Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Passed (Consensus scoring is Complete)
• Curation Status (Adult): Released - Under Revision 1.1.1
• Status (Pediatric): Incomplete (Consensus scoring is Incomplete)
• GENE/GENE PANEL: VWF
• Condition: von Willebrand Disease
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• VWF ⇔ 0008668 (von willebrand disease, type 1; vwd1): Assertion Pending
• VWF ⇔ 0010191 (von willebrand disease, type 3; vwd3): Assertion Pending
• VWF ⇔ 0013304 (von willebrand disease, type 2; vwd2): Assertion Pending

Actionability Rationale

This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Final Consensus Scores

Gene Condition Pairs: VWF ⇔ 0010191 (OMIM:277480)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Bleeding complications / Pharmacological intervention for scheduled procedures	2	3C	3A	2	10CA
Bleeding complications / Anti-hemorrhagic interventions in trauma settings	2	3C	3A	2	10CA
Bleeding complications / Pharmacological intervention for scheduled procedures	2	3C	3A	2	10CA
Bleeding complications / Anti-hemorrhagic interventions in trauma settings	2	3C	3A	2	10CA
Clinically significant bleeding / Pharmacological prophylaxis	2	3C	2B	2	9CB
Clinically significant bleeding / Pharmacological prophylaxis	1	3C	0B	2	6CB

Gene Condition Pairs: VWF ⇔ 0008668 (OMIM:193400) VWF ⇔ 0013304 (OMIM:613554)

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

Von Willebrand disease (VWD) is the most common inherited bleeding disorder with prevalence estimates from <0.1% to 2% in the general population, with variation in estimates likely based on diagnostic criteria. Clinically relevant cases may have a 10-fold lower prevalence, estimated between 1/50,000 to 1/8,500. The prevalence of VWD type 3 has been estimated as 0.5 to 6 per million, increasing with the rate of consanguinity. [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15]

Clinical Features

VWD is a bleeding disorder due to deficient or defective plasma von Willebrand factor (VWF), a large, multimeric protein that mediates platelet adhesion and stabilizes coagulation factor VIII (FVIII). Individuals primarily manifest mucocutaneous bleeding such as bruising, gingival bleeding, epistaxis, and menorrhagia. Bleeding after dental extraction, minor wounds, and surgical procedures are common. Spontaneous bleeding (joint and gastrointestinal bleeding) is not common except in more severe cases. Diagnosis is based on bleeding symptoms and confirmed VWF impairment. There are 3 types of VWD and each may be categorized into mild, moderate, and severe based on severity of VWF impairment.
Type 1 (50-75% VWD) is a partial deficiency of functionally normal VWF. It typically manifests as mild to moderate bleeding, but may be more severe with low VWF levels. Type 2 (~20-45% VWD) has normal or modestly decreased VWF levels but VWF function is abnormal. It typically manifests as mild to moderate bleeding, but may be more severe. Type 2 is divided into 4 subtypes depending on the VWF dysfunction. Type 2A has reduced VWF binding to platelets due to a deficiency of VWF multimers. Type 2B has increased VWF binding to platelets, leading to depletion of VWF multimers. Manifestations may include thrombocytopenia that worsens in stressful situations, such as infection, surgery, pregnancy, or treatment with desmopressin. Type 2M has reduced VWF binding to platelets with normal levels of VWF multimers. Type 2N has impaired binding to FVIII which lowers FVIII levels and mimics mild hemophilia A. Type 3 (<5% of VWD) is a complete deficiency of VWF with very low levels of FVIII and manifests with severe mucocutaneous and musculoskeletal bleeding. [2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22]

Natural History

The severity of bleeding symptoms varies and depends on the primary deficiency of VWF and secondary deficiency of FVIII. ABO blood group appears to be an important contributor to penetrance and reduced VWF level in type 1 VWD Individuals; non-O blood groups have higher VWF levels than those with O blood group. VWD may only become apparent on hemostatic challenge. Bleeding history may become more apparent with increasing age. Type 3 is often apparent early in life, though cases have been diagnosed in adulthood. Mild type 1 may not be diagnosed until midlife, despite a history of bleeding episodes. Joint bleeds, or hemarthrosis, is not a common symptom but can lead to arthropathy and joint damage. Life-threatening bleeding that involves the brain or gastrointestinal tract can occur in individuals with type 3, in some individuals with type 2, and, rarely, in individuals with type 1. VWD affects males and females with equal frequency, though it may be disproportionately symptomatic in women of child-bearing age due to the increased risk of menorrhagia, hemorrhagic ovarian cysts, and post-partum hemorrhage. For patients managed within specialized centers, prognosis is favorable even for the most severe forms. [2, 3, 4, 7, 11, 12, 13, 15, 18, 20, 21]

