Therapeutics: Hemophilia Management in the ED
/Understanding how to acutely manage trauma or hemorrhage in patients with hemophilia is an important role for Emergency Providers. Morbidity and mortality for patients with hemophilia has improved with advanced prophylaxis. However, bleeding-related complications remain a leading cause of death and disability. Patients are generally knowledgeable about their disease and emergency physicians should feel comfortable starting treatment based on patient-reported symptoms and bleeding prior to initiating a diagnostic workup. Early consultation with the patient’s treating hematologist is essential, but should not delay treatment with factor replacement in severe or life-threatening hemorrhage. This post will detail further the pathophysiology and therapies for the bumps, bruises and bleeding of the hemophilias.
Normal Hemostasis
Normal hemostasis balances a multitude of pro-coagulant and anti-coagulant factors. In tissue injury, pro-coagulant factors achieve hemostasis in three overlapping stages: initiation, amplification, and propagation: [1]
Initiation occurs on exposure of a tissue factor-bearing cell at the site of injury.
Platelets and cofactors are activated via amplification, on the surface on the anionic phospholipid-bearing platelet surface
This leads to propagation, which generates a burst of thrombin, and finally fibrin polymerization.
Hemophilia A and B
Hemophilia A – genetic deficiency of Factor VIII, most common (~1 in 5000 male births), generally males are affected; female carriers may have mild disease and rarely severe disease
Hemophilia B – genetic deficiency of Factor IX, less common (~1 in 15 – 30,000 male births), generally less severe disease, AKA “Christmas disease”
Acquired Hemophilia A – spontaneously acquired antibodies inhibit Factor VIII or prevent binding of vWF, leading to an increased rate of destruction. Rare, approximately 1.4/1,000,000 people worldwide, and usually associated with underlying autoimmune disorder (SLE, RA) or malignancy (leukemia, adenocarcinoma), or related to pregnancy.
| Hemophilia A, B | Clinical Presentation | |
|---|---|---|
| Mild | 5-40 U/dL, 5-40% normal activity | Prolonged bleeding with major trauma or surgery Rare spontaneous bleeding |
| Moderate | 1-5 U/dL, 1-5% normal activity | Severe bleeding with minor trauma or surgery Occasional spontaneous bleeding |
| Severe | <1 U/dL, <1% normal activity | Spontaneous bleeding |
(Adapted from: Srivastava A et al. WFH Guidelines for the management of hemophilia, 3rd edition. Haemophilia. 2020;26(S6):1-158; and Escobar MA, Key NS. Hemophilia A and hemophilia B. In: Kaushansky K, Lichtman MA, Prchal JT, Levi MM, Press OW, Burns LJ, et al. Williams Hematology, 9e. New York, NY: McGraw-Hill Education; 2015.)
Diagnosis and Clinical Presentation
Most patients with moderate or severe disease are diagnosed early in childhood.
Consider a new diagnosis of hemophilia in:
Neonates with persistent oozing from the umbilical stump
Children refusing to crawl/walk/move an extremity (elbows, knees, ankles are most commonly affected)
Septic joint workup in children, as hemarthrosis can be accompanied by mild fever and is difficult to discern in the absence of family history
Non-accidental trauma workup, as mild trauma may cause hematoma, oral injury, or frenulum bleeding
Severe disease often manifests within the first year of life, and hemarthrosis often presents when a child is learning to walk. Spontaneous hemarthrosis can be accompanied by fever, making it difficult to discern from a septic joint without known family history.
Mild disease is usually diagnosed later in life in the setting of prolonged post-surgical bleeding.
Workup
Clinical signs do not distinguish Hemophilia A and B. Conventional coagulation tests are of limited utility. The aPTT is prolonged in both hemophilia A and B. However, patients with mild hemophilia and factor levels greater than 30% may have normal results. Definitive testing involves specific factor assays. In hemophilia A and B, PT/INR should be normal. Prolongation should raise suspicion for different or combined coagulopathy. Because vWF stabilizes factor VIII, certain subtypes of von Willebrand Disease have similar presentation and laboratory findings as hemophilia A, including low factor VIII activity. [3]
Any patient with suspected coagulopathy including hemophilia should be referred to a hematologist for workup and testing upon discharge.
