AHA is a rare but life-threatening bleeding disorder, typically occurring in the elderly. According to recent data, the incidence in subjects aged <65
yrs is 0.28 per million per year, but increases up to 5.97 in those aged 65–85
yrs and to 16.6 in individuals older than 85 yrs [2
]. On the whole, more than 80% of diagnosed patients are aged >60
]. Moreover, these data are likely to be underestimated because of undiagnosed and unreported cases. Therefore, the impact of AHA is not negligible in elderly patients, in whom the differential diagnosis with other age-correlated bleeding conditions should be also taken into account () [16
AHA: differential diagnosis in the elderly.
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 [9
]. Indeed, a prolonged aPTT may be attributable to coagulation factor deficiencies, lupus anticoagulant (LAC), or heparin therapy (). The presence of LAC may also be associated with a prolonged aPTT that is not corrected with normal plasma, but in this case no bleeding tendency is shown. Quantitative coagulation factor assays should be also performed which reveal a reduced level of FVIII:C in AHA. Milder reduction of factor IX, XI, and XII plasma levels may also be shown; increasing dilutions of patient plasma with normal plasma lead to diluting the autoantibody and to normalizing activities of factors other than FVIII, which remains inhibited even by the diluted specific autoantibody. These tests also enable the detection of more rare cases due to antibodies against coagulation factors other than FVIII [6
]. The diagnosis is then confirmed by a Bethesda (or its Nijmegen modification) positive assay. It is noteworthy to remark that the mixing test may be easily carried out in all laboratories and allows the identification of patients who require further investigations at a specialized centre.
Table 3 Diagnostic tests in AHA in the elderly (see Huth-Kuhne et al., modified ).
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) [6
]. However, about half of the cases are apparently idiopathic although in some patients an underlying disorder may be diagnosed long after the onset of the bleeding abnormality [6
], as reported in patient no. 2.
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 [1
]. In elderly patients, however, especially in those presenting posttreatment high FVIII:C levels, an adequate prolonged prophylaxis with antithrombotic agents, following inhibitor eradication, should be considered (see Case 1
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 [6
]. Bleeding complications are fatal in 10%–20% of the cases, but the overall mortality in AHA patients is also higher, in particular, in elderly patients and over the first weeks after the onset of symptoms, because of the underlying associated diseases, diagnostic delays, inadequate treatment of acute bleeds, bleeding complications during invasive procedures for controlling hemorrhages, or adverse events of treatment (infections, sepsis on immunosuppressive therapy, see Case 3
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 [5
]. Prednisone (1
mg/Kg/day for 4–6 weeks) remains the first-line treatment, alone or in combination with cyclophosphamide (1.5–2
mg/Kg/day). The latter should be administered for a maximum of six weeks, and the risk/benefit ratio of immunosuppressive therapy should be taken into account for each elderly patient individually [5
]. Other approaches should be considered for refractory patients. In particular, rituximab may be suggested when first-line immunosuppressive treatment fails or is contraindicated [5
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.