2. How effective are interventions for preventing harm?

Patient Management

Note on VWD treatment options: There are three common treatment options that may be used alone or at the same time. The most common and preferred treatment is desmopressin, which increases the plasma concentration of VWF by releasing endogenous stores. However, not all patients respond to desmopressin and it may be contraindicated in type 2B and type 3. A second option is replacement therapy with factor concentrates (VWF or combined VWF/FVIII). A third option is agents that promote hemostasis and wound healing, but do not alter VWF levels, such as oral contraceptives, topical agents (bovine thrombin and fibrin sealant), and antifibrinolytics (tranexamic acid and aminoproic acid). Treatment depends on VWD type and severity, bleeding history, treatment response, age, comorbidities, and the nature or potential bleeding. [2, 3, 5, 7, 8, 10, 11, 15, 16, 17, 19, 23]

To establish the extent of disease and needs in an individual with VWD, the following evaluations are recommended at diagnosis:
• A personal and family history of bleeding to help predict severity and tailor treatment
• A joint and muscle evaluation for those with type 3 VWD
• Screening for hepatitis B and C and HIV if the diagnosis is type 3 VWD or if the individual received blood products or plasma-derived clotting factor concentrates before 1985
• Baseline serum iron and ferritin to assess iron stores, as many individuals with VWD (particularly women with menorrhagia) are iron deficient. (Tier 4) [2]

Affected individuals benefit from care in a comprehensive bleeding disorders program for education, treatment, and genetic counseling. (Tier 4) [2]

As most cases of VWD are relatively mild and patients do not suffer from serious spontaneous bleeding, prophylaxis is rarely indicated. Exceptions include patients with more severe VWD. Evidence for prophylactic treatment with factor concentrates is insufficient and limited to observational and retrospective studies. However, clinical experience with prophylaxis indicates reduced bleeding frequency, joint disease, and improved quality of life. Thus some believe that prophylactic treatment of VWD is justified, particularly for type 3. Three studies of mostly patients with type 3 have reported that prophylaxis is effective in abolishing bleeding, with a reduction in mucosal bleeding of 50-60% reported in one study. (Tier 2) [8, 19, 22, 24]

To determine clinical response to desmopressin, a test infusion during a non-bleeding state should be performed at diagnosis. The majority of patients with type 1 respond adequately. In a prospective study of 77 patients with type 1, 83% had complete and 13% had partial responses. However, desmopressin response is reduced in other VWD types. Only 13% of type 2 patients were responsive in a prospective study. Desmopressin may be useful and efficacious in type 2A only when FVIII levels need to be raised. Its use in type 2B is controversial due to thrombocytopenia and lack of evidence on effectiveness, but a test of response is acceptable. There is limited experience with type 2M. Type 2N typically responds to desmopressin, but the altered VWF has a reduced half-life. Type 3 is typically unresponsive. Some guidelines limit this testing recommendation to only those with type 1 and selected patients with type 2. (Tier 1) [3, 5, 15]

Before major surgery, a dosing study of factor concentrates should be considered, particularly in patients with type 3. (Tier 1) [15]

Patients should also be monitored for factor activity during surgery. Whenever possible, major surgical procedures should be performed in hospitals with around-the-clock laboratory capability and with clinical monitoring by a team that includes a hematologist and a surgeon skilled in the management of bleeding disorders. (Tier 2) [3, 6]

In a prospective study, VWF/FVIII concentrate was administered for 71 surgical or invasive diagnostic procedures in 39 patients with a good clinical response observed in 71% of procedures. Additional studies have reported even higher efficacy in surgical events (excellent or good results in 100%). In a prospective study of VWF concentrate, 50 patients with clinically severe VWD (5 with type 1, 27 with type 2 and 18 with type 3) were treated for 108 surgical or invasive procedures, with an excellent or good outcome in 100% of cases. (Tier 1) [3, 15]

