Acquired haemophilia a secondary to multiple myeloma: management of a patient with a mechanical mitral valve

Abstract

A 77-year-old man with a mechanical mitral valve on warfarin presented with an acute drop in haemoglobin and large spontaneous haematoma. He was found to have a new coagulopathy with initial labs notable for a prolonged activated partial thromboplastin time (APTT). Further workup revealed factor VIII levels less than 1%, abnormal mixing studies and elevated Bethesda titres, which was consistent with an acquired factor VIII inhibitor. Given his bone marrow biopsy result, which was positive for plasma cell myeloma, this coagulopathy was thought to be an acquired haemophilia A secondary to multiple myeloma. Anticoagulation was a challenge in this patient given his mechanical mitral valve and acquired haemophilia A. Although the patient was at risk of thrombosis due to a mechanical mitral valve, he had a bleeding diathesis and anaemia not responsive to transfusion. The decision was made to hold anticoagulation and the patient was started on myeloma treatment which included CyBorD, rituximab and daratumumab. After initiation of treatment APTT and factor VIII normalised. He eventually restarted anticoagulation under direction of his primary care doctor.

Background

It is important for physicians, especially internists, to be able to workup anaemia of unclear aetiology with abnormal coagulation factors. When patients are admitted who are on warfarin, APTT may be overlooked while focus is on prothrombin time and international normalized ratio (PT/INR). Evaluation of the entire coagulation cascade is essential for complete workup of coagulopathy and in order to initiate proper response in a timely manner. This case was particularly complex because there are limited data on management of patients with coagulopathies who require anticoagulation. There is a known relationship between acquired haemophilia A and a number of pathologies, multiple myeloma being one of them. However, there are limited reports on acquired haemophilia A secondary to multiple myeloma and none that consider patients requiring anticoagulation. This causes a dilemma in patients who require anticoagulation, such as our patient with a mechanical mitral valve.

Case presentation

A 77-year-old man with a medical history of hypertension, mitral regurgitation postmechanical mitral valve replacement and extramedullary C4 plasmacytoma, postresection in January/2018, presented to his outpatient haematologist for a bone marrow biopsy in December/2018 due to concern for multiple myeloma. After the biopsy was completed labs revealed a haemoglobin of 60 g/L which was an acute drop from a baseline haemoglobin of 85 g/L recorded 1 week prior to the clinic visit. In the clinic, the biopsy site was checked and did not appear to be the source of bleeding. The patient was sent to the emergency department for further evaluation.

In the emergency department, vital signs were stable. The patient denied signs or symptoms of blood loss including shortness of breath, fatigue, palpitations, haematochezia or haemoptysis; however, physical examination revealed a large right-sided flank haematoma. A CT chest, abdomen and pelvis was obtained to evaluate the haematoma due to concern for a retroperitoneal bleed. CT showed evidence of a large soft-tissue haematoma extending from the medial and inferior right scapula along the right posterior chest wall, measuring 20.6×4.8x25.5cm. Additionally, multiple lytic lesions within the axial and appendicular spine were noted.

Investigations

Initial labs sent on admission were notable for a haemoglobin of 60 g/L, PT 24.2 s, INR 2.11 and APTT >150 s. There were no signs of renal insufficiency and calcium was within normal limits. The patient had been on warfarin for his mechanical mitral valve, but this had been held 2 days prior to admission in anticipation of the bone marrow biopsy and had not yet been restarted. After being transfused five units of packed red blood during the first 36 hours of admission, haemoglobin rose from 60 to 68 g/L but APTT remained >150 s and INR, checked every 6 hours, was variable, ranging from 1.79 to 3.19. Mixing studies were sent which showed a greater than 50% correction of the APTT on the immediate mix but prolonged time for the incubated mix. Factor II, V, VIII, IX, X, XII, XIII, Von Willebrand assay, and Bethesda titres were sent with notable results for factor VIII.

Differential diagnosis

On initial presentation, our initial explanation for acute on chronic anaemia was haematoma secondary to traumatic bone marrow biopsy in the setting of warfarin use. It quickly became apparent that the haematoma was spontaneous given that the patient had not undergone any significant trauma to the area of concern. Supratherapeutic dosing of warfarin and vitamin K deficiency were considered, however, INR was within target range. Due to the presence of a mechanical mitral valve and lack of response to packed red blood cell transfusion, there was concern for haemolytic anaemia. Workup including haptoglobin, bilirubin and lactate dehydrogenase was not suggestive of haemolysis. The differential was adjusted with the finding of prolonged APTT and included disseminated intravascular coagulation, factor inhibitor, factor deficiency, liver disease, malignancy and connective tissue disease.

