Acquired Haemophilia: Review and Meta‐Analysis Focused on Therapy and Prognostic Factors

Abstract

Acquired haemophilia (AH) is a rare disease that occurs at a rate of approximately 1 person per million each year. Anti-factor VIII is the most commonly recognized autoantibody directed against a clotting factor, and is associated with bleeding complications that can be life threatening. These bleeding episodes, however, can be controlled when the correct diagnosis is made quickly and appropriate therapy is applied. Although the aetiology of this disorder remains obscure, about 40–50% of cases are associated with other conditions, mainly the post-partum period, underlying malignancies, drug administration or autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus. This article provides a succinct review of the clinical features, laboratory diagnosis, prognostic factors and therapeutic management of patients with AH. The bleeding pattern of AH patients is quite different from that observed in congenital haemophilia. The most common complaints are bleeding into the skin or muscles, haematuria, haematemesis or melaena and prolonged post-partum or post-operative bleeding (Green & Lechner, 1981; Morrison et al, 1993). Iatrogenic bleeding is also common, after attempts to insert intravenous lines or catheterize the bladder. Often the first indication of the presence of an inhibitor is persistent bleeding after a surgical procedure that defies all attempts to control blood loss (Boggio & Green, 2001). In contrast to patients with congenital haemophilia, haemarthroses are relatively uncommon. The reason for this variant bleeding pattern, however, is unclear (Hay, 1998). Severe or life-threatening bleeding occurs in more than 80% of patients, and some 20% die, either directly or indirectly related to the presence of the autoantibody. Deaths are more frequent during the first few weeks after its appearance (Green & Lechner, 1981). Patients are rarely diagnosed in the presymptomatic state via the discovery of a prolonged activated partial thromboplastin time (APTT). The APTT assay is a reliable screening test for factor VIII (FVIII) inhibitor detection as it is typically prolonged when FVIII activity decreases to 45% of the mean normal level or less. Furthermore, mixing studies with patient plasma and normal plasma will not normalize the APTT, and FVIII activity will be reduced. Weak autoantibodies, however, may not prolong the APTT unless the mixture is incubated for at least 1 or 2 h at 37°C (Boggio & Green, 2001). Of note, when high-titre FVIII inhibitors are present, activity of factors XII, XI and IX may be artificially depressed but, if the assays are repeated in increasing dilutions of patient plasma, the true level of the above-mentioned factors will emerge while the FVIII activity will remain at the lower levels (Pruthi & Nichols, 1999). The inhibitor can be roughly quantified using the Bethesda assay (Kasper et al, 1975), which measures residual FVIII after incubation of patient plasma with normal plasma for 2 h at 37°C. The Nijmegen modification of the Bethesda assay uses a buffered normal plasma and FVIII-deficient plasma, instead of buffer, to dilute normal and patient plasmas, thereby stabilizing FVIII activity (Verbruggen et al, 1995). This modification results in fewer false-positive results, although it is more expensive. Both methods, however, tend to underestimate the inhibitor potency because of its non-linear complex reaction kinetics, which often results in the persistence of low levels of FVIII after prolonged incubation (Hay, 1998). Indeed, the recovery and half-life of exogenous FVIII may be markedly reduced even in patients with low inhibitor titres (Morrison & Ludlam, 1995). Finally, the Bethesda assay can be modified to measure the degree to which an inhibitor inactivates porcine FVIII, in order to determine whether this product could be a viable therapeutic alternative (Kasper, 1991). In most patients, FVIII autoantibodies are idiopathic. However, the disorder is associated with other conditions in about 40–50% of cases, which mainly occur in relation to the post-partum period, autoimmune diseases, underlying malignancies and drug administration. The association between pregnancy and AH has long been recognized. The bleeding disorder usually follows pregnancy, most commonly 1–4 months after delivery, although cases appearing more than 1 year post partum have been described (Michiels, 2000). In addition, the inhibitor appears during pregnancy in 2·5–14% of patients (Solymoss, 1998; Michiels, 2000). The potency of the inhibitor is rather low in the majority of cases, with a median titre of about 20 Bethesda units (BU) (Hauser et al, 1995; Solymoss, 1998). This may explain why the natural history of pregnancy-associated AH is characterized in the majority of cases by a spontaneous disappearance of the inhibitor after a mean period of 30 months (Michiels et al, 1997; Michiels, 2000). Mortality rates also tend to be lower in this subgroup of patients, ranging between 0% and 6% (Hauser et al, 1995; Solymoss, 