General anesthesia is preferred, and regional anesthesia must be performed with caution, particularly when spinal and epi-medullar anesthetic procedures are planned. In that case, no formal recommendations exist and contraindications are relative. Special attention should be paid to patients with increased risk of difficult intubation. In case of difficult intubation, the use of a fiberscope or videolaryngoscope may reduce the risk of bleeding and mucosal lesions. Avoiding any trauma during positioning, transport, and mobilization is the rule. (Tier 4) [11]

Prophylaxis before minor surgery is recommended. A systematic review of 8 studies assessed minor surgeries covered with desmopressin (total of 609 patients of whom 225 underwent 232 procedures; most patients had type 1). Results indicated consistent prevention of bleeding control associated with surgery, with bleeding only observed in 1.8%. (Tier 1) [3, 5, 15]

During dental procedures where a deep cleaning is needed or heavy plaque and/or calculus accumulation may induce bleeding with scaling, adequate coverage should be given prior to and possibly after the procedure. The procedure may also be carried out in several visits to prevent excessive bleeding. (Tier 2) [16, 17]

Prophylaxis for oral surgery is recommended in persons with mild to moderate VWD. Effectiveness data for antifibrinolytics in oral surgery for patients with VWD was not available. However, two randomized, controlled trials of people with hemophilia undergoing dental extraction (total of 58 individuals) indicated beneficial effects in reducing the number of bleedings, the amount of blood loss, and the need for therapeutic clotting factor concentrates. For postoperative bleeding, the combined risk difference of both trials was -0.57 (95% CI: -0.76 to -0.37), with the quality of the evidence for this outcome is rated as moderate. (Tier 1) [3, 5, 15, 25]

Topical agents, such as fibrin sealant or bovine thrombin, have been used with good results as adjuncts for oral surgery in persons with VWD. Careful attention to hemostasis of an extraction socket and suturing of sockets is also important in oral surgery. (Tier 2) [3]

Individuals with VWD should be vaccinated against hepatitis A and B, particularly those who may receive replacement therapy. (Tier 2) [3, 7, 23]

Patients should wear or carry medical alert information (e.g., bracelet or card) and have an emergency treatment letter available. (Tier 2) [8, 17]

To prevent hemorrhagic ovarian cysts, combined oral contraceptives may be used. (Tier 2) [3, 6]

Women planning for pregnancy should have, before conception, an evaluation with a hematologist and high-risk obstetrician skilled in management of VWD. Bleeding phenotype should be assessed, historical diagnosis reviewed, and response to treatment established. Pregnant women should be referred to a center or team with high-risk obstetrics capabilities and expertise in hemostasis for prenatal care, delivery, termination of pregnancy, miscarriage management, and factor monitoring. Women with type 1 generally do not require prophylaxis for delivery. In type 2, treatment is required for operative delivery or if there is perineal trauma. Women with type 3 require treatment for all types of delivery. Bleeding after delivery is not common in type 1, whereas type 2A, 2B, and 3 women usually need replacement therapy post-partum to prevent immediate or delayed bleeding. Healthcare providers should inform women of the risk of delayed bleeding, encourage them to report any excessive bleeding, and continue to monitor factor levels during the post-partum period. (Tier 2) [3, 6, 7, 9, 10, 15, 18, 19]

In one study of women with VWD, 30% had bleeding following miscarriage and 10% of spontaneous or elective abortions were complicated by excessive bleeding requiring transfusion. Factor levels should be checked in women presenting with spontaneous miscarriages and in those opting for termination of pregnancy. Women with moderate or severe VWD are best served with abortion care at a center with an obstetrician, hematologist, and anesthesiologist experience in managing coagulation disorders. (Tier 2) [6, 9, 26]

Surveillance

Individuals with milder forms of VWD can benefit from being followed by treatment centers with experience in the management of bleeding disorders. (Tier 4) [2]

Individuals with type 3 should be followed in experienced centers and should have periodic evaluations by a physiotherapist to monitor joint mobility. (Tier 4) [2]

Circumstances to Avoid

Persons with VWD should be counseled to avoid aspirin, other nonsteroidal anti-inflammatory drugs (NSAIDs), and other platelet-inhibiting drugs. (Tier 2) [3, 6, 16, 26, 27]

Patients with untreated VDW should not be offered prophylaxis (mechanical or pharmaceutical) for venous thrombotic embolism (VTE), unless the risk of VTE outweighs the risk of bleeding. (Tier 2) [8, 28]

