (29). This study reports a term newborn with severe type 3 VWD who suffered a large intracranial bleeding presumably subsequent to sinus venous thrombosis (29). This case is remarkable in two aspects: First, with respect to the low-risk of perinatal intracranial hemorrhage even in neonates with VWD type 3, and second, VWD type 3 with FVIII or VWF:RCo levels <5 IU/dL does not seem to protect from thromboembolism. Guidelines for the management of hemophilia advice is atraumatic delivery of neonates with known or suspected bleeding disorders, however primary cesarean section in the absence of complications is not obligatory. To answer the question whether the presented case could have an impact on the recommended management these authors carried out a worldwide survey including 24 participating specialized centers (29). Except a single case from Sweden of a female neonate with VWD type 3 who also had an inhibitor against VWF no further cases were reported. The conclusion is that central nervous system bleeding in term neonates with severe VWD type 3 is a rare event that required additional risk factors for manifestation. Therefore, the amendment of current guidelines does not seem to be mandatory.

Since VWD is not considered to be clinically more severe than hemophilia, the same guidelines should be applied. According to the guidelines for the management of hemophilia, delivery of infants at-risk should be as atraumatic as possible to decrease the probability of bleeding. Vacuum extraction, forceps, fetal-scalp-electrodes, and fetal scalp-blood-sampling should be avoided. A cesarean section should be performed for obstetrical indications only (evidence grade II-2C).


- GENETIC CONSIDERATIONS -

The VWF gene is located near the tip of the short arm of chromosome 12. Mutations that cause VWD have been identified throughout this gene. Such mutations include large deletions, insertions, splice-site mutations, and nonsense and missence mutations. The use of gene-specific polymerase chain reaction primers has facilitated the diagnosis in some subtypes of the disease. A database of such mutations is available online at the University of Sheffield (32). Prenatal genetic testing may be achieved by either chorionic villous sampling or amniocentesis. When testing is performed for VWD, knowing the subtype is imperative. Regarding type 1 VWD, the genotype-phenotype correlation can be inconsistent. The phenotype is relatively mild and very responsive to current medical management. As a result of the risks that are associated with testing, current recommendations are that prenatal testing is of limited use in this population (4). Further clarification of the molecular basis of type 1 disease is required before clinical genetic testing is implemented.

In the case of type 2 VWD, the correlation between phenotype and genotype is more consistent. This consistent correlation, coupled with the fact that mutations are relatively well localized, provides a good rationale for genetic testing (33). Prenatal diagnosis is certainly important for women who are known to be carriers of the most severe type 3 disease. The most common mutation reported in type 3 is a frameshift mutation in exon 18 (33).


Tranexamic Acid

Oral tranexamic acid is FDA approved for the treatment of ovulatory abnormal uterine bleeding; and intravenous formulation is approved for use in hemophilia. This medication works by competitively blocking plasminogen-binding sites, preventing plasma formation, fibrin degradation, and clot degradation. Women with heavy menstrual bleeding appear to have higher numbers of endometrial plasminogen activators and more local fibrinolytic activity than women with normal menses. In the treatment of heavy menstrual bleeding, tranexamic acid has proved to be superior to placebo, mefenamic acid, and luteal-phase progestins. The women taking tranexamic acid believed that the reduction in menstrual blood loss was meaningful enough to improve their overall quality of life, including social, leisure, and physical activities, as well as work inside and outside the home. The most commonly prescribed and studied treatment regimen is oral tranexamic acid 1 g to 1.3 g every 6-8 hours during menstruation (34).


Desmopressin (DDAVP)

This drug, a synthetic analog of vasopressin, promotes the release of VWF from endothelial cell storage sites. It is used to treat patients with bleeding disorders, notably, VWD during episodes of acute abnormal uterine bleeding. It should be utilized only when all other hormonal and non-hormonal therapies have failed. Collaboration with a hematologist is strongly encouraged before treatment of abnormal uterine bleeding with desmopressin (34).


American Society of Hematology (ASH) Guidelines

Antepartum hemorrhage is uncommon, but PPH has been observed in up to 37.5% of women with type 2 VWD not receiving adequate prophylaxis (35). It is therefore recommended that women have their VWF/FVIII levels monitored during the third trimester to facilitate planning for delivery. The need for therapeutic intervention depends on level of VWF and FVIII, thrombocytopenia, and type of VWD. With the rise of FVIII and VWF during pregnancy, women with mild type 1 VWD rarely need treatment, while type 3 disease (where VWF and FVIII do not increase with pregnancy) will require factor replacement. When FVIII or VWF:RCo levels are less than 50 IU/dL, prophylaxis is recommended prior to vaginal or surgical delivery. DDAVP, a synthetic analogue of vasopressin that increases VWF and FVIII, is an option for certain patients; however, there is the potential risk of hyponatremia at the time of delivery (35). ASH has developed a series of brief, evidence-based pocket guides to help physicians provide quality care to patients. The guides cover such topics as thrombocytopenia in pregnancy, heparin-induced thrombocytopenia, red blood cell transfusion, anticoagulant dosing and management, and VWD.


SUMMARY

VWD is a common cause of menorrhagia and other bleeding problems. This disorder affects the reproductive system as well as other body systems, so patients may need access to other health care providers in addition to obstetricians and gynecologists. Many resources exist for patients and healthcare providers through the Hemophilia Foundation's Project Red Flag, and the ASH. Despite the therapeutic physiologic effect of pregnancy on patients with VWD, bleeding complications remain a significant risk to both mother and fetus. Because the risk of bleeding varies by subtype, accurate diagnosis of the disease is an essential step of care to provide recommendations regarding optimal therapy and genetic counseling. Overall, the preferred management for pregnancy that is complicated by VWD is anticipating complications by monitoring bleeding parameters. Therefore, with adequate monitoring, prophylaxis, and observation, patients with VWD can be expected to tolerate the course of pregnancy with minimal risk.

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