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Acquired Coagulation Factor Inhibitors
Acquired coagulation factor inhibitors are autoantibodies directed against native clotting factor in persons without an underlying bleeding disorder. Although rare, these disorders can result in life-threatening hemorrhage, which can be difficult to manage. The following factor inhibitors will be discussed: factor VIII (FVIII), von Willebrand factor (VWF), factor V (FV), prothrombin, and thrombin.
Inhibitors of Factor VIII
Pathophysiology and Epidemiology
Acquired FVIII inhibitors are autoantibodies that bind to native FVIII in a person without congenital hemophilia A. Antibody binding leads to functional FVIII deficiency. The incidence is 1.48 per million person years, although this rate increases with age. In those over the age of 85, the incidence is 14.66 per million person years; in those under the age of 16, it is only 0.045 per million person years. In approximately 40%–50% of cases, the acquisition of the FVIII inhibitor is related to an underlying condition such as autoimmune diseases (e.g., rheumatoid arthritis and systemic lupus erythematosus), malignancy, dermatological disorders, and pregnancy. The association between FVIII inhibitor and underlying disorder decreases with age. In a large observational study, an acquired inhibitor was secondary to an associated condition in all patients less than 40 years but in only 25% of those over 85 years. Pregnancy-associated FVIII inhibitor development is discussed in Chapter 117 .
Clinical Manifestations
Approximately 6% of patients may initially present for evaluation of a prolonged activated partial thromboplastin time (aPTT) without personal history of bleeding. Although 94% will have bleeding at presentation, approximately one-third will have only minor bleeding that does not require any treatment. The most common sites of bleeding include the subcutaneous tissue, muscle, gastrointestinal tract, and genitourinary tract. In contrast to congenital hemophilia A, hemarthroses are rare. Most patients will have only one bleeding event, though one-third may have two or more. Approximately one-third of patients with an acquired FVIII inhibitor have spontaneous resolution; however, this may not occur for over 12 months (range 10–21 months) after diagnosis. In one report, fatal bleeding occurred in 9%–22% of patients, occurring a median of 19 days after diagnosis, but sometimes much later. In the European registry (EACH2), fatal bleeding occurred in only 3%. Overall, higher inhibitor titers were associated with more severe bleeding. However, in a retrospective cohort, the inhibitor titer in those with fatal hemorrhage was identical to that in those who did not require any hemostatic therapy. Therefore, at this time there are no parameters that are adequately predictive of inhibitor resolution or fatal bleeding.
Diagnosis
These patients have a prolonged aPTT, with a normal prothrombin time (PT) and thrombin time. aPTT mixing studies may correct immediately after mixing with normal pooled plasma (NPP) but will again prolong after incubation consistent with the time and temperature dependence of acquired FVIII inhibitors. Factor VIII, IX, and XI activity assays that are performed to investigate the prolonged aPTT typically demonstrate a markedly reduced FVIII activity level, whereas other clotting factor activities will be normal. Most patients will have an FVIII activity <5%. An inhibitor to FVIII, measured using the Bethesda assay (see Chapter 132 ), will be present.
Management
Two major aspects of management of acquired FVIII inhibitors include treatment of acute bleeding and eradication of the inhibitor.
Hemostatic Treatment
Minor bleeding such as ecchymoses or epistaxis that is self-limited does not require active treatment, although close monitoring and follow-up is necessary. For bleeding requiring treatment, several options are available: desmopressin, human (h) FVIII infusions, bypassing agents (recombinant factor VIIa [rFVIIa] and activated prothrombin complex concentrate [aPCC], such as FEIBA), and recombinant porcine (rp) FVIII ( Table 126.1 ).
Table 126.1
Treatment Options of Acquired FVIII Inhibitors
| Dose | Patient Population | Duration of Response | Monitoring | Potential Side Effect | |
|---|---|---|---|---|---|
| Desmopressin | 0.3 μg/kg | FVIII >5% Inhibitor titer <2 BU/mL |
Variable | FVIII activity | Hyponatremia, seizures |
| Human FVIII concentrates | 100 or 20 IU/kg for each Bethesda titer + 40 IU/kg | Inhibitor titer <5 BU/mL | Variable | FVIII activity | |
| Recombinant factor VIIa | 70–90 μg/kg | All | 2–3 hours | None | Thrombosis |
| FEIBA | 75–100 U/kg Max: 200 U/kg/day |
All | 8–12 hours | None | Thrombosis |
| Recombinant porcine FVIII | 200 U/kg (alternative 50–100 U/kg if no porcine FVIII titer is negative) | Porcine inhibitor titer <20 BU/mL | 4–12 hours | FVIII activity | Inhibitor to porcine FVIII |
Desmopressin
Desmopressin is only effective when FVIII activity is >5%. The effect of desmopressin decreases with subsequent dosing, and thus its use is limited to bleeding that requires a short duration of therapy. Additionally, the half-life of the released FVIII will be shortened secondary to binding of the inhibitory antibody, but the exact duration is variable from patient to patient.
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