With the help of heme-onc fellow Dr. Allyson Pishko, we went through the case of a patient with kappa light chain multiple myeloma who initially presented to his PCP with shoulder pain and was found to have a rotator cuff tear and large intramuscular hematoma. His labs were notable for a 4g hemoglobin drop over 3 weeks and an isolated elevated aPTT to 90. Ultimately, our patient was diagnosed with an acquired factor VIII inhibitor as the cause of his coagulopathy and bleed.
We reviewed that an isolated prolonged aPTT can be secondary to inherited causes (hemophilia A or B, factor XI or XII deficiency, deficiency of the contact factors including kininogen and prekallikrein, and von Willebrand disease) or acquired causes (heparin, inhibitors to factors VIII, IX, XI, XII, acquired von Willebrand disease, or lupus anticoagulant).
A history of bleeding is key in narrowing this differential:
- Patients with inherited or acquired deficiencies in factor VIII or factor IX can present with significant and often life-threatening bleeding.
- Patients with inherited or acquired von Willebrand disease may present with easy bruising or mucosal bleeding, or only with laboratory abnormalities.
- Patients with acquired or inherited deficiencies of factor XI, factor XII, or the contact factors usually do not have significant bleeding and present more commonly with an isolated prolonged aPTT discovered incidentally on labs.
- Patients with lupus anticoagulant present with thrombosis rather than bleeding.
We next reviewed the work-up of a prolonged aPTT in a bleeding patient:
- Mixing Study: Differentiates a factor deficiency from a factor inhibitor.
- Patient’s plasma and normal pooled plasma are mixed and aPTT is measured over 1 to 2 hours.
- If the aPTT corrects, the patient has a deficiency of factor VII (which has been corrected by the addition of normal factors in the pooled plasma).
- If the aPTT does not correct, the patient likely has an inhibitor (which also inhibits the normal factors in the pooled plasma). Some inhibitors will demonstrate “slow reaction kinetics”, in which the aPTT initially corrects, but over time becomes prolonged again as the inhibitor exerts its activity.
- Our patient’s aPTT remained abnormally prolonged on the mixing study, suggesting the presence of an inhibitor.
- Factor Assays: Identify which factor has been affected by an inhibitor.
- Our patient’s assay showed <1% factor VIII activity, confirming the diagnosis of an acquired factor VIII inhibitor.
- Bethesda Assay: Confirms the presence of a factor VIII inhibitor AND quantifies the strength of the inhibitor.
- Serial dilutions of the patient’s plasma are made with normal plasma. The reciprocal of the dilution at which factor VIII activity is 50% is called the Bethesda Unit. The stronger the inhibitor, the more dilutions required to attain 50% factor VIII activity, and the higher the Bethesda Units.
- A low titer inhibitor is considered <5 Bethesda units and a high titer inhibitor is consider >5 Bethesda units.
- Our patient had a Bethesda assay of 9 units.
A few notes on acquired factor VIII inhibitors (acquired hemophilia A):
- Associated with pregnancy and the post-partum state in young patients and with rheumatic disease (RA and SLE), malignancies (solid>liquid), and drug reactions in older patients. In up to one half of patients, an associated disorder is not identified.
- Patients present with large hematomas and severe mucosal bleeding. Bleeding can be severe and life-threatening, including intracranial hemorrhage and retroperitoneal bleeds, so inpatient monitoring is essential while managing these patients.
We discussed that inhibitors can also be acquired in patients with inherited hemophilias, but in contrast to the presentation above, these inhibitors develop against the factor preparations that patients have been receiving for prophylaxis or treatment of bleeding due to their genetic condition. These inhibitors are most common in patients with severe hemophilia and low factor VIII levels to begin with (immune system recognizes factor infusions as foreign) and can make management of bleeding in these patients challenging. The Bethesda Assay is also used in these patients to quantify and trend inhibitor activity. See this week’s NEJM for an RCT using a new monoclonal antibody agent as prophylaxis in patients with hemophilia A and factor VIII inhibitors.
Finally, we reviewed the goals for management of acquired factor VIII inhibitors: 1) control bleeding, 2) eradicate the inhibitor, and 3) treat the underlying disease.
Agents available to control bleeding come in two flavors.
- Replacement agents: DDAVP, human factor VIII concentrate, and recombinant factor VIII concentrate.
- Generally reserved for patients with no or only very mild bleeding and low Bethesda units as it is otherwise difficult to overcome the inhibitor with large quantities of factor VIII.
- Bypassing agents: Activated prothrombin complex concentrate (aPCC; includes factors II, VII, IX, X; also called FEIBA or Factor Eight Inhibitor Bypassing Agent), recombinant activated human factor VIIa (Novo-7), and recombinant porcine factor VIII.
- Used in most patients to bypass the need for factor VIII by utilizing the extrinsic coagulation pathway. The major risk with these activated agents is thrombosis.
Eradicating the inhibitor is done with immunosuppression, usually prednisone +/- rituximab or cyclophosphamide.
Our patient received Novo-7 and FEIBA to control bleeding, then was started on prednisone and rituximab with normalization of his factor VIII activity and aPTT over the next several months.
1. Kruse-Jarres, et al. Acquired hemophilia A: Updated review of evidence and treatment guidance. American Journal of Hematology 2017.
2. Eby, CS. Bleeding and Thrombosis Risks in Plasma Cell Dyscrasias. American Society of Hematology Education Program 2007.
3. Oldenburg, et al. Emicizumab Prophylaxis in Hemophilia A with Inhibitors. NEJM 2017.