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Hemophilia And Von Willebrand Disease In Children: Emergency Department Evaluation And Management

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Table of Contents

Abstract
Case Presentations
Introduction
Critical Appraisal of the Literature
Etiology And Pathophysiology
1. Hemostasis And The Coagulation Cascade
2. Pathophysiology Of Von Willebrand Disease
3. Pathophysiology Of Hemophilia
Differential Diagnosis
1. Timing Of Diagnosis
2. Typical Presenting Symptoms Of Inherited Bleeding Disorders At Diagnosis
  1. Hemarthrosis
  2. Hematomas/Soft-Tissue Bleeds
  3. Mucosal Bleeding
  4. Intracranial Hemorrhage
  5. Postsurgical Bleeding
Prehospital Care
Emergency Department Evaluation
Diagnostic Studies
1. Laboratory Studies
2. Imaging Studies
  1. Head Imaging
  2. Joint And Soft-Tissue Imaging
Treatment
1. Treatment Of Bleeding From Hemophilia
Special Populations
1. Patients With Hemophilia With Inhibitors
  1. FEIBA Versus Recombinant Factor VIIa For Refractory Bleeding In Patients With Inhibitors
2. Patients With Mild Hemophilia A: Treatment With Desmopressin
3. Patients In Resource-Limited Settings
Controversies And Cutting Edge
Disposition
Summary
Risk Management Pitfalls In Hemophilia And Von Willebrand Disease In Children
Time- And Cost-Effective Strategies
Case Conclusions
Acute Management Of Common Bleeds In Patients With Hemophilia
Emergency Department Workup For Suspected Bleeding Disorder
Tables
1. Table 1. Differential Diagnosis For Bleeding Disorders By Abnormality In Prothrombin Time & Partial Thromoboplatin Time Studies
2. Table 2. Summary Of The United Kingdom Haemophilia Centre Doctor's Organisation Evaluation Guidelines
3. Table 3. Available Factor Replacement Products
4. Table 4. Dosing And Duration Of Therapy For Hemophilia-Related Bleeds
5. Table 5. Dosing Of Von Willebrand Factor Concentrates For Major And Minor Bleeding And Surgery
References

Abstract

Hemophilia and von Willebrand disease are the most common inherited bleeding disorders encountered in the emergency department. Evidence suggests that the management of bleeding disorders in the emergency department is currently suboptimal, and literature to guide evaluation and management in this setting is limited, though some guidelines do exist. The emergency clinician must have a high index of suspicion for new diagnoses, particularly in young patients with unprovoked bleeding and children with multiple or severe bleeds. The foundation of hemophilia treatment is urgent clotting factor replacement, with replacement goals guided by the presenting complaint. Bleeding in von Willebrand disease may be treated with products containing von Willebrand factor or with desmopressin. This review focuses on the epidemiology, pathophysiology, common presentations, evaluation strategies, and emergency management of these bleeding disorders.

Case Presentations

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?

Introduction

Hemophilia and von Willebrand disease (vWD) represent the most common inherited bleeding disorders, and, consequently, those most likely to be encountered in the emergency department (ED).¹Hemophilia A and B are X-linked recessive disorders caused by the deficiency or absence of coagulation factors VIII and IX, respectively. The overall incidence of hemophilia is 1 per 5000 male births. Hemophilia A is significantly more common than hemophilia B, representing 80% of all hemophilia cases.²Significant and often life-threatening bleeding (either spontaneous or trauma-induced) is the hallmark of this disease.³Historically, hemophilia was associated with a dismal prognosis, with most patients dying at a young age of uncontrolled hem-orrhage.³However, life expectancy has increased dramatically in the past 50 years with the advent of plasma-derived and recombinant clotting factor concentrates for treatment of hemophilia. Life expectancy for hemophilia patients in developed countries with comprehensive longitudinal care now approaches that of the general male population.^4,5

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.⁶Unlike 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.⁷Von 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 500,000.⁹Therefore, 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.^10,¹¹In some cases, a new diagnosis of a bleeding disorder may be first identified in the ED.^11,12However, 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.^1,10Expert guidelines for the evaluation and management of patients with inherited bleeding disorders exist,^13-15but such recommended standards are often not met in the ED care of patients with hemophilia.¹⁶Thus, evidence-based knowledge of ED evaluation and management of inherited bleeding disorders is critical.

