1 Ematologia, Università Sapienza, Roma, Italia.
2 Ematologia, Azienda Ospedaliera Universitaria Policlinico Umberto I, Roma, Italia.
3 Ematologia, Dipartimento Medicina Traslazionale e di Precisione, Università Sapienza Roma, Italia.
Received: May 11, 2020
Accepted: June 18, 2020
Mediterr J Hematol Infect Dis 2020, 12(1): e2020045 DOI 10.4084/MJHID.2020.045
| This is an Open Access article distributed
under the terms of the Creative Commons Attribution License
(https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Haemophilia A is a rare acquired bleeding disorder caused by Factor
VIII autoantibodies, which neutralise FVIII activity. These inhibitors
differ from alloantibodies against FVIII, which can occur in congenital
Haemophilia A after repeated exposures to plasma-derived or recombinant
FVIII products. In most cases, the disease occurs suddenly in subjects
without a personal or familiar history of bleedings, with symptoms that
may be mild, moderate, or severe. However, only laboratory alterations
are present in ̴ 30% of patients. The incidence varies from
1 to 4 cases per million/year; more than 80% of patients are elderly,
males and females are similarly affected. There is a small peak of
incidence related to pregnancy in young women aged 20–40 years. The
disease may be underdiagnosed in the elderly. The diagnostic algorithm
is based on an isolated prolonged activated partial thromboplastin
time, normal thrombin time, absence of Lupus Anticoagulant, and a
mixing test that reveals the presence of an inhibitor: the finding of
reduced FVIII activity and the detection of neutralising autoantibodies
against FVIII lead to the diagnosis. The disease is idiopathic
in 44%-63% of cases, while in the other etiological factors
are present. Bleeding prevention and treatment are based on therapeutic
tools as by-passing agents, recombinant porcine FVIII concentrate or,
in a limited number of cases, FVIII concentrates and desmopressin. As
soon as the diagnosis has been made, immunosuppressive therapy must be
started to eradicate the inhibitor. Better knowledge of the disease,
optimal management of bleeding and eradication of the inhibitor have
significantly reduced morbidity and mortality in most patients.
Severe bleedings at diagnosis were found to be 60%, 70% and 87% in 3 studies, respectively.[7,30,45] Mortality rate bleeding-related ranged from 2.9% to 9% (median 4.0%),[7,8,42,43] while mortality rate disease-related was reported to be 22% and 11%, respectively. Some prognostic factors were also identified. Age >65 years vs < 65, related diseases (malignancy vs post-partum vs others), inhibitor titre at diagnosis (>10 BU/mL vs <10 BU/mL), the achievement of inhibitor eradication (no vs yes) had a significant negative impact on overall survival (OS) on univariate analysis, but only inhibitor eradication, age at diagnosis and underlying diseases had a consistent, independent significant prognostic value on multivariate analysis. Regarding disease-related survival, the same four variables showed a significant prognostic value on univariate analysis, but only inhibitor eradication and age remained statistically significant on multivariate analysis. Age appeared to be the only prognostic factor associated with survival in the UK study. Age over the median of the studied group (76.3 years), low haemoglobin level at diagnosis, presence of neoplasia and failure of inhibitor eradication were significant negative prognostic factors in the EACH2 study, while gender, inhibitor titre and FVIII:C did not. A study, aimed at identifying risk factors in patients treated with a uniform immunosuppressive regimen for inhibitor eradication, showed that the time to partial response to therapy did not depend significantly on age, gender, underlying disorder, and poor performance status (PS), i.e. WHO-PS >2; baseline FVIII:C<1% was significantly associated with time to partial response, while inhibitor titre >20 BU/mL did not; only baseline FVIII:C <1% remained significantly related with time to partial response on multivariate analysis. Baseline FVIII:C<1% and WHO-PS>2 were significantly associated with a lower rate of complete response to therapy, both on univariate and multivariate analysis. Patients with poor PS were more likely to die before achieving a complete response. Baseline FVIII:C <1%, inhibitor >20 BU/mL, age >74 years, WHO-PS >2, male gender, malignancy and renal failure were associated with a poor OS on univariate analysis, but only three baseline factors remained independent predictors of poor OS on multivariate analysis: FVIII:C <1%, WHO-PS >2, and malignancy. In the same patients' population presence of anti-FVII, I IgA autoantibodies were identified as a potential predictor of recurrence and poor outcome of AHA.