1998). It is advisable to evaluate all these patients for lupus or rheumatoid arthritis because a certain subset of patients might have one of these disorders, which would require a change in the therapeutic approach (Shobeiri et al, 2000). An important clinical issue regarding pregnancy-related inhibitors is its possible recurrence in subsequent pregnancies, which makes counselling of women with this profile essential. In this regard, results are conflicting and, although most series have found that inhibitors tend not to recur in patients who attain a complete remission (Coller et al, 1981; Michiels, 2000; Yee et al, 2000), Solymoss (1998) reported on three patients who had six subsequent pregnancies; four of these pregnancies (66%) had an anamnestic response of the inhibitor. FVIII inhibitors may be associated with additional derangement of the immune system such as rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, dermatomyositis and graft-versus-host disease after allogeneic bone marrow transplantation (Green & Lechner, 1981; Kessler, 2000). More rarely, AH is associated with organ-specific autoimmune diseases such as myasthenia gravis, multiple sclerosis, Graves' disease and autoimmune haemolytic anaemia (Hoyle & Ludlam, 1987; Sievert et al, 1996; Van den Brink et al, 2000; Meiklejohn & Watson, 2001). In contrast to post-partum inhibitors, rheumatoid arthritis patients usually have high-titre inhibitors that do not decline without therapy or with prednisone alone. The addition of an alkylating agent, however, results in the disappearance of the inhibitor in the majority of cases (Green & Lechner, 1981). Approximately 10% of patients with AH have an underlying malignancy, either solid or haematologic (Green & Lechner, 1981; Rizza et al, 2001). The association between AH and haematologic malignancies, especially lymphoproliferative disorders, is in line with the broad range of autoimmune phenomena that frequently complicate these conditions (Sallah et al, 2000). Nevertheless, the association between AH and solid tumours is not so clear. In fact, some authors consider that the appearance of FVIII antibodies in patients with solid tumours may well be a non-causal association as these neoplasms are common in elderly patients in whom AH usually appears (Hultin, 1991; Hay, 1998). To clarify this issue, Hauser & Lechner (1999) reviewed all 27 well-documented cases found in the literature in which FVIII antibodies were associated with solid tumours, and found that immunosuppressive treatment led to the disappearance of the antibody in the majority of cases, whereas removal of the tumour by surgery was successful in only one case. In keeping with this, they concluded that immunosuppression should be regarded as the front-line therapy in patients with cancer-associated FVIII inhibitors. Indeed, they found it unlikely that tumour treatment could effectively remove the antibody. Sallah et al (1998), nevertheless, reported five patients with AH and solid tumours who underwent tumour treatment with very different results. Three patients with early-stage neoplasms had treatment directed towards the inhibitor, which did not completely eliminate it, whereas surgical resection of the tumour or chemotherapy resulted in its complete eradication. Conversely, in the remaining two patients with metastatic carcinoma, the inhibitor persisted despite long-term immunotherapy. These results prompted the authors to perform a new review of the literature, and they found 41 cases of patients with cancer-associated FVIII inhibitors, including patients with solid and haematologic malignancies (Sallah & Wan, 2001a). In 22% of patients, the treatment of cancer led to the disappearance of the inhibitor, whereas the majority of patients who failed treatment had an advanced or metastatic malignancy. The authors thus concluded that: (1) it seems reasonable to treat the primary malignancy in patients with cancer-associated FVIII inhibitors because it is easier to eradicate the antibody when the tumour is controlled; and (2) the presence of an underlying malignancy in a patient with a FVIII inhibitor should not be considered as a constraint against the use of immunotherapy to suppress the production of the antibody, even in those cases that fail to respond to treatment of the primary tumour. The decision to administer immunosuppressive agents in these patients should, nevertheless, take other factors, such as age, type of malignancy and severity of bleeding, into consideration. Despite the fact that it is difficult to relate any illness specifically to a drug in elderly patients, many of whom are on a range of medications, certain agents including antibiotics (penicillins, sulphonamides, chloramphenicol) and anticonvulsants (diphenylhydantoin) have well-established associations with AH (Green & Lechner, 1981; Morrison et al, 1993; Bossi et al, 1998). Frequently, drug-induced anti-FVIII arises after hypersensitivity reactions and remits shortly after withdrawing the offending drug. However, the pathophysiology of this phenomenon remains unknown. On the other