Disseminated intravascular coagulation (DIC) was less likely as there was no thrombocytopenia, fibrinogen levels were high and factor levels, aside from factor VIII, were within normal limits. Liver disease was less likely due to the patient having no history of liver disease, transaminases and platelets were within normal limits, and hepatitis panel was negative.

The patient did not have a history of connective tissue disease, rheumatological background or physical examination findings of rashes or lesions associated with many of the autoimmune pathologies. Mixing studies were abnormal, suggesting severely decreased factors or a factor inhibitor. Further workup identified low factor VIII activity, which was also inconsistent with liver disease. At this time, factor VIII deficiency or factor VIII inhibitor were the most likely aetiologies. The Bethesda titre was positive, solidifying the diagnosis of a factor VIII inhibitor. In light of the patient’s new diagnosis of multiple myeloma, it is thought that the patient developed an acquired inhibitor secondary to the malignancy.

Treatment

A haematologist was consulted due to prolonged APTT, abnormal mixing study results and inappropriate response to packed red blood cell transfusions. Despite having a mechanical mitral valve, anticoagulation was not restarted in the setting of anaemia, haematoma and coagulopathy. Based on biopsy results dexamethasone, 40 mg intravenous was given for 4 days, followed by bortezomib 3 mg intravenous once a week and cyclophosphamide 660 mg intravenous every 2 weeks. Due to a lack of improvement in APTT and factor VIII levels, treatment with rituximab 750 mg intravenous weekly was also initiated. Slow improvement in APTT and factor VIII was seen. Daratumumab 1900 mg intravenous weekly was subsequently initiated for 8 weeks. Thereafter daratumumab was modified to biweekly for 1 month, and then further adjusted to monthly treatments until the present time.

Due to concern for acute bleeding recombinant coagulation factor VIIa, a bypassing agent, was available throughout the patient’s hospitalisation. However, the patient did not necessitate its use. He was transfused with packed red blood cells as needed for a haemoglobin below 70 g/L, requiring a total of 14 units throughout his admission of 24 days. The patient was discharged once he was no longer transfusion dependent, which occurred once daratumumab was added to his treatment. He continued to undergo therapy with daratumumab for multiple myeloma as an outpatient.

Outcome and follow-up

The patient’s haematoma gradually decreased in size during his admission without intervention. He continued therapy with daratumumab and dexamethasone with factor VIII and APTT improvement to 33 IU/dL and 119 s, respectively, within 4 weeks after discharge. As of March 2020, his factor VIII levels were 113 IU/dL and APTT 56 s with continuation of treatment with daratumumab and dexamethasone. Under direction of his primary care physician, he restarted warfarin 8 weeks after discharge with PT/INR, APTT and factor VIII levels monitored weekly.

Discussion

Acquired inhibitor against factor VIII, also termed acquired haemophilia A, is a rare occurrence seen in 1–4 per million people per year.¹ The prevalence of this autoantibody has a biphasic distribution with a smaller peak in younger patients, often postpartum women, and a much larger peak in older patients, often men aged 65–85.² There is a wide range of patient presentation with minimal symptoms at times, therefore, the incidence is likely underestimated due to a challenge with diagnosis. This leaves undiagnosed patients at high risk for severe bleeding and increased mortality.¹ In contrast to patients with congenital haemophilia A which is X-linked and associated with large haemarthrosis, acquired haemophilia A is distributed equally among men and women and is associated with bleeding into skin, soft tissue and mucous membranes.¹

The diagnosis of acquired haemophilia A is based on detecting an isolated prolonged APTT not corrected in mixing studies and a reduced factor VIII level with evidence of factor VIII inhibitor activity on Bethesda assay.² Half of reported cases of acquired haemophilia A are associated with autoimmune disease, infections, medications and malignancy while the rest occur in patients with no known medical problems. About 10% of acquired haemophilia A has been associated with an underlying malignancy, most frequently lymphoproliferative diseases including multiple myeloma, chronic lymphocytic leukaemia, Waldenstrom macroglobulinaemia and non-Hodgkin's lymphoma. While Bethesda titres have been found to be lower in this population of patients, their underlying neoplasm makes for a poorer prognosis.³ There are limited case reports that describe an association between multiple myeloma and acquired haemophilia A. In those cases, the diagnosis was often made in the setting of postprocedural bleeding, with gastrointestinal or soft-tissue bleeds.⁴

The treatment of acquired haemophilia A is twofold; supportive treatment during acute bleeds and removal of the inhibitor. If there is an underlying disease associated with the autoantibody then treatment of that disease should lead to disappearance of the inhibitor.

