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The Case of the Missing Factors: Hemophilia Management


Case Presentation

A 25 year old male with a past medical history of Hemophilia A presents with swelling and pain at the left elbow increasing in severity over past 3 days. This swelling and pain is typical of his recurring bleeding episodes in the same joint. He denies any trauma to the area. Vital signs were stable – he was afebrile. The joint is warm to touch, extremely tender, but without overlying cellulitis. The left upper extremity is neurovascularly intact.

He recently moved here from Florida and has not established care with a hematologist. He does not know the type of factor VIII previously used for his primary prophylaxis, nor his baseline factor levels. He has had limited access to healthcare for the past several years.

Clinical Question

How are acute bleeding episodes, such as hemarthroses, managed in the emergency department in patients with hemophilia?

Summary of Evidence

Background:

  • Clinical manifestation of hemophilia includes easy bruising and recurrent bleeding into joints and deep muscles. Hemarthrosis is the most common complication with elbows, knees, and ankles most often affected. Of note, patients may develop pain in the affected joint before any clinical signs can be detected, so it is important that even vague joint symptoms be taken seriously. (1)

  • Hemophilia can be well managed with primary prophylaxis; this requires adequate access to clotting factors. This is not always the case in certain resource-limited patient populations; which leads to increased risk of bleeds and poorer health outcomes, including chronic arthropathies. (2)

  • Most dangerous bleeds in hemophilia include: (3)

  • Head Trauma with potential evolving ICH

  • Throat and neck hemorrhages with potential airway obstruction.

  • Intra-abdominal hemorrhage.

  • Bleeding in closed space with potential for compartment syndrome.

  • Post-traumatic and post-surgical bleeding.

Management of acute bleeding:

  • Factor Replacement (Factor VIII or Factor IX): This is the preferred and first line method of treatment. The approach to management is to administer appropriate therapy as quickly as possible, reserving diagnostic and laboratory testing until after factor levels have been raised. An effort should be made to administer the patient's usual product whenever possible. In the ED, we will dose factor based on acute needs -- consider severity of disease and severity of bleed. (1, 3)

  • Severity of disease: Mild = 5-40% factor activity; Moderate = 1-5% factor activity; Severe = <1% factor activity. If the patient does not know baseline factor level, assume level = 0%

  • Severity of bleeding: Mild to moderate (soft tissue, muscle, hemarthroses, epistaxis) – replace factor up to 50%; severe (GI, CNS, Neck/Throat, major trauma) – replace factor to 100%

  • Other products to consider:

  • Cryoprecipitate – contains FVIII, use only when FVIII concentrates are not available as it is difficult to achieve hemostatic levels of factor. (4)

  • FFP – contain FVIII and FIX, use only when plasma-derived or recombinant factors are not available. Volume overload is a limiting factor in its administration. Both FFP and Cryoprecipitate raise theoretical concerns for viral transmission. (4)

  • DDAVP – used in mild hemophilia with baseline factor levels > 10%, may be administered intravenously or intranasal. Patients must have documented efficacy before using this drug, as it is not effective in all cases of mild hemophilia. Can increase factor VIII by 3x – 5x. (5)

  • TXA - can be a useful adjunct for the treatment of mucocutaneous bleeding and menorrhagia. One study found TXA in combination with FVIII increased 4-fold clot firmness, though TXA alone did not increase clot formation. (6)

  • Arthrocentesis in the emergency department is not usually necessary for hemoarthroses but maybe considered if there is concern for neurovascular compromise, severe pain, or suspicion of infection. (7) However, there are some case studies that show arthrocentesis for patients with recurrent hemarthroses may decrease long-term joint damage. These studies were conducted in specialty clinics and were limited in study size and generalizability. (8)

  • Imaging of the joint is also usually not necessary, an ultrasound maybe considered if swelling or erythema is concerning for infection. US may also be used to determine bleeding resolution as well as to detect early bleeding or chronic arthropathy. One study found that US was as effective as MRI in evaluating for arthropathy. (9)

  • Compartment Syndrome diagnosis relies on serial physical exams. It is a fairly rare complication of acute bleeding in hemophilia but one that requires immediate surgical intervention. (10)

Recommendations

  • In patients with known hemophilia, give deficient factor as soon as possible. Although preferable to use the same factor type patient has previously used, access to factor maybe limited.

  • If intrinsic factor levels are unknown, assume 0%.

  • Mild to moderate bleeds require factor replacement up to 50%. Severe bleeds require factor replacement up to 100%.

  • For Hemophilia A: 1U FVIII/kg = 2% increase in plasma FVIII

  • For Hemophilia B: 1U FIX/kg = 1% increase in plasma FIX.

  • In resource-limited settings, consider FFP and cryoprecipitate.

  • Antifibrinolytic therapy, such as TXA, can be a useful adjunct for mucosal bleeding.

  • US can be as effective as MRI when imaging is necessary for diagnosis or reassessment following intervention.

References

  1. Singleton T1, Kruse-Jarres R, Leissinger C. Emergency department care for patients with hemophilia and von Willebrand disease. J Emerg Med. 2010 Aug;39(2):158-65.

  2. Carneiro JDA, Blanchette V, Ozelo MC, Antunes SV, Villaca PR, Young NL, Castro D,Brandão LR, Carcao M, Abad A, Feldman BM. Comparing the burden of illness of haemophilia between resource-constrained and unconstrained countries: the São Paulo-Toronto Hemophilia Study. Haemophilia. 2017 Sep;23(5):682-688.

  3. Schwartz KR, Rubinstein M. Hemophilia And Von Willebrand Disease In Children: Emergency Department Evaluation And Management. Pediatr Emerg Med Pract. 2015 Sep;12(9):1-20.

  4. Woods GM, Dunn MW, Dunn AL. Emergencies in Hemophilia. Clin Pediatr Emerg Med. 2018 Jun;19(2):110-121

  5. Leissinger C1, Carcao M, Gill JC, Journeycake J, Singleton T, Valentino L. Desmopressin (DDAVP) in the management of patients with congenital bleeding disorders. Haemophilia. 2014 Mar;20(2):158-67.

  6. Hvas AM, Sørensen HT, Norengaard L, Christiansen K, Ingerslev J, Sørensen B. Tranexamic acid combined with recombinant factor VIII increases clot resistance to accelerated fibrinolysis in severe hemophilia A. J Thromb Haemost. 2007 Dec;5(12):2408-14.

  7. Rodriguez-Merchan EC. Articular Bleeding in Hemophilia. Cardiovasc Hematol Disord Drug Targets. 2016;16(1):21-24.

  8. Manners PJ, Price P, Buurman D, Lewin B, Smith B, Cole CH. Joint Aspiration for Acute Hemarthrosis in Children Receiving Factor VIII Prophylaxis for Severe Hemophilia: 11-year Safety Data. J Rheumatol. 2015 May;42(5):885-90.

  9. Doria AS, Keshava SN, Mohanta A, Jarrin J, Blanchette V, Srivastava A, Moineddin R, Kavitha ML, Hilliard P, Poonnoose P, Gibikote S. Diagnostic accuracy of ultrasound for assessment of hemophilic arthropathy: MRI correlation. AJR Am J Roentgenol. 2015 Mar;204(3):W336-47.

  10. Rodriguez-Merchan EC. Acute compartment syndrome in haemophilia. Blood Coagul Fibrinolysis. 2013 Oct;24(7):677-82.

 

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