During preparation for airway management during surgery, traumatic oro-tracheal intubation should be avoided. (Tier 4) [11]

For patients with type 2, central neuraxial anesthesia should be avoided unless VWF activity is more than 0.5 iu/ml and the hemostatic defect has been corrected. This may be difficult to achieve in type 2 and neuroaxial anesthesia should not be given in cases of type 3. (Tier 2) [10]

Individuals should avoid activities involving a high trauma risk, particularly head injury. (Tier 4) [2]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Dominant
Most VWD type 1 and most type 2A, type 2B, and type 2M are inherited in an autosomal dominant (AD) manner. VWD type 2N (more commonly identified in a compound heterozygous state rather than classical homozygous form), type 3 and rarely some types of 2A are inherited in an autosomal recessive (AR) manner. [2, 3, 8, 10, 12, 13, 14, 15, 19, 21]

Prevalence of Genetic Variants

The prevalence of VWF pathogenic variants in the general population is unknown. VWF is the only gene in which pathogenic variants are known to cause VWD. However, not all individuals with VWD have a pathogenic variant in VWF. Pathogenic variants have been identified in 50-65% of individuals with type 1, ~90% with type 2, and ~90% with type 3. (Tier 3) [2, 12]

Penetrance

Type 1 is marked by incomplete penetrance. Pathogenic variants for type 1 resulting in plasma VWF levels lower than 25 IU/dL are mostly fully penetrant. Those resulting in higher VWF levels are often incompletely penetrant. Pathogenic variants causal for AD types other than type 1 (types 2A, 2B, and 2M) are often fully penetrant. (Tier 4) [2, 3, 12, 15, 20]

The prevalence of self-reported bleeding symptoms in patients with VWD registered at hemophilia treatment centers are:
Epistaxis: Type 1=53-61%, Type 2=63%, Type 3=66-77%
Menorrhagia: Type 1=32%, Type 2=32%, Type 3=56-69%
Bleeding after dental extraction: Type 1=17-31%, Type 2=39%, Type 3=53-70%
Ecchymoses: Type 1=50%, Type 2=not reported, Type 3=not reported
Bleeding from minor cuts or abrasions: Type 1=36%, Type 2=40% Type 3=50%
Gingival bleeding: Type 1=29–31%, Type 2=35%, Type 3=56%
Postoperative bleeding: Type 1=20–47%, Type 2=23%, Type 3=41%
Hemarthrosis: Type 1=2–3%, Type 2=4%, Type 3=37–45%
Gastrointestinal bleeding: Type 1=5%, Type 2=8%, Type 3=20%. (Tier 3) [3]

The prevalence of ovarian cysts in women with VWD has been estimated as 6.6%. (Tier 3) [9]

Women are at an increased risk of bleeding complications during pregnancy compared to controls, with a 10-fold antepartum hemorrhage risk. Risk of post-partum hemorrhage is also higher, 15-30% in the first 24 hours and 22-29% after 24 hours compared with <1-5% in the general population. (Tier 3) [3, 15]

Relative Risk

The frequency of symptoms in 222 patients with VWD (43% with mild VWD) compared to 341 healthy controls are:
Profuse bleeding from small wounds: OR=30.0 (95% CI: 8.1–111.1)
Profuse bleeding at site of tonsillectomy/adenoidectomy: OR=11.5 (95% CI: 1.2–111.9)
Easy bruising: OR=9.9 (95% CI: 3.0–32.3)
Profuse bleeding after surgery: OR=5.8 (95% CI: 1.3–26.4)
Muscle bleeding (ever): OR=4.8 (95% CI: 0.7–31.4)
Frequent nosebleeds: OR=3.8 (95% CI: 0.9–15.7)
Profuse bleeding at site of dental extraction: OR=3.2 (95% CI: 0.9–11.3)
Blood in stool (ever): OR=2.8 (95% CI: 0.7–11.7)
Joint bleeding (ever): OR=2.5 (95% CI: 0.6–10.2)
Menorrhagia: OR=2.5 (95% CI: 0.6–9.9)
Hemorrhage at time of delivery: OR=2.1 (95% CI: 0.3–13.5)
Frequent gingival bleeding: OR=0.7 (95% CI: 0.3–2.0)
Hematuria (ever): OR= 0.5 (95% CI: 0.1–2.3). (Tier 3) [3]