hand, the strong immune properties of both interferon (IFN) alpha and fludarabine may explain the appearance of autoantibodies against FVIII and other immune phenomena reported with their use (Tiplady et al, 2000; Sallah & Wan, 2001b). The two main goals of AH treatment are to arrest bleeding and to eradicate the inhibitor. The first objective is necessary because bleeding episodes are usually relentless and can be life threatening. The second objective is required to restore normal haemostasis and may be accomplished using some type of immunotherapy. The management of acute bleeding episodes in patients with AH is complicated by the lack of prospective studies evaluating the different therapeutic modalities and the variable response to these approaches. One important principle to consider is the prevention of risk situations for bleeding. Severe bleeding can occur from trivial injuries, intramuscular injections, intra-arterial blood sampling and any invasive procedure, all of which should be avoided. Drugs that interfere with platelet function, such as aspirin or non-steroidal anti-inflammatory agents, should also be avoided. The choice of therapeutic agents depends on the severity of bleeding and the inhibitor titre. Ideally, the most effective treatment is one that will increase the plasma FVIII level sufficiently to control bleeding. Several strategies, such as desmopressin, human FVIII (hFVIII) or porcine FVIII (pFVIII), may raise the FVIII level. If the inhibitor titre is high (> 5 BU), or bleeding continues despite infusions of hFVIII or pFVIII concentrates, FVIII bypassing agents, such as activated prothrombin complex concentrates (APCC) or recombinant factor VIIa (rFVIIa), may be used. During the last two decades, desmopressin (1-deamino-8-δ-vasopressin, DDAVP) has been demonstrated to be effective in both mild haemophilia A and von Willebrand's disease (VWD) (Mannucci et al, 1977). The intravenous infusion of 0·3 µg/kg to a normal person produces a two- to threefold increase in FVIII and von Willebrand factor (VWF) plasma levels. This release of endogenous stored FVIII protein could overcome or neutralize the inhibitor in patients with low-titre inhibitors, usually < 3 BU (De la Fuente et al, 1985; Vicente et al, 1985; Chistolini et al, 1987; Mudad & Kane, 1993). Another possible action mechanism for this agent is a desmopressin-induced increase in VWF, which may block the FVIII autoantibody by inhibiting the binding of FVIII to VWF (Boggio & Green, 2001). Desmopressin, however, is only effective in a few patients with low inhibitor titres (< 3 BU), and a trial of desmopressin in patients with high inhibitor titres or with severe bleeding only delays the use of more effective approaches. Large doses of plasma-derived or recombinant hFVIII may be useful in patients with inhibitor titres under 5 BU (Morrison & Ludlam, 1995; Cohen & Kessler, 1996). The dose of hFVIII needed to neutralize a circulating inhibitor and provide FVIII haemostatic levels [0·3–0·5 international units (IU)/ml] can only be predicted roughly from the inhibitor titre because of the variable kinetics of these autoantibodies. The recommended dose is 20 IU/kg for each BU of inhibitor plus 40 additional IU. The plasma FVIII level should be determined 10–15 min after the initial bolus and, if it is not adequate, another bolus should be administered (Kasper, 1995). Another approach is to administer an initial bolus of 200–300 IU/kg followed by continuous infusion of about 4–14 IU/kg/h (Blatt et al, 1977). Some authors double or triple the dose of hFVIII that should be given to a haemophiliac of the same weight without inhibitor and often find beneficial clinical responses despite poor post-infusion assay results (Ekert et al, 1979; Rizza & Matthews, 1982). As expected, the half-life of hFVIII administered to patients with AH cannot be predicted. Autoantibodies are extremely difficult to saturate by the addition of antigen (FVIII); therefore, hFVIII therapy must be closely monitored and the dosage adjusted or discontinued depending on plasma FVIII levels. Porcine FVIII concentrates (Hyate:C®) have been used extensively for the treatment of bleeding episodes in patients with both auto- and alloantibodies (Morrison et al, 1993; Hay et al, 1996). The degree of homology between hFVIII and pFVIII means that pFVIII can function haemostatically in humans, whereas the critical epitopes recognized by human autoantibodies are often sufficiently different to achieve high levels of circulating FVIII. These facts provide the rationale for the therapeutic use of pFVIII concentrates (Hay, 1998, 2002; Pruthi & Nichols, 1999). An anamnestic rise in the antihFVIII inhibitor titre has been reported to follow for 25–35% of patients with congenital haemophilia treated with pFVIII (Gatti & Mannucci, 1984; Kernoff, 1984; Hay et al, 1996). Nevertheless, in a multicentre survey, only 15% of patients with AH increased their antihFVIII inhibitor titre after treatment with pFVIII (Morrison et al, 1993). The pharmacokinetic profile of pFVIII is unpredictable in patients with AH. Close