Specific AHA Populations
Two papers have recently regarded AHA in the elderly: one review from 80 studies, including 159 cases and a cases report concerning a small number of patients. In the first one, most patients were men (64%) with a mean age of 76.1. Mortality was high, despite the number of therapies used for inhibitor eradication, probably due to the lack of rapid diagnosis and to inadequate management and monitoring. The other one described only 6 patients, but, interestingly, 4 were 90 or older: The Authors underlined that AHA shows a wide variety of symptoms in the elderly, indicating the need of individualised management.
Regarding pregnancy-related AHA, a survey carried out in 42 Italian Haemophilia Centres, identified 20 cases of post-partum AHA among 96 patients (20.8%), diagnosed during 15 years: 19/20 cases were idiopathic, and in six the inhibitor was identified because of surgical bleeding. Nine women did not require haemostatic treatment. The inhibitor was diagnosed for the occurrence of significant bleeding at a median time after delivery of 60 days (1–150). Eighteen women received treatment for inhibitor eradication with an excellent outcome. In two patients without bleedings, the inhibitor disappeared without therapy. No relapse was recorded in subsequent pregnancies occurred in 4 women. In the EACH2 registry, 42 cases (8.4%) of peripartum-associated AHA were diagnosed over 6 years. Evidence of antepartum inhibitors was found in 8 women, and 2 babies had postnatal bleeding, suggesting a transplacental transfer of the autoantibody. The median time between delivery and diagnosis of AHA was 89 days (21–120). Bleedings were successfully managed, and most women achieved inhibitor eradication. In conclusion, pregnancy-associated AHA is rare, but the awareness of it is crucial for rapid and appropriate management. Relapses during the subsequent pregnancies are very rare.
Treatment and Prevention of Bleeding
|Table 1. Bleeding treatment or prevention.|
Inhibitor Eradication: Immunosuppressive Therapy (Ist)
Corticosteroids alone or associated with cyclophosphamide have been used as first-line treatment, while other immunosuppressants or the monoclonal anti-CD20 antibody, rituximab, have been given as second/third-line therapy. In the only randomised study published until now, 31 AHA patients were initially treated with prednisone, if the autoantibody persisted and there was no rise in FVIII:C, patients were randomised to either prolong prednisone for other 6 weeks or taper prednisone and start cyclophosphamide or continue prednisone and add cyclophosphamide. About 1/3 of patients responded to prednisone alone, while in 50% of prednisone-resistant patients, cyclophosphamide-containing regimens achieved eradication of the inhibitor. In conclusion, patients should be initially treated with prednisone, while cyclophosphamide appeared to be an effective second-line therapy for prednisone-resistant patients. In a metanalysis concerning 234 patients, cyclophosphamide with or without prednisone was found to be more effective in inducing inhibitor eradication than corticosteroids or no immunosuppressive treatment at all. However, the superiority of cyclophosphamide over prednisone was not confirmed with regard to OS, probably for increased infection-related mortality due to haematological toxicity of this drug. In a prospective, non-randomised study, no statistically significant difference was found regarding the eradication rate of the inhibitor. The median time to complete remission (CR), namely FVIII:C normal, inhibitor undetectable, IST stopped or properly reduced, between patients treated only with corticosteroids (mostly prednisolone) and patients receiving corticosteroids combined with a cytotoxic drug, (mostly cyclophosphamide): CR were 76% and 78%, reached at a median time of 49 and 39 days, respectively. In another meta-analysis, concerning 359 patients, CR (absence of FVIII inhibitors and normalisation of FVIII:C) was recorded in 68% of patients treated with prednisone alone, in 82% of those treated with dual therapy (prednisone and cyclophosphamide or azathioprine) and in 94% of those treated with combined chemotherapy (prednisone, cyclophosphamide and vincristine). Inhibitor eradication was more probably achieved by patients treated with IST than by those untreated at all; in addition, patients undergoing combination therapy had a lower risk of death. In the EACH2 study, first-line IST was evaluated in 294 patients: corticosteroids were given alone in 142 patients and combined with cyclophosphamide in 83; rituximab-based regimens were administered in 51 patients, 18 patients were treated with other regimens. Complete remission (CR) was defined as complete disappearance of inhibitor, factor VIII:C over 70%, IST stopped; stable CR was considered as persistent CR without relapses during follow-up. The median time