Empiric Treatment of Acute or Suspected Bleeding
Treatment is based on history, symptoms, and mechanism of injury, even in the absence of clinical findings of hemorrhage. Treatment should be initiated before any diagnostic workup. A patient with head trauma should be given factor replacement before any imaging and even without radiographic evidence of bleeding.
Ask patient/family if they brought their product and dosing information with them
Do not delay administration of product for diagnostic workup or hematology consultation
Empiric initial dose for an unstable patient assumes factor activity < 1% [4, 5]
Hemophilia A: 50 U/kg recombinant Factor VIII
1 U/kg raises factor level approximately 2%
Hemophilia B: 100 – 120 U/kg Factor IX
1 U/kg raises factor IX level approximately 1%
Factor replacement can be administered IV push over 1-2 minutes or per label instructions
For life threatening bleeding in the absence of factor-specific products
Hemophilia A patients can be given cryoprecipitate
1 U cryoprecipitate = ~80 U of FVIII
Patients on prophylactic emicizumab have increased risk of thrombosis and cryoprecipitate should be avoided
Hemophilia B patients can be given FFP in emergent setting.
The volume of FFP required poses a high risk of volume overload
Cryoprecipitate does not contain factor IX
Patients with acquired inhibitors to factor VIII or IX may be treated with increased doses of factor concentrates or with bypassing agents composed of activated clotting factors. Do not empirically treat with a bypassing agent unless the patient is known to have inhibitors.
| Site of Hemorrhage | Desired Factor Level (% Normal) | Hemophilia A / Factor VIII | Hemophilia B / Factor IX | |
|---|---|---|---|---|
| Life Threatening | CNS | 100 | 50-75 | 100-120 |
| Neck / Retropharyngeal | 100 | 50 | 100 | |
| Abdominal / Retroperitoneal | 100 | 50 | 60-80 | |
| Gastrointestinal | 60-100 | 30-50 | 60-100 | |
| Serious | Hemarthrosis | 30-50 | 25 | 30-50 |
| Intramuscular | 30-50 | 25 | 30-50 | |
| Oral / epistaxis | 30-50 | 25 | 30-50 | |
| GU / renal | 50 | 25 | 50 |
(Adapted from: Srivastava A et al. WFH Guidelines for the management of hemophilia, 3rd edition. Haemophilia. 2020;26(S6):1-158; and Escobar MA, Key NS. Hemophilia A and hemophilia B. In: Kaushansky K, Lichtman MA, Prchal JT, Levi MM, Press OW, Burns LJ, et al. Williams Hematology, 9e. New York, NY: McGraw-Hill Education; 2015.)
Life-threatening Bleeding:
Head trauma:
Factor repletion to at least 100% normal
Treat at time of injury, regardless of imaging findings
Significant head trauma with negative imaging should be treated for at least 3 days
Radiographic intracranial hemorrhage requires treatment for at least 3 weeks [4]
There are no clear recommendations or evidence to guide the use of CT imaging. One small, retrospective study proposes use of PECARN rules for pediatric head trauma with hemophilia, however this has not been prospectively studies or validated [6].
Disposition for all patients will be made in conjunction with the treating hematologist. Patients with documented ICH or significant mechanism of injury should be admitted for continued product administration.
If patient and hematologist are comfortable with discharge:
Counsel patient on risk of late or recurrent bleeding 3-4 weeks after injury
Monitor for symptoms for 4 weeks
Discharge with return precautions, adequate product supply, dosage instructions by hematologist, and hematology follow up
Neck / Retropharyngeal
Increase factor level to 80-100%
Patients with traumatic injury should be monitored for development of hematoma.
Patients with an expanding hematoma may require intubation for anticipated clinical course and airway compromise.