Expressivity

Type 1 is marked by variable expressivity, while there is largely consistent expressivity of specific VWF mutations causing Type 2. (Tier 4) [12]

The relationship between VWF level and VWD phenotype is only partially explained by specific VWF variants as there are multifactorial genetic and environmental influences on VWF levels. (Tier 4) [10]

Blood group contributes approximately 25% of the variance in plasma VWF level given ABO glycosylation of VWF influences its rate of clearance. (Tier 3) [2]

4. What is the Nature of the Intervention?

Nature of Intervention

Desmopressin is administered subcutaneously, intravenously, or intranasally. It is safe in pregnancy and at delivery. The main limitation of desmopressin is the progressive reduction of responsiveness after repeated treatments. Its strong antidiuretic effects are also a concern. Minor adverse effects of desmopressin are common but these effects rarely limit clinical use. Cases of stroke and seizure have rarely been reported.
Factor concentrates are administered intravenously. Adverse reactions are rare. Severe reaction may reveal the development of antibodies against the administered factor. There is a risk of deep vein thrombosis with sustained levels of FVIII, making close monitoring necessary. A meta-analysis of thrombotic events reported 7 events among 361 patients with VWD (<2%). A separate meta-analysis of non-thrombotic, non-inhibitor adverse events in 374 patients with VDW, reported 39 adverse events (10%), though none were severe.
Antifibrinolytic drugs can be administered orally or intravenously. Adverse effects include nausea, vomiting, diarrhea, and abdominal pain. Tranexamic acid is not contraindicated during pregnancy or puerperium. [2, 3, 8, 10, 11, 15, 16, 19, 23, 29, 30]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

Mild type 1 may not be diagnosed until midlife, despite a history of bleeding episodes, indicating a delay in diagnosis despite clinical symptoms. [2]

Date of Search: 07.10.2017

Reference List

1. Qu Y, Nie X, Yang Z, Yin H, Pang Y, Dong P, Zhan S. The prevalence of hemophilia in mainland China: a systematic review and meta-analysis. Southeast Asian J Trop Med Public Health. (2014) 45(2):455-66.

2. A Goodeve, P James. von Willebrand Disease. 2009 Jun 04 [Updated 2014 Jul 24]. In: MP Adam, HH Ardinger, RA Pagon, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK7014

3. Nichols WL, Hultin MB, James AH, Manco-Johnson MJ, Montgomery RR, Ortel TL, Rick ME, Sadler JE, Weinstein M, Yawn BP. von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia. (2008) 14(2):171-232.

4. van Galen KP, Mauser-Bunschoten EP, Leebeek FW. Hemophilic arthropathy in patients with von Willebrand disease. Blood Rev. (2012) 26(6):261-6.

5. Windyga J, Dolan G, Altisent C, Katsarou O, Lopez Fernandez MF, Zulfikar B. Practical aspects of DDAVP use in patients with von Willebrand Disease undergoing invasive procedures: a European survey. Haemophilia. (2016) 22(1):110-20.

6. Committee Opinion No.580: von Willebrand disease in women. Obstet Gynecol. Obstetrics and gynecology. (2013) 122(6):1368-73.

7. Castaman G, Goodeve A, Eikenboom J. Principles of care for the diagnosis and treatment of von Willebrand disease. Haematologica. (2013) 98(5):667-74.

8. Nordic Hemophilia Council. Nordic guidelines for diagnosis and management of von Willebrand disease. (2008) Accessed: 2017-07-24. Website: http://nordhemophilia.org/library/Files/PDF-skjol/NordicGuidelinesVWD_SL23APR2008b.pdf

9. Lee CA, Chi C, Pavord SR, Bolton-Maggs PH, Pollard D, Hinchcliffe-Wood A, Kadir RA. 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. (2006) 12(4):301-36.

10. Management of Inherited Bleeding Disorders in Pregnancy: Green-top Guideline No. 71 (joint with UKHCDO). BJOG. (2017) 124(8):e193-e263.

11. OrphanAnesthesia. Anaesthesia recommendations for patients suffering from Von Willebrand disease. (2014) Accessed: 2017-07-24. Website: www.orphananesthesia.eu

12. Cumming AM, Keeney S, Jenkins PV, Nash MJ, O'Donnell JS. Clinical utility gene card for: von Willebrand disease. Eur J Hum Genet. (2011) 19(5).