laboratory monitoring is therefore recommended to adjust the dose according to plasma FVIII recovery and clinical response. The initial dose of pFVIII can be calculated using this formula: plasma volume (ml) × antiporcine antibody titre (U/ml) (neutralizing dose) + desired FVIII coagulant activity (FVIII:C) increment × body weight (kg)/1·5 (augmenting dose) (Gatti & Mannucci, 1984). If the antipFVIII inhibitor titre is unknown, 50–100 IU/kg pFVIII concentrate should be given to patients whose antihFVIII antibody titre is < 50 BU. In patients with inhibitors titres between 50 and 100 BU, pFVIII can be administered at a dose of 100–200 IU/kg (Kernoff, 1984). In the largest reported series of patients with AH treated with pFVIII, a good or excellent response was observed in 78% of patients, whereas the response was partial and poor in 11% and 9% of patients respectively (Morrison et al, 1993). The average dose was 90 IU/kg repeated every 12 h. It is generally believed that pFVIII recovery in vivo, monitored by ex vivo assays of plasma FVIII activity, provides a guide to response and cost-effective dosing, usually in the range of 1 U/ml. Over time, pFVIII levels may decline as antibodies develop against the porcine protein, rendering the patient resistant to this agent. Interestingly, the kinetics of pFVIII alloantibodies are similar to those appearing in haemophiliacs treated with hFVIII (type 1 pattern) (Green et al, 1999). The main adverse events associated with pFVIII administration are allergic reactions and thrombocytopenia. The incidence of transfusion reactions is low (about 3–7% of infusions) and mainly dose related (Hay et al, 1996). The risk of reactions may be reduced if the product is given by continuous infusion (O'Gorman et al, 2001; DiMichele et al, 2002; Hay, 2002). The fall in platelet count, which has been attributed to porcine VWF contaminating the concentrate (Altieri et al, 1986), is usually mild and of no clinical significance unless large doses of pFVIII are administered several times a day (Gringeri et al, 1991; Hay et al, 1996; Hay, 2002). The incidence of thrombocytopenia depends on the monitoring frequency and dose of pFVIII. This complication may also be reduced by the administration of pFVIII via continuous infusion, which suggests that this might be the preferred way of administering this product (O'Gorman et al, 2001; DiMichele et al, 2002; Hay, 2002). Activated prothrombin complex concentrates (APCC) have been used extensively in the treatment of bleeding episodes in patients with FVIII inhibitors (Kurczynski & Penner, 1974). The products in most widespread use are FEIBA® and Autoplex®. The composition of Autoplex® has been examined recently (Lundblad et al, 1998), and the major components are activated factor IX (FIXa) and FVIIa with small amounts of FXa, FXIa and thrombin. This suggests that, after its infusion, FXa and thrombin are rapidly inactivated by antithrombin, whereas FXIa and FIXa generate additional FVIIa, which may be the main active component (Turecek et al, 1999). The composition of FEIBA® has also been examined, and similar FVIIa, but lower FIXa, concentrations were found compared with Autoplex® (Roberts, 1999). Although there are some reports about the use of APCC in AH (Söhngen et al, 1997; Ji et al, 1998), most of the experience has been gained in patients with congenital haemophilia and inhibitors (Lusher et al, 1980; Hilgartner & Knatterud, 1983; Negrier et al, 1997; Penner, 1999). In a French study, FEIBA® was administered to 60 patients with FVIII inhibitors, six of whom had autoantibodies (Negrier et al, 1997). The product was considered effective in 81% of bleeding episodes. Doses averaged 70 IU/kg every 8–12 h and generally did not exceed 200 IU/kg/d (Negrier et al, 1997). Furthermore, excellent results were obtained in 13 of 17 patients receiving Autoplex® at doses 50 although doses were generally 1999). The recommended dose for both products is IU/kg/d in doses (> 200 have been associated with adverse events et al, 1983; & 1977). Indeed, in a of adverse events with three patients with AH and respectively et al, 2002). has to be and the dose adjusted to the clinical response because there are no laboratory assays that with response (Hay, 1998). FVIIa has demonstrated clinical in patients with congenital haemophilia and inhibitors et al, 1996; et al, 1998; Negrier & 2000). The haemostatic mechanism is by the of a complex between factor and FVIIa, after several results in the of thrombin & 2001). might of on the of activated In fact, thrombin could be on the activated platelet by the addition of doses of even in the of FVIII or IX et al, 1998; et al, 1998; 2001). In an alternative action mechanism on concentrations of may overcome the by thrombin in the of FVIII et al, 2000). The dose of has not been Although patients reported by Hay et al a range of doses 90 µg/kg every second range there was no in the of treatment between and A of of given every other is the recommended The half-life of this product half-life in such frequent infusions et al, episodes are usually