What are the causes and management of acquired factor 8 deficiency?

Acquired Factor VIII Deficiency: Causes and Management

Primary Causes

Acquired factor VIII deficiency (acquired hemophilia A) is caused by autoantibodies directed against factor VIII in the coagulation cascade, occurring without any prior personal or family history of bleeding disorders. 1

Autoimmune and Idiopathic Causes

• Approximately 50% of cases are idiopathic with no identifiable underlying condition 1
• Autoimmune disorders including rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, and inflammatory bowel disease are associated with acquired factor VIII inhibitors 2, 3
• Myositis has been reported in association with acquired hemophilia A 2

Malignancy-Associated Causes

• Solid tumors and hematologic malignancies can trigger autoantibody formation against factor VIII 1
• The mechanism involves immune dysregulation in the setting of malignancy 1

Pregnancy and Postpartum Period

• Pregnancy-associated acquired hemophilia A typically presents in the postpartum period 1
• This represents a distinct clinical entity requiring specific management considerations 1

Infectious Triggers

• Respiratory infections have been documented as precipitating factors 2
• Parvovirus B19 infection has been reported in association with acquired hemophilia A, though this is rare 2

Drug-Induced Causes

• Certain medications can trigger autoantibody formation, though specific agents vary 1
• Removal of precipitant medications is part of the management strategy 1

Diagnostic Approach

Laboratory Findings

• Prolonged activated partial thromboplastin time (aPTT) that does not correct on 50:50 mixing studies after 1-2 hour incubation is the hallmark finding 1, 4
• Isolated low factor VIII level (often <1-3%) with normal other intrinsic factors 2, 3
• Bethesda assay should be performed to quantify inhibitor titer, though it may underestimate the true potency of autoantibodies due to their type 2 kinetics 1

Critical Diagnostic Pitfalls

• Immediate correction of aPTT with normal plasma does not exclude acquired hemophilia A—if clinical presentation is suggestive, proceed with factor VIII assay 1
• Lupus anticoagulant can cause artifactual lowering of factor levels; specific testing should be performed to distinguish this from true factor VIII deficiency 1
• Repeat factor assays at higher serial dilutions to attenuate the effect of the inhibitor on measurement 1

Management Strategy

Acute Bleeding Control

For severe bleeding episodes, bypassing agents are first-line therapy because they circumvent the need for factor VIII entirely. 1

First-Line Bypassing Agents

• Recombinant factor VIIa (rFVIIa): 90 μg/kg bolus every 2-3 hours until hemostasis is achieved 1
• Activated prothrombin complex concentrates (aPCCs): 50-100 IU/kg every 8-12 hours, maximum 200 IU/kg/day 1
• Prophylactic use of bypassing agents is recommended prior to any invasive procedures 1

Alternative Therapies (Only if Bypassing Agents Unavailable)

• Recombinant or plasma-derived factor VIII concentrates can be used, but are less effective due to inhibitor presence 1
• Desmopressin may be considered in select cases with low-titer inhibitors 1, 5

Inhibitor Eradication (Immunosuppression)

All patients diagnosed with acquired hemophilia A should receive immunosuppressive therapy immediately following diagnosis to eradicate autoantibodies. 1

First-Line Immunosuppression

• Corticosteroids alone: Prednisone 1 mg/kg/day orally for 4-6 weeks 1
• Corticosteroids plus cyclophosphamide: Prednisone 1 mg/kg/day PLUS cyclophosphamide 1.5-2 mg/kg/day for maximum of 6 weeks 1, 3
• The combination regimen is preferred for more rapid inhibitor eradication 1

Second-Line Therapy

• Rituximab should be used if first-line immunosuppressive therapy fails or is contraindicated 1, 3, 5
• Multiple courses may be necessary for refractory cases 3

Therapies NOT Recommended

• High-dose intravenous immunoglobulin is not recommended for inhibitor eradication, though it may have a role in acute bleeding management 1, 3
• Immunoabsorption/immunotolerance regimens should only be used in life-threatening bleeds or research settings 1

Special Clinical Scenarios

Compartment Syndrome

• Acquired hemophilia A can present with spontaneous compartment syndrome, requiring urgent fasciotomy 4
• Ensure adequate hemostatic therapy before surgical intervention to prevent catastrophic postoperative bleeding 4

Paradoxical Thrombosis

• Venous thromboembolism can occur paradoxically in patients with acquired hemophilia A 2
• This represents a challenging management scenario requiring careful balance of anticoagulation and bleeding risk 2

Monitoring and Follow-Up

After achieving complete sustained response, monitor aPTT and factor VIII:C monthly for the first 6 months, every 2-3 months up to 12 months, and every 6 months during the second year and beyond. 1

Thromboprophylaxis Considerations

• Following inhibitor eradication with sustained response, thromboprophylaxis should be considered according to standard guidelines, especially in patients with very elevated factor VIII:C levels 1
• This addresses the rebound hypercoagulable state that can occur after successful treatment 1

Prognosis

• Acquired hemophilia A carries high morbidity and mortality, particularly in elderly patients 2, 6
• Mortality rates are significant if diagnosis is delayed or treatment inadequate 2
• The disorder can be stubborn and refractory to standard therapies in some cases, requiring escalation to second-line agents 2

Critical Clinical Pearls

• Do not wait for mixing studies to complete if clinical suspicion is high—begin workup with factor VIII assay immediately 1
• Any elderly patient with spontaneous bleeding and isolated aPTT prolongation should be evaluated for acquired hemophilia A 4, 6
• The absence of personal or family bleeding history does not exclude this diagnosis 6
• Treatment of underlying conditions (autoimmune disease, malignancy, infection) is essential alongside immunosuppression 1