13. Von Willebrand disease. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=903

14. Von Willebrand disease type 3. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=166096

15. Mannucci PM, Franchini M, Castaman G, Federici AB. Evidence-based recommendations on the treatment of von Willebrand disease in Italy. Blood Transfus. (2009) 7(2):117-26.

16. Anderson JA, Brewer A, Creagh D, Hook S, Mainwaring J, McKernan A, Yee TT, Yeung CA. Guidance on the dental management of patients with haemophilia and congenital bleeding disorders. Br Dent J. (2013) 215(10):497-504.

17. Hemophilia of Georgia. Protocols for the Treatment of Hemophilia and von Willebrand Disease. (2015) Accessed: 2017-07-21. Website: http://www.hog.org/publications/page/protocols-for-the-treatment-of-hemophilia-and-von-willebrand-disease-2

18. James AH, Kouides PA, Abdul-Kadir R, Edlund M, Federici AB, Halimeh S, Kamphuisen PW, Konkle BA, Martinez-Perez O, McLintock C, Peyvandi F, Winikoff R. Von Willebrand disease and other bleeding disorders in women: consensus on diagnosis and management from an international expert panel. Am J Obstet Gynecol. (2009) 201(1):12.

19. Laffan MA, Lester W, O'Donnell JS, Will A, Tait RC, Goodeve A, Millar CM, Keeling DM. The diagnosis and management of von Willebrand disease: a United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards in Haematology. Br J Haematol. (2014) 167(4):453-65.

20. Von Willebrand disease type 1. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=166078

21. Von Willebrand disease type 2. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=166081

22. Berntorp, E., Astermark, J., Baghaei, F., Bergqvist, D., Holmström, M., Ljung, R., Ljungberg, B., Nilstun, T., Norlund, A., Palmblad, J., Petrini, P, Stigendal, L., Säwe, J., Lindblom, J., Syversson, A. Treatment of Hemophilia A and B and von Willebrand Disease, A Systematic Review. (2011) Accessed: 2017-07-25. Website: www.sbu.se

23. Keeling D, Tait C, Makris M. Guideline on the selection and use of therapeutic products to treat haemophilia and other hereditary bleeding disorders. A United Kingdom Haemophilia Center Doctors' Organisation (UKHCDO) guideline approved by the British Committee for Standards in Haematology. Haemophilia. (2008) 14(4):671-84.

24. Berntorp E, Astermark J, Baghaei F, Bergqvist D, Holmstrom M, Ljungberg B, Norlund A, Palmblad J, Petrini P, Stigendal L, Sawe J. Treatment of haemophilia A and B and von Willebrand's disease: summary and conclusions of a systematic review as part of a Swedish health-technology assessment. Haemophilia. (2012) 18(2):158-65.

25. van Galen KP, Engelen ET, Mauser-Bunschoten EP, van Es RJ, Schutgens RE. Antifibrinolytic therapy for preventing oral bleeding in patients with haemophilia or Von Willebrand disease undergoing minor oral surgery or dental extractions. Cochrane Database Syst Rev. (2015)

26. Guiahi M, Davis A. First-trimester abortion in women with medical conditions: release date October 2012 SFP guideline #20122. Contraception. (2012) 86(6):622-30.

27. Scottish Intercollegiate Guidelines Network (SIGN). Antithrombotics: indications and management. A national clinical guideline.. (2000) Accessed: 2017-07-24. Website: http://www.sign.ac.uk/

28. National Clinical Guideline Centre for Acute and Chronic Conditions. Venous thromboembolism in adults admitted to hospital: reducing the risk. (2015) Accessed: 2017-07-14. Website: https://www.nice.org.uk/guidance

29. Coppola A, Franchini M, Makris M, Santagostino E, Di Minno G, Mannucci PM. Thrombotic adverse events to coagulation factor concentrates for treatment of patients with haemophilia and von Willebrand disease: a systematic review of prospective studies. Haemophilia. (2012) 18(3):e173-87.

30. Franchini M, Makris M, Santagostino E, Coppola A, Mannucci PM. Non-thrombotic-, non-inhibitor-associated adverse reactions to coagulation factor concentrates for treatment of patients with hemophilia and von Willebrand's disease: a systematic review of prospective studies. Haemophilia. (2012) 18(3):e164-72.