Gastrointestinal
Increase factor level to 80-100%
Prior to the 1980s and the adoption of robust screening and purification of blood-derived productions, patients with hemophilia commonly acquired HIV, viral hepatitis, and concomitant liver disease with risk for variceal bleeding. Any patient with hemophilia who presents with life-threatening upper GI bleed should be administered product to increase factor levels to 100% along with transfusion and standard care. Risk of transmission of blood-borne pathogens has been significantly reduced by modern practices of screening and purification.
Lower GI bleeding in the setting of hemophilia can be treated less emergently and in conjunction with the patient’s hematologist.
Serious Bleeding:
Hemarthrosis
Increase factor level to 40-60% of normal
Hemarthrosis is common in hemophilia. Patients with recurrent bleeding in the same joint, termed a “target joint,” often describe a prodrome at onset of bleeding prior to clinically apparent effusion.
Any patient complaining of usual symptoms of hemarthrosis should be treated with factor regardless of clinically apparent effusion.
Routine hemarthrosis does not require imaging and should not be aspirated, as this may worsen bleeding.
When bleeding stops, the blood resorbs, and the symptoms gradually subside over a period of several days. Pain usually improves in 6 to 8 hours and subsides in 12 to 24 hours. Repeated hemarthrosis causes cartilaginous destruction and iron deposition, resulting in chronic hemophilic arthropathy. Acute bleeding into a chronically affected joint may be difficult to distinguish from the pain of degenerative arthritis. [3] If bleeding does not respond to replacement therapy, an inhibitor or alternative diagnosis (septic joint) should be suspected. Prior to any arthrocentesis with concern for septic joint, the patient’s factor should be repleted.
Intramuscular
Increase factor level to 40-60% and monitor for compartment syndrome
Patients with recurrent intramuscular hematomas can develop pseudotumors (blood cysts) in muscle or bone, most commonly: retroperitoneal, pelvic, or involving the lower extremities. These are rare but can expand, compromising the surrounding vasculature, or predisposing to infection if sinus tracts develop. Diagnose with CT or MRI and consult treating hematologist. [3]
Oral / Epistaxis
Topical antifibrinolytic agents such as nasal spray or mouthwash may have benefit in mucosal bleeding. Localized bleeding that responds to topical TXA may not require factor repletion. If bleeding fails to response or may compromise airway, factor should be repleted to 30-50%. [4]
GU / Renal
Hematuria is common and often benign. Atraumatic, painless hematuria does not require additional imaging [5]
The necessity to treat with factor is disputed and treatment decisions are best made in conjunction with the patient’s hematologist. Some courses recommend factor repletion to 50% normal activity in the setting of ongoing gross hematuria. Antifibrinolytic agents should not be used as intrarenal clotting may cause damage. [4]
Mild or Moderate Bleeding:
Superficial wounds or lacerations can be treated conservatively with direct pressure and wound care
Topical hemostatic agents may be useful
DDAVP can be given for hemophilia A patient with mild/moderate bleeding if patient has a documented previous response to DDAVP but should not be given empirically
DDAVP is contraindicated in children < 2 years
IV dosing: 0.3 μg/kg, diluted in at least 50-100 mL of 0.9% saline and given by slow infusion over 20-30 minutes. Can cause flushing, abdominal pain and discomfort with administration.
Intranasal dosing: 150 mcg as single spray for pts < 50kg and 300 mcg as 2 sprays in each nostril for patients > 50 kg
Do not give more than once due to tachyphylaxis and risk of hyponatremia
Mild and moderate bleeding generally do not require emergent factor replacement if patient is able to secure close hematology follow up. Ideally, patient’s treating hematologist should be contacted prior to discharge.
For deeper wounds, patient’s home factor should be brought in and administered at lower dosing, generally to factor level of 30% [2, 4]
Hemophilia with Inhibitors
Since the advent of better blood product treatments and testing as well as robust prophylactic treatment which patients can often administer at home, the major complication of hemophilia is the development of inhibiting antibodies to administered factor products. Inhibitor antibodies may either inhibit the function of the specific factor (VIII or IX) or increase its rate of degradation.
