A Rare Case of Acquired Factor VIII Inhibition in an Elderly Female

Abstract

Acquired hemophilia A is a rare condition characterized by the development of autoantibodies against coagulation factor VIII. It often initially presents as serious bleeding in the absence of risk factors and carries high morbidity and mortality if not diagnosed early. Due to its rare nature, data is limited, and guidelines are primarily based on expert opinion. Here we present a case of an elderly patient with severe gastrointestinal bleeding found to have activated partial thromboplastin times, plasma mixing studies, and coagulation factor activity levels consistent with acquired hemophilia A. We hope to bring awareness of this rare disease and promote its consideration in the differential of unexpected bleeding to improve safety outcomes.

1. Introduction

Acquired hemophilia A (AHA) is a very rare coagulation disorder, occurring at approximately 1–1.5 cases per million people per year.1 While other acquired coagulation disorders can occur, AHA develops from autoantibodies directed against coagulation factor VIII. Coagulation factor VIII appears to be the most commonly affected coagulation factor in acquired coagulation factor deficiency disorders.1 Though acquired hemophilia A is idiopathic in up to 50% of cases, it is associated with pregnancy, autoimmune conditions, malignancy, and medications.2 AHA is a disorder of the elderly, with a median age of 73.9–78 years.3 Acquired hemophilia A carries an elevated risk of clinically significant bleeding and high rates of morbidity and mortality. A high index of suspicion of AHA is warranted in cases of unexpected bleeding for prompt diagnosis and treatment to improve survival outcomes.

2. Case report/presentation

An 87-year-old female presented to the emergency department referred by her primary care physician for acute anemia identified on routine laboratory evaluation. Her medical history was only remarkable for normocytic anemia, worked up to be due to iron deficiency, being treated with weekly intravenous iron infusions for one year. She had no active complaints and denied any active bleeding, lightheadedness, dizziness, changes in bowel habits, or skin changes. She abstained from alcohol and recreational drug use. On initial evaluation, her vital signs revealed a heart rate of 87 beats per minute and blood pressure of 101/47 mmHg. Physical exam was significant for scleral icterus and bruising on her lower extremities. Initial laboratory workup revealed hemoglobin 7.6 g/dL, MCV 78 fL, platelets 364 k/uL, aPTT 191s, PT 11.9 s, INR 1.08s, total bilirubin 3.3 mg/dL, and indirect bilirubin 2.7 mg/dL. ANA titers were within normal limits. Stool guaiac was found to be positive. A mixing study revealed persistently elevated aPTT (90.2s). CT imaging of the chest, abdomen, and pelvis did not identify any clear source of bleed but did reveal a mass in the rectum, as seen in Fig. 1. Initially, one unit of packed red blood cells was administered along with intravenous fluids and iron supplementation. Subsequent hemoglobin levels improved to 8.2.

Fig. 1.

CT imaging of the abdomen and pelvis. A mass suspicious for malignancy is seen here at the junction of the ileocecal valve, as seen by the red arrow.

Her hospital course was complicated by progressively worsening melanotic stools. Surgery and gastroenterology were consulted and a colonoscopy and endoscopy were recommended but were deferred due to coagulopathy. On hospital day 3, the patient was found to have acute lethargy and confusion, for which stat labs were ordered revealing Hgb 7.6 mg/dL and aPTT >400s. The patient was administered three units of packed red blood cells, two units of fresh frozen plasma, and one unit of cryoprecipitate. She was transferred to the ICU for closer management, where subsequent aPTT improved to 142.6. The trend of aPTT and Hgb is seen in Table 1. Her hospital course was further complicated by worsening gastrointestinal bleeding and a loss of pulse on hospital day 4. Advanced cardiopulmonary life support was initiated, and spontaneous circulation returned after 22 min. Her mental status deteriorated and she was intubated to protect her airway. Ultimately the patient’s family decided that the patient would have wished for comfort measures. Subsequently, the patient was placed into hospice care and ultimately passed away within one day. Posthumous laboratory evaluation revealed markedly decreased factor VIII activity (<1%). Reduced factor VIII levels in the setting of inappropriate correction of aPTT on mixing study suggested acquired hemophila A.

Table 1.

Laboratory Trends of Hgb, PT, aPTT, and Platelets.

Hospital Day	1	2	3	4	5	Normal Range
Hgb (mg/dL)	7.6	8.1	7.8	7.2	4.6	12.0–15.0
PT (s)	11.9	12.2	11.9	12.1	11.4	9.5–12.8
aPTT (s)	191.0	145.9	>400	142.6	152.3	24–37
Platelets (k/uL)	364	287	309	309	302	150–450

The trend of hemoglobin here is stable except at day 5 when the gastrointestinal bleeding worsened. PT levels were found to be within normal limits throughout the patient’s hospital course. The aPTT remained high despite treatment with aPCC; the peak was seen on day 3 when the aPTT was measured >400. Platelet values remained within normal limits through the patient’s hospital course.

