Acquired hemophilia A (AHA) is a very rare disease, caused by the development of autoantibodies, directed against circulating factor VIII of coagulation. Age distribution is bimodal, with a first peak occurring among young women in the postpartum period, and a second major peak of incidence among elderly patients in whom it is frequently associated with malignancy and drugs. This disease often represents a life-threatening bleeding condition, especially in the elderly, thus requiring a prompt therapeutic intervention, including control of acute bleeding and eradication of the inhibitor by immunosuppressive therapy. The diagnosis of AHA should be considered in any elderly patient who presents with bleeding and prolonged activated Partial Thromboplastin Time. Moreover, the coexistence of a series of underlying diseases associated with AHA should be always searched for. An early recognition and an adequate treatment of this coagulation disorder and of the possible associated diseases play a significant role for a favourable outcome, but concomitant morbidities in the elderly may limit aggressive therapy and may complicate the clinical scenario. We report 3 consecutive elderly patients successfully treated with recombinant activated factor VII and standard immunosuppressive regimens, with remission of the disease.
Acquired haemophilia A (AHA) is a very rare disease, with an estimated annual incidence between 1.3 and 1.5 per million per year [
The pattern of bleeding in AHA differs from that in congenital haemophilia A. Bleeding tends to occur in soft tissue, muscle, retroperitoneal space, and gastrointestinal or genitourinary tracts. In contrast with patients with congenital haemophilia A, patients with haemarthroses are rare. Iatrogenic bleeding is also common. Rates of mortality from acquired haemophilia up to 44% have been reported, with most deaths occurring in the first few weeks [
Diagnosis may be challenging, since the patient will have no personal or family history of bleeding disorders. However, in any patient who presents with recently-onset severe or deep tissue bleeding and an unexplained isolated prolonged activated Partial Thromboplastin Time (aPTT), AHA should be considered [
Diagnosis of AHA in the elderly (see [
The diagnosis of AHA should be considered in the presence of both |
(1) acute/recent bleeding in elderly patients with no previous |
history of bleeding, |
(2) unexplained isolated aPTT |
Treatment of AHA focuses on 2 goals: control of acute bleeding and immunosuppressive therapy to eradicate FVIII inhibitors. Acute bleeding episodes are usually treated with bypassing agents and good efficacy is seen with both recombinant activated (rFVIIa) and activated prothrombin complex concentrates (aPCCs). Eradication of the autoimmune inhibitor antibody with immunosuppression is indicated as soon as the diagnosis has been confirmed, because patients remain at risk of potentially fatal bleeding until the inhibitor is suppressed. Steroids, alone or in combination with cyclophosphamide or azathioprine, induce remission in about 70% of the patients. [
We report clinical features and treatment of three patients with a history of bleeding occurring in the elderly in whom AHA was diagnosed.
A 70-year-old man presented with large posttraumatic left leg haematoma. The patient had a history of coronary heart disease (acute myocardial infarction treated with percutaneous transluminal coronary angioplasty and stenting, 10 years earlier), therefore he was on chronic antiplatelet treatment (aspirin 100 mg/day). About 3 years earlier, because of haematuria, he performed an abdominal ultrasonography (US) that revealed a renal mass confirmed at computed tomography (CT) scan, but the patient did not perform further controls. As gastrointestinal bleeding (melena, due to multiple peptic ulcers) occurred one year earlier, treated with endoscopic haemostasis and blood transfusion, aspirin was stopped and substituted for clopidogrel. One month later an US confirmed the renal neoplasm (diameters approximately 12 cm and irregular burden, with a central necrotic area); for this reason he was administered sunitinib, scheduled for a nine-cycle therapy. Surgical treatment of the neoplasm was not considered in this patient because of his high bleeding tendency. After a few weeks, because of a rectal bleeding, he was admitted in an emergency care unit: clopidogrel was stopped and laboratory tests revealed prolonged aPTT, normal platelet counts and anaemia. In the suspect of AHA, he was treated with rFVII (90
Because of the leg haematoma and lower back pain, he was finally referred to our hospital. On admission, coagulation tests confirmed the prolonged aPTT (92 seconds, normal 26–44), not corrected at mixing test, with normal prothrombin time (PT), international normalized ratio (INR), and bleeding time (Ivy, 3 minutes, normal values
A 68-year-old man presented with multiple spontaneous haematomas (gluteal, neck, and lower limbs), in the absence of personal or family history of bleeding or clotting disorders. His past medical history included type 2 diabetes mellitus, arterial hypertension, prostatic hypertrophy, psoriasis, and arthrosis. At that time he was taking nonsteroidal anti-inflammatory drugs (NSAIDs) because of back pain. A previous haematoma of the left arm, after an effort, occurred approximately 6 weeks before the admission, when he also was on NSAID treatment; one month later he reported a gluteal and leg haematomas immediately after an intramuscular NSAID injection because of his recurrent back pain. A week later he presented with a wide neck haematoma unsuccessfully treated with tranexamic acid, therefore he was referred to our hospital. On admission, laboratory investigations revealed anaemia (haemoglobin 8.2 g/L) and normal platelet count (
The day after the admission, the patient had dyspnoea and haemoglobin levels further decreased (7.0 g/dl), thus transfusions with packed red blood cells were required (2 Units). A CT scan confirmed the presence of a large haematoma in the neck. Because of the reduction of haemoglobin levels and the harmful site of bleeding, a 90
A 87-year-old woman presented with persistent rectal bleeding and large ecchymoses. Her past medical history included Hodgkin’s disease about 10 years earlier, in apparent long-term remission, and type 2 diabetes mellitus.