Acute severe bleeding episodes are typically managed with use of bypassing agents or by raising factor VIII levels. Bypassing agents that have been proven effective include activated prothrombin complex concentrate and recombinant activated factor VIIa.¹ In the case of our patient, a bypassing agent was deemed unnecessary due to his haemodynamic stability. However, in the event of severe bleeding, it would have proved difficult to determine when to use the agent considering the mechanical mitral valve increasing the risk for thrombus formation.

Inhibitor eradication can be accomplished through various options including but not limited to steroids, cytotoxic drugs, rituximab and intravenous immunoglobulin. Treatment is managed on a case-by-case basis but can initially be started at prednisone 1 mg/kg per day in combination with cyclophosphamide 1–2 mg/kg per day for 5 weeks. Rituximab 375 mg/m2 weekly for a maximum of four cycles is recommended as first-line therapy in patients with Factor VIII levels<1 IU/dL or Bethesda titre levels>20.⁵ Salvage therapy cyclosporine has been used at a dose of 200–300 mg/day alone or in combination with steroids. Intravenous immunoglobulin has been studied as an adjuvant medication but reported to not be a first-line agent. Plasmapheresis has been used as a rapid antibody removal therapy in the event of severe bleeding.¹

In our case, we hypothesised that our patient’s plasma cells were producing the inhibitor and causing his acquired haemophilia A. Our team used CyBorD and rituximab, known first-line treatments for multiple myeloma, with the intention that by treating multiple myeloma we would eradicate the inhibitor causing this patient’s coagulopathy.⁶ Although clinical response was noted, the patient required less transfusions and lab work showed improvement of APTT and factor VIII, he continued to be transfusion dependent and APTT and factor VIII were not within normal ranges. Daratumumab, which is used for multiple myeloma that has relapsed or recurred, was given as a therapy to our patient. Daratumumab is a monocolonal antibody that targets CD38 cells, which is highly expressed in myeloma and induces cell death.⁷ To our knowledge, daratumumab has not been used as a therapy for acquired haemophilia A secondary to multiple myeloma.

The complexity of treating patients increases dramatically when their comorbidities pose risks to treatment. Patients with mechanical mitral valves, where warfarin is the current guideline recommendation for anticoagulation, should be anticoagulated to an INR goal of 2.5–3.5.⁸ During the episodes of acute bleeding, it is unclear whether anticoagulation should be held and if so, when to restart it. The risk of severe bleeding must be weighed against the risk of life threatening thrombosis. This decision should include discussions with the patient and pertinent specialists.

Literature on patients with inherited bleeding disorders necessitating anticoagulation is scarce. One study approached this difficult decision by considering four principles: bleeding phenotype of the patient, characteristics of the anticoagulant, intensity of anticoagulant therapy and duration of planned therapy.⁹

In our case, the patient did not have an inherited disorder such as congenital haemophilia A. However, characteristic of the anticoagulant played a role in our inpatient decision-making process. We considered choosing an anticoagulant with a short half-life and ability to be reversed quickly should the need arise, such as unfractionated heparin or low molecular weight heparin. For oral choices, anticoagulants with immediate reversibility such as warfarin were considered.

The diagnosis of acquired haemophilia A may be difficult to identify early on and management can be complex. It is imperative that patients with this condition are diagnosed and treated in a timely manner to prevent life-threatening bleeds. In patients with underlying conditions necessitating long-term anticoagulation, such as a mechanical mitral valve, it is crucial to use a multidisciplinary approach to devise a treatment plan which may include using anticoagulants with the appropriate characteristics and bypassing agents when needed for severe bleeds.

Learning points.

• Anaemia of unclear aetiology should prompt internists to assess the entire coagulation cascade so as to not overlook APTT or factor levels. Every prolonged APTT should be clarified and suspect of undiscovered pathology, such as acquired haemophilia, especially in cases with bleeding.

• Acquired factor VIII inhibitor is a rare syndrome that necessitates early detection and diagnosis as well as consultation with specialists.

• There is a lack of data on management of patients who necessitate anticoagulation but are coagulopathic, therefore, treating these patients requires interdisciplinary decision making.