to FVIII:C>70% and undetectable inhibitor in patients treated with corticosteroids alone were 32 and 34 days, respectively, while in those receiving corticosteroids and cyclophosphamide 40 days and 32 days, respectively. Complete remission was reached at a median time of 108 days in patients receiving corticosteroids alone and of 74 days in those undergoing corticosteroids and cyclophosphamide and CR rates were 58% and 80% in the two groups, respectively. Complete remission was obtained by 61% of patients treated with rituximab-based regimens. Relapses occurred in 18% of patients treated with corticosteroids alone, while in those receiving combined therapy or rituximab-based regimens in 12% and 3%, respectively; stable CR was recorded in 48%, 70% and 59% of each group, respectively. Underlying disease or sex did not affect the remission; age showed a moderate influence; on the contrary, baseline low inhibitor level (<16 BU/mL) and higher FVIII:C were significantly associated with faster inhibitor eradication and normalisation of FVIII:C level. At last follow-up (median 262 days), death rates were similar among the groups: 28% in patients treated with corticosteroids only, 33% in those treated with corticosteroids and cyclophosphamide and 20% in those treated with rituximab-based regimens; 4 patients receiving corticosteroids and cyclophosphamide died for sepsis due to the immunosuppression, one of them was neutropenic. Another study investigated prospectively standardised IST: 102 patients received prednisolone initially for 3 weeks; then oral cyclophosphamide was added if remission was not reached, (weeks 4–6); then rituximab was given with prednisolone (weeks 7-10) if lack of response. Partial remission (PR) was defined as FVIII:C>50%, no active bleeding, no haemostatic drugs for 24 h, CR as PR plus inhibitor absence, prednisolone tapered to less 15 mg/day and any other immunosuppressive therapy stopped; PR was achieved by 83% and CR by 61% of patients, respectively. The median time to PR and CR was 31 days and 79 days, respectively. Forty-eight % of the patients were alive in stable CR after a median observation time of 403 days. In resistant or relapsed patients, other therapeutic approaches have been experienced: cyclosporine alone or in combination with corticosteroids, mycophenolate mofetil or multiple immunosuppressive drugs, with variable results.[18,22] Based on the experience gained in congenital HA with inhibitor, immunotolerance induction (ITI) protocols has been proposed in very selected cases for inhibitor eradication: Budapest protocol and the modified Bonn-Malmo protocol (MBMP). However, these expensive procedures require ad hoc specialised clinical departments. High-dose intravenous immunoglobulins (IVIG), alone or in combination with corticosteroids, are no longer considered suitable for the inhibitor eradication.[1,8,89] Rituximab has been used since the early 2000s for the treatment of AHA: two reviews were recently published on its placement in the first-line therapy or subsequent lines. Both publications concluded that rituximab may be considered a safe and useful treatment for AHA, but that it should be placed on second-line therapy in resistant or relapsed patients after first-line treatment.[92,93] Rituximab is also effective in pregnancy-related AHA.[94,95,96]
Complications of IST are frequent and sometimes fatal: patients, especially if elderly, should be monitored for the occurrence of adverse events, particularly infections. In the UK study, sepsis occurred in 33% of cases and led to death in 12% of them; in the GTH-AH 01/2010 study, 54 infections were diagnosed in 37/102 patients, and 16/102 died from sepsis; in the SACHA registry death rate for IST was 12% and in the EACH2 study 4.2%. Complications of corticosteroid therapy include: increased blood sugar levels (12%), gastroduodenal ulcer (4%), muscle disorders (4%), and psychiatric disorders (3%).[8,43] After inhibitor eradication elevated levels of FVIII:C are often observed and constitute an independent thrombotic risk factor. In a recent study, a cohort of 111 AHA patients, followed for a median time of 25.6 months, was evaluated for relapse pattern. In 14% of them, one or more relapses occurred after remission obtained with IST. Median time from diagnosis and from the first remission to the first relapse was 13.4 months and 12.0 months, respectively. Underlying lymphoproliferative diseases were predictive of relapse; older age and male gender appeared to be more frequently associated with recurrence, while FVIII:C and inhibitor levels at diagnosis were not. Moreover, relapse was not associated with worse OS. The authors suggested that the patients should be followed up after remission for at least 2 years (Table 2).
|Table 2. Immunosuppressive treatment.|
Recommendations and suggestions derived from guidelines are summarised and listed below.