treated with two or three but the treatment of major may for several infusion is a new of administration et al, 1998; et al, 2001; et al, with a in the of the product and the haemostatic response 2001). The most experience with the use of in patients with AH from Hay et al The authors treated bleeding episodes with The average dose of was 90 µg/kg every h for a median of and the median of doses was was used as and of patients had good and partial responses when the agent was given as the response rate was patients who did not respond h were unlikely to respond if treatment was (Hay et al, 1997). has good and few However, there have been some reports of clinical and in patients receiving & 1999). the experience of patients receiving more than doses of has been (Roberts, 2001). events rarely, and most could be attributed to in the clotting mechanism rather than a of the (Roberts, 2001). Nevertheless, the association of with administration of the drug makes patient monitoring necessary when using this agent. of are its high and the lack of monitoring The of post-infusion prothrombin time and levels has been for monitoring the of although haemostatic levels have not been 1996; et al, 2000). therapy of FVIII inhibitors is at the of the autoantibody or the of the for its Despite the fact that to of patients who do not experience a spontaneous of their autoantibodies et al, this is and the patient remains at risk as long as the antibody (Green et al, 1993). As attempts to the disappearance of these inhibitors are in the of the have been used to antibody production even often of the reports and the of controlled clinical makes of Furthermore, the choice of immunosuppressive agents should take into the of the the bleeding complications and the titre of the antibody (Pruthi & Nichols, 1999). given at doses of 1 the inhibitor in of patients (Green & Lechner, 1981; et al, 1981; et al, but the addition of may increase this response rate to (Green et al, 1993; & 1997; et al, 1999). on the the of prednisone and has been the of treatment for many However, other such as prednisone with (Söhngen et al, or prednisone with and et al, have also In the of A has been used either or in with as a therapy et al, 1996; et al, 1998; et al, 2000; et al, 2000). The successful use of intravenous in patients with AH was first reported by et al is attributed to the presence of antibodies in the although in some patients, the inhibitor level may that there is also of antibody In a prospective multicentre on the of in patients with the response rate was et al, although some of these patients also other In a subsequent literature review of patients treated by with no other immunosuppressive therapy was more in that the complete response rate was only et al, 1996). the of is and clinical results are to a first choice for the of FVIII autoantibodies. removal of the antibody may be when a is especially in cases of severe bleeding. Several have been such as et al, 1981; et al, et al, and to protein A et al, or antibodies against human et al, 2001). these have effective in this clinical but, with few et al, 1998; et al, they are with immunosuppressive and their is very difficult to In fact, as these do not to the time to they should be used in association with immunosuppressive agents in order to long-term and inhibitor with hFVIII concentrates are used in patients with congenital haemophilia and FVIII alloantibodies et al, 2000). In are rarely, if in with AH. A few authors have administered a of hFVIII concentrate and immunosuppressive agents in order to eradicate the inhibitor et al, & 2000). The rationale this approach is that intravenous hFVIII infusion will the for anti-FVIII antibody and thus more and effective of these by et al treated 12 patients with and prednisone after with hFVIII and a was obtained in of 12 Nevertheless, the same authors have recently reported very similar results in a series of six patients treated with without FVIII infusion, that without FVIII might be as good as with FVIII et al, 2002). On the other hand, & administered and to patients with AH and compared their results with six treated with Although were not a time to and a lower were observed in the Finally, hFVIII was administered to three patients with FVIII autoantibodies who had failed to respond to different immunosuppressive agents et al, 2000). In one the FVIII inhibitor and the FVIII level increased from < to months after of FVIII administration. However, these results are and studies will be needed to the true of these authors have that AH is associated with a high which between and 22% (Green & Lechner, 1981; Hay et al, 1997). However, few have that most of these patients are very and have other which may or may not be related to the FVIII inhibitor et al, 2001). the majority of these patients immunosuppressive agents, which are associated with multiple in this & 1995). of this, that AH should be considered not only as a but also as a disorder with an increased which is mainly therapy few studies have In their et al treated three patients with and two of from et al treated 12