Critical Appraisal Of The Literature

A literature search was performed in PubMed using the search terms hemophilia, factor VIII deficiency, factor IX deficiency, Christmas disease, children, and pediatric. This search yielded 5999 results that were evaluated by the authors, with 118 papers deemed relevant to this review of hemophilia A and B. A separate search was conducted using the search terms von Willebrand disease, children, and pediatric. This search yielded 1132 results which were reviewed, identifying 30 relevant references for vWD. The Cochrane Database of Systematic Reviews was searched using the key terms hemophilia and von Willebrand disease. This search yielded 12 results, 3 of which were relevant to this ED-focused review.

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.¹⁷A 1998 study by Rosenberg and Goedert estimated that nearly half of all patients with hemophilia living in the United States were infected with HIV.¹⁸Despite 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.⁷Many 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.⁸These 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.

Risk Management Pitfalls In Hemophilia And Von Willebrand Disease In Children

“I wanted to confirm on imaging that an intracranial bleed was actually present before I infused factor.”
Factor should be administered immediately upon suspicion of intracranial hemorrhage. Delay in factor administration has the potential to increase morbidity and mortality, and the risk of factor administration is minimal. When in doubt, infuse factor.
“This patient had a high-titer inhibitor, so I gave higher doses of factor to overcome the inhibitor to try to stop the bleeding.”
High-titer inhibitors (> 5 BU/mL) cannot be overcome with higher doses of factor concentrates. A bypassing agent (FEIBA or rFVIIa) is required to treat bleeding in these patients.
“This patient with severe hemophilia only had minimal head trauma and has a normal examination. He can’t have a significant ICH.”
Most patients with hemophilia with ICH report only minor trauma history, and many will have a completely normal physical examination.
“This infant has no family history of hemophilia, so he can’t have hemophilia.”
Thirty percent of cases of hemophilia are new mutations without any family history. Maintain a high index of suspicion for hemophilia in a male patient with significant bleeding, and maintain a low threshold for screening PT/PTT.
“We don’t have any factor VIII concentrates available here. There is nothing I can do for this patient with hemophilia A and worsening hemarthrosis.”
In settings where factor VIII concentrate is unavailable, cryoprecipitate (which contains high levels of factor VIII) may be used at a dose of 1 bag/6 kg body weight, to a max of 10 bags, initially to treat acute bleeding.
“This patient’s factor VIII level is low. He must have hemophilia A.”
This is likely the case, but he may also have type 2N or type 3 vWD. Distinguishing between these diseases will help guide factor replacement, and a von Willebrand panel should be sent.
“This patient with hemophilia did not bring his factor concentrate with him to the ED, and we don’t stock his brand of concentrate here, so we should wait until his factor arrives from home to treat his hemarthrosis.”
There is no clear evidence that switching between factor brands increases the risk of inhibitor development. Depending on the severity of the bleed and the anticipated delay in acquiring the patient’s home product, administration of another brand of product may be appropriate. However, recombinant products are preferred, rather than switching from a recombinant product to a plasma-derived product.
“This patient with vWD needs emergent surgery. We can just give desmopressin preoperatively, and that should be fine.”
This may be true; however, a documented response to desmopressin with an appropriate increase in vWF is necessary before relying on this therapy. If the patient has not been shown to be responsive to desmopressin (either has not had a test confirming desmopressin response or has had a test which showed nonresponsiveness to desmopressin), a factor product containing large concentrations of vWF is indicated rather than using desmopressin.
“My patient with hemophilia is complaining of numbness along the lateral thigh and is having trouble extending his right leg. We should get a neurology consultation and head imaging, as this may be a stroke.”
These are typical presenting signs of an iliopsoas hemorrhage. Treatment should be centered on factor replacement to 80%, and imaging should be directed at the psoas region by CT, MRI, or ultrasound. Significant blood loss in this area is possible, and transfusion may be required.
“This patient has menorrhagia and easy bruising, and her mother and sister have a history of similar symptoms. She already had a normal von Willebrand panel test, so she can’t have vWD.”
Many factors affect measured vWF levels, including stress, illness, exercise, reproductive hormone levels, and specimen storage and transport. False negatives are common, and a single negative test does not rule out the disease, especially in patients with signs and symptoms suggestive of the disease.

Tables

Table 1. Differential Diagnosis For Bleeding Disorders By Abnormality In Prothrombin Time & Partial Thromoboplatin Time Studies

References

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.

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