Diagnosis: suspect AHA when a sudden abnormal haemorrhage occurs in subjects, not on anticoagulation, without personal or family bleeding history, who show an isolated prolonged aPTT (absence of LA) and a mixing study consistent with an inhibitor. An unexplained prolongation of aPTT before surgery or an invasive procedure should always be investigated. However, in ̴ 30% of cases, only laboratory alterations occur. The diagnosis must be made by a Haemophilia Centre with expertise on coagulation disorders and management of inhibitors against coagulation factors. Test and monitor anti-FVIII inhibitor with Bethesda Nijmegen-modified assay. If treatment with rpFVIII concentrate is planned, test and monitor also anti-prFVIII inhibitors.
• Avoid invasive procedures: if necessary, they must be performed in a Haemophilia Centre or after consultation with it.
• Look for an underlying cause, or disease as soon as the diagnosis of AHA has been made. Treat any underlying condition.
• Treatment of bleeding. Start anti-haemorrhagic therapy in the presence of clinically relevant bleeding symptoms By-passing agents (APCC, rFVIIa) must be considered as first-line treatment; if the by-passing agent, administered initially, is ineffective, the other one should be tried at an early stage. Recombinant and plasma-derived FVIII concentrates and DDAVP should be reserved to patients with measurable FVIII:C levels and low inhibitor titre, but accurate laboratory monitoring is necessary; DDAVP is not recommended in the elderly. Porcine recombinant FVIII is also considered as first-line treatment, but its use should be reserved for highly specialised Haemophilia Centres. By-passing agents or rpFVIII should be used in the prevention of bleeding in the event of surgery or invasive procedure. In exceptional cases (very severe bleeding and lack of response to standard treatments), plasmapheresis and/or immunoadsorption, in combination with high doses of FVIII concentrates can be considered.
• Inhibitor eradication. All AHA patients should receive IST immediately after diagnosis. First-line treatment should be oral prednisone/prednisolone either alone or associated with oral cyclophosphamide: this approach allows to reach a CR (persistent undetectable inhibitor, <0.6 UB/mL, and levels of FVIII:C >70% and IST stopped) in 60-80% of cases, after a median time of 5-6 weeks. Rituximab can be considered as first-line therapy when standard first-line treatment is contraindicated. Second-line therapies should be attempted if a response to first-line treatment is not reached within 3-5 weeks: rituximab, alone or in combination with corticosteroids, if never given before, cyclosporin, mycophenolate mofetil or multiple immunosuppressive agents. At present, ITI does not appear to be an advisable therapeutic approach. The use of high-dose IVIG is contraindicated. Prognostic markers at baseline (FVIII:C >1% vs < 1% and inhibitor titre >20BU/mL vs < 20BU/mL) should be identified to optimise IST regarding the combination of corticosteroids with cyclophosphamide or other immunosuppressants such as rituximab for first-line therapy.
• Monitoring after response to IST: aPTT, FVIII:C and inhibitor titre must be monitored monthly within 6 months, every 2-3 months between 6 and 12 months, and every 6 months after 12 months.
• Thromboprophylaxis after response to IST: mechanical or pharmacological thromboprophylaxis in hospitalised non-bleeding patients is indicated when FVIII:C is over 50%, while subjects with prior need for anticoagulation or antiplatelet therapy can restart it at this moment. Patients showing very high levels of FVIII:C, during or after IST, should be evaluated for thromboprophylaxis.
• IST in children with AHA: there are no particular recommendations, given the low frequency of cases. Anti-haemorrhagic and eradication treatments are similar to those of adults.
• IST in pregnancy-associated AHA: prednisone/prednisolone must be considered as first-line therapy choice; cyclophosphamide and other alkylating agents must be avoided; rituximab is believed to be an appropriate second-line therapy.
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