On admission, laboratory investigations revealed severe anaemia (haemoglobin 6.7 g/L) and mild reduction of platelet count (
AHA is a rare but life-threatening bleeding disorder, typically occurring in the elderly. According to recent data, the incidence in subjects aged
AHA: differential diagnosis in the elderly.
(1) Mild-moderate hereditary haemophilia diagnosed after |
the age of 60 years [ |
(2) Lupus anticoagulant |
(3) Bleeding complications of anticoagulant treatments |
(4) Trauma |
(5) Abuse of NSAIDs |
(6) Other acquired bleeding disorders (acquired von |
Willebrand disease, acquired platelet dysfunctions, |
uremia, and liver cirrhosis) |
The diagnosis of AHA should be considered in any elderly patient who presents with bleeding and an isolated prolonged aPTT. The mixing test is a simple assay able to reveal the presence of inhibitors of coagulation [
Diagnostic tests in AHA in the elderly (see Huth-Kuhne et al., modified [
(1) |
patient and normal plasma after 1-2 h incubation |
compared to an immediate mix is typical of FVIII |
autoantibodies. |
(2) |
IX, X, XI, XII levels measured; an isolated low FVIII level |
is suggestive of AHA. |
(3) |
should be repeated to confirm the presence of the inhibitor. |
When AHA is diagnosed, the possible coexistence of an underlying disease responsible for this immunologic complication should be suspected and intensively searched for. In particular, in elderly patients AHA is often secondary to haematologic or solid malignancy or drugs (e.g., antibiotics, phenytoin, methyldopa, interferon, fludarabine, and clopidogrel) [
Our case reports confirm the complexity of the management of AHA in elderly patients, in whom the clinical picture is complicated by comorbidities and concomitant drug intake. The latter may facilitate bleeding complications, as occurred in patients no. 1 and 2, or delay the diagnosis, when antiplatelet or anticoagulant drugs are administered. The coexistence in AHA patients, in particular in the elderly, of overt cardiovascular/thromboembolic diseases (see patient no. 1) and/or risk factors such as diabetes mellitus, neoplasm, arterial hypertension, high body mass index, requiring antithrombotic treatment, represents a challenging issue in this setting. The occurrence of severe bleeding leads to the withdrawal of such treatments and in many cases to the administration of bypassing agents (APCCs, rFVIIa), with possible increase of thromboembolic risk. This risk is further enhanced by the reduced mobility due to hospitalization or muscle bleeding or by activation of coagulation induced during sepsis. Thus an accurate balance of bleeding and thrombotic risk should be carefully taken into account when these patients are treated for the bleeding complications, in terms of doses and duration of bypassing agent administration. Presently, however, evidence of rFVIIa and aPCC thrombogenicity is limited, therefore according to recent recommendations, bypassing agents should not be considered contraindicated in the presence of severe or life-threatening bleed and also in patients at thromboembolic risk [
An early and appropriate therapeutic approach is crucial for a favourable outcome, which also depends on the treatment and the prognosis of any possible concomitant disease or triggering condition [
Therefore, patients with AHA should be managed by a hemophilia center with laboratory and clinical experience in this setting, in particular because of the complexity of treatment. Immunosuppressive regimens in the elderly should aim to eradicate the inhibitor as rapidly as possible, reducing the time of exposure to the side effects of immunosuppressive therapy [
Despite the lack of definite conclusions on the optimal hemostatic and inhibitor eradicating approaches, a series of effective options is presently available, giving the opportunity of tailoring the treatment of this rare but severe disease, even in the “fragile” elderly patients.