A 7-year-old boy with a history of severe hemophilia B, who receives scheduled prophylactic factor IX 3 times a week, presents to the emergency department after rolling off a bed 3 feet from the ground and striking his head. He complains of a mild headache at this time. On examination, there is no palpable scalp hematoma, and the neurologic examination is entirely normal. The patient’s last prophylactic factor infusion was 2 days ago. Given his normal examination at this time, is head imaging indicated? Should he receive a factor IX infusion? If so, when should it be administered, and how much should be given? The patient uses AlphaNine® SD brand factor IX for his factor replacement at home, but your emergency department only stocks BeneFIX® brand factor IX. Is it okay to switch factor products? Are there risks to doing so?
A 17-year-old adolescent boy with a history of severe hemophilia A with a high-titer inhibitor presents to the emergency department with pain and swelling in his right knee that developed at school that day. There is no history of antecedent trauma. Examination of the affected knee reveals a large effusion and pain with flexion > 90°. Are there laboratory studies or imaging that could aid in diagnostic decision-making? Should you perform arthrocentesis either diagnostically or therapeutically? Should you treat with a factor VIII concentrate? How does the presence of a high-titer inhibitor change your management? Your ED stocks both FEIBA and recombinant factor VIIa as bypassing products. Is one better than the other for this patient? Can this patient be discharged from the emergency department after treatment or does the presence of inhibitors preclude home management?
A 16-year-old girl presents to the emergency de-partment with a 1-month history of menorrhagia. Her primary care physician has seen her for this complaint previously and has sent laboratory tests, including a complete blood count and prothrombin time/partial thromboplastin time, which were normal. Her von Willebrand panel was significant for a low von Willebrand factor antigen level (vWF:Ag) of 20 IU/dL and a low ristocetin cofactor activity level (vWF:RCo) of 22 IU/dL. She has not started any treatment. What is her likely diagnosis, and what treatment options are available for this patient to decrease menorrhagia? Should she receive oral contraceptive pills, desmopressin, and/or aminocaproic acid? What risks are associated with these therapies? Should her family members seek testing for bleeding disorders?
Von Willebrand disease is significantly more common than hemophilia; however, bleeding in vWD is generally much less severe than that seen in hemophilia. Epistaxis, menorrhagia, oral bleeding, easy bruising, and greater-than-expected postsurgical bleeding are typical presentations of vWD compared to hemophilia, in which more-severe joint, intracranial, and intramuscular hemorrhages are observed.6 Unlike hemophilia, vWD affects men and women equally, with a prevalence as high as 1% of the population, although significantly fewer people will be symptomatic from the disease.7 Von Willebrand disease is not an X-linked disorder, and multiple genetic inheritance patterns exist. Among these, autosomal dominant is the most common pattern. Von Willebrand disease is caused by quantitative or qualitative deficiencies in von Willebrand factor (vWF), a glycoprotein important for platelet aggregation and adhesion to sites of vessel injury.8
Together, vWD and hemophilia A and B represent the vast majority of clinically significant inherited bleeding disorders. Other inherited bleeding disorders do exist and include functional or quantitative deficiencies in clotting factors II, V, VII, X, XI, and XIII, as well as fibrinogen deficiencies. However, these deficiencies, collectively known as the rare bleeding disorders, represent only 3% of all bleeding disorders and each occur with a prevalence of 1 in 500,000.9 Therefore, they will not be addressed in detail within this review. Acquired bleeding disorders also will not be reviewed here.
In patients diagnosed with hemophilia, ED visits are frequent. Not surprisingly, the majority of these visits are for acute bleeding, where prompt and appropriate intervention by an emergency clinician is critical in mitigating morbidity and mortality.10,11 In some cases, a new diagnosis of a bleeding disorder may be first identified in the ED.11,12 However, several lines of evidence indicate that many emergency clinicians have little experience and lack familiarity in evaluating and managing patients with the common inherited bleeding disorders.1,10 Expert guidelines for the evaluation and management of patients with inherited bleeding disorders exist,13-15 but such recommended standards are often not met in the ED care of patients with hemophilia.16 Thus, evidence-based knowledge of ED evaluation and management of inherited bleeding disorders is critical.
A search of The National Guideline Clearinghouse (www.guideline.gov) yielded 2 sets of guidelines for hemophilia from the World Federation of Hemophilia and the British Committee for Standards in Haematology, and 1 guideline for vWD from the National Heart, Lung, and Blood Institute of the National Institutes of Health. Most recommendations regarding acute treatment of inherited bleeding disorders contained within the hemophilia guidelines are level IV (based on case series/historically controlled studies), with the exception of recommendations for factor prophylaxis, which have stronger evidence (level II, based on randomized controlled trials). For vWD, recommendations are largely derived from case series and retrospective reports (almost all grade C recommendations with level IV evidence).
The absence of a significant number of large randomized trials for hemophilia is multifactorial. Modern hemophilia care began with the development of plasma-derived factor concentrates in the 1960s. Subsequent research was confounded by the staggering number of patients with hemophilia who were affected by HIV infections contracted via plasma-derived clotting factor infusions in the late 1970s and early 1980s.17 A 1998 study by Rosenberg and Goedert estimated that nearly half of all patients with hemophilia living in the United States were infected with HIV.18 Despite being the most common inherited clotting factor deficiency, hemophilia remains a rare disease, and randomized controlled trials generally require multicenter participation to accrue an adequate number of patients. Modern national registries for patients with hemophilia have aided in consolidating retrospective information on these patients, but they have not effectively facilitated a large number of prospective multicenter trials.19
Defining vWD has been challenging for the purpose of creating cohorts of subjects.7 Many patients with abnormal testing on von Willebrand laboratory panels have no clinical manifestations of bleeding, and, yet, some patients with equivocal testing on von Willebrand panels are significantly symptomatic.8 These complications have made accurate identification of a study population more challenging. Because of the rational basis for giving factor concentrates in cases of acute bleeding in pediatric patients, the relatively low risk of doing so in the era of recombinant factor concentrates, and excellent infection screening for plasma-derived products, a randomized trial withholding factor concentrates for patients with acute bleeds is not feasible, nor is it appropriate.
Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are equally robust. The findings of a large, prospective, randomized, and blinded trial should carry more weight than a case report.
To help the reader judge the strength of each reference, pertinent information about the study, such as the type of study and the number of patients in the study will be included in bold type following the references, where available. The most informative references cited in this paper, as determined by the author, will be noted by an asterisk (*) next to the number of the reference.
Kevin R. Schwartz, MD; Max Rubinstein, MD
September 2, 2015
October 1, 2018
Upon completion of this article, you should be able to:
Physician CME Information
Date of Original Release: September 2, 2015. Date of most recent review: August 15, 2015. Termination date: September 2, 2018.
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