3. Discussion

Acquired Hemophilia A (AHA) is a rare variant of hemophilia A that commonly occurs in the elderly as compared to the congenital form. The annual incidence of AHA for children younger than 16 years of age is 0.045 per million per year, whereas for adults greater than 85 years of age the yearly incidence is as high as 14.7 per million per year.4 Acquired hemophilia develops by the formation of autoantibodies, also known as inhibitors, to coagulation factors. Coagulation factor VIII is the most common coagulation factor to be affected, as seen in AHA.1 Though AHA is often idiopathic, it can occur in association with pregnancy, autoimmune conditions, and malignancy.2 Medications associated with AHA include antibiotics, NSAIDs, amiodarone, rivastigmine, sunitinib, heparin, phenytoin, chloramphenicol, and methyldopa.3 Due to the rare nature of this disorder, data is limited; however, some studies have shown mortality rates of up to 23% within one year of diagnosis.5 The most obvious risk factor in our patient was the colonic mass seen on CT imaging of the abdomen. Unfortunately, the mass was unable to be evaluated for malignancy due to the critical condition of our patient and ultimate medical course. However, upon review of the literature, it appears that acquired factor VII inhibitor has been seen with colorectal cancers6

Acquired Hemophilia A usually presents with clinically significant bleeding in the elderly or in the postpartum period. New onset of bleeding without any previous history of bleeding should raise suspicion for acquired hemophilias.7 Classically, patients will present with subcutaneous bleeding in the form of purpura or soft tissue hematomas. However, unlike the congenital form of Hemophilia A, hemarthrosis is uncommon.8 More severe conditions such as gross gastrointestinal bleeding can develop, as was the case in our patient. Workup is initiated by evaluating a complete blood count (CBC) and a coagulation panel. CBC will reveal a normal platelet count and an isolated prolonged activated partial thromboplastin time (aPTT) at least two to three times the normal limit. Prolonged aPTT can indicate a deficiency of intrinsic coagulation factors VIII, IX, XI, or XII, or an inhibitor to these factors. The coagulation pathway is highlighted in Fig. 2. A mixing study may then be performed to distinguish between a factor deficiency and a factor inhibitor. This is done by mixing a 1-to-1 ratio of normal plasma with the patient’s plasma. Correction of aPTT after mixing study indicates a deficiency of coagulation factors, whereas a lack of correction of aPTT correction suggests a coagulation factor autoantibody or inhibitor. Quantitative assays of factor activity and factor inhibitors are diagnostic of acquired hemophilia.9 In this patient, the mixing study did not appropriately correct the aPTT, and the coagulation factor VIII activity levels were low, suggesting an acquired factor VIII (FVIII) inhibitor or autoantibody.

Fig. 2.

The Coagulation Pathway. The coagulation pathway is displayed here. It is separated into the intrinsic, extrinsic, and common pathway. An inhibitor of coagulation factor VIII is displayed in red to demonstrate acquired hemophilia A.

Treatment for acquired hemophilia A is primarily directed towards hemostasis management and eliminating factor inhibitors. For patients with minor bleeding and less than 5 Bethesda units (BU) of inhibitor, observation is sufficient as titers of the factor inhibitor have sometimes disappeared on their own.10 In patients with coagulation FVIII activity levels greater than 5% and inhibitor levels less than 2%, desmopressin is effective for minor bleeding.10 For major bleeding with inhibitor levels less than 5 BU, FVIII replacement and desmopressin are considered first-line therapy.4 However, bypass agents such as activated prothrombin complex concentrate (aPCC) or recombinant activated Factor VII (rFVIIa) are used for higher levels of inhibitor concentration.4 These agents work by bypassing the coagulation cascade to produce thrombin, which would otherwise be limited by FVIII. Our patient was treated with aPCC instead of desmopressin of direct FVIII replacement, partially improving aPTT levels and bleeding to some extent. Quantitative evaluation of FVIII activity levels unfortunately returned posthumously.

The development of acquired coagulation factor inhibitors usually involve an antibody which binds to and inactivates coagulation factors. Subsequently, the coagulation cascade, as shown in Fig. 2, is compromised and clots are not able to be effectively formed, leading to uncontrolled bleeding. The underlying mechanism is poorly understood; however, it is likely that the acquired inhibitors are antibodies binding to domains of the coagulation factors, preventing their effective function. Specifically, for acquired inhibitors to coagulation factor VIII, it is hypothesized that autoantibodies bind most commonly to the A2 and A3 domains of coagulation factor VIII.3 Coagulation factor VIII is then unable to effectively serve as a cofactor to coagulation factor IV to convert factor X into factor Xa. Malignancy is one of the most common causes for acquired inhibitor production and it is likely related to the immunogenic properties of the malignancy. The underlying mechanism is poorly understood and requires further investigation.

Decreasing the levels of factor inhibitors is an essential mainstay of chronic therapy as these patients remain at high risk for future bleeds. First-line treatment includes prednisone (1 mg/kg/day) by itself or with the addition of cyclophosphamide (50–100 mg/day).11 Some evidence suggests better patient outcomes with a combination of prednisone and cyclophosphamide.12

4. Conclusion

This is a case of acquired hemophilia A in a patient likely secondary to lower GI malignancy.

Acquired hemophilia A is a rare disorder that presents with new-onset clinically-significant bleeding, typically in the elderly. Due to its rare nature, there is limited data, though studies have suggested significant mortality with delayed diagnosis. Physicians should maintain a high suspicion of acquired hemophilia in patients with unexpected bleeding. We present our case to bring awareness of the catastrophic outcomes associated with delayed diagnosis and treatment and hope to bring awareness of this rare condition.