About 20% of severely affected patients with hemophilia A develop factor VIII inhibitors
3% or fewer with hemophilia B develop inhibitors against factor IX
Patients are categorized as high or low responders. This is confusing nomenclature, but patients who are low responders can receive treatment with normal factor while those who are high responders require treatment with a bypassing agent, which contains activated clotting factors therefore enzymatically “bypassing” the deficiency in factor VIII or IX. Patients with an inhibitor to either Factor VIII or IX are treated with the same bypassing agents. [4,7]
Acquired Hemophilia
Patients without inherited coagulopathy may develop an inhibitor later in life, usually to factor VIII. Acquired hemophilia is rare and usually in the setting of underlying autoimmune disease, malignancy, pregnancy, or drug exposure. [5, 7]
Presents with mucosal, cutaneous, or muscular bleeding
Unlike traditional hemophilia, hemarthrosis is uncommon
Treatment of Patients with Acquired Hemophilia or Hemophilia with Inhibitors:
Emergency treatment of these patients should be done in conjunction with hematology consultation. Patients with low titers and high response can be treated with larger doses of regular Factor VIII or Factor IX products. Patients with high antibody titers (>5 Bethesda Units) and low response to traditional factor replacement, are treated with bypassing agents, which contain activated clotting factors and therefore enzymatically “bypassing” a deficiency in factor VIII or IX. These agents have been associated with increased thrombotic risk and should only be administered with hematology consultation.
1st line treatment: rFVIIa - 90-120 mcg/kg every 2-3 hours
Limited evidence of success with high dose bolus 300 mcg/kg with success [4] but this is not widely recommended
2nd line: activated prothrombin complex concentrates (e.g., FEIBA) 50 - 100 U/kg every 8 to 12 hours [3]. These agents are 2nd line as they have increased frequency of thrombotic complications including microangiopathy and DIC.
Post by Anne Grisoli, MD @anniegenvie17
Dr. Grisoli is a PGY-1 in Emergency Medicine at the University of Cincinnati
Peer Editing by Logan Walsh, MD @loganwalsh and Ryan LaFollette, MD @lafoller
Dr. Walsh is a Chief Resident at the University of Cincinnati and incoming Critical Care Fellow at Washington University. Dr. LaFollette is as Associate Professor of Emergency Medicine and co-editor of TamingtheSRU.com
References:
Hoffman M, Monroe DM, 3rd. A cell-based model of hemostasis. Thromb Haemost. 2001;85(6):958-65.
Srivastava A, Santagostino E, Dougall A, Kitchen S, Sutherland M, Pipe SW, et al. WFH Guidelines for the management of hemophilia, 3rd edition. Haemophilia. 2020;26(S6):1-158.
Escobar MA, Key NS. Hemophilia A and hemophilia B. In: Kaushansky K, Lichtman MA, Prchal JT, Levi MM, Press OW, Burns LJ, et al. Williams Hematology, 9e. New York, NY: McGraw-Hill Education; 2015.
Escobar MA. Products used to treat hemophilia: dosing. In: Berntorp E, Hoots K, Lee CA. Textbook of hemophilia. Third ed. Chichester, West Sussex: Wiley Blackwell; 2014. p. 180-4.
Bhat R, Cabey W. Evaluation and Management of Congenital Bleeding Disorders. Hematol Oncol Clin North Am. 2017;31(6):1105-22.
Gardner A, McLean TW, Winslow JE, 3rd. Computed tomography scans in children with hemophilia after minor head trauma. Pediatr Emerg Care. 2022;38(1):e27-e8.
Stowell SR, Lollar JS, Meeks SL. Antibody-mediated coagulation factor deficiencies. In: Kaushansky K, Lichtman MA, Prchal JT, Levi MM, Press OW, Burns LJ, et al. Williams Hematology, 9e. New York, NY: McGraw-Hill Education; 2015.
