Treatment of bleeding
Principles
The majority (89%) of patients with acquired hemophilia present with bleeds [1]. Bleeds often constitute a medical emergency and can recur during treatment. In a British cohort, bleeding was the cause of death in 9% of the patients [2]. Approximately 70% of patients with acquired hemophilia require hemostatic treatment [3]. The choice of hemostatic agent and strategy is depending on the severity of the bleeding episode, patient characteristics as well as the availability of specific products. Severe bleeding is defined as life or limb threatening, bleeding in the central nervous system, deep muscles, or retroperitoneal bleedings. Haemoglobin <80 g/L or haemoglobin drop >20 g/L is also considered severe bleeding. Mild bleeding is muscle and subcutanous bleeds without any substantial effect of function and without causing significant anemia.
Patients with persistent inhibitors should be monitored even following the initial disease phase, since major bleeds can occur even after many months [2]. There is no consistent correlation between the titres of inhibitors or the residual factor level and the severity of the bleeding symptoms; thus, it is the phenotype, rather than the inhibitor titre, which should guide the choice of treatment [1,2]. Blood red cells, plasma and thrombocytes should be transfused as required for management of major bleeding episodes. Specific hemostatic products include bypassing agents and coagulation factor concentrates. The results from the EACH2 study in patients with AHA showed that bleeding control with bypassing agents were superior to FVIII and desmopressin (bleeding control 93.3% vs 68.3%; P = .003) [4]. Inhibitor titer, treatment monitoring and immediate availability should guide the decision [3].
See Table1 for an overview of products and dosing.
Bypassing agents
Two bypassing agents are commonly used in treating bleeds: FEIBA®, which is an activated prothrombin complex concentrate (aPCC), a plasma-derived, virus- inactivated product, containing small amounts of activated factors II, VII, IX and X and NovoSeven® which is recombinant, activated factor VII. The other activated factor VII (Sevenfact®) is not approved in Europe yet.
There is no conclusive data on whether one of those bypassing agents is superior, since both have showed comparable efficacy in controlling bleeds [2,4,5]. The initial choice depends therefore on factors such as availability and previous clinical experience. Combination treatment can be considered if monotherapy is inefficient [6].
aPCC (FEIBA®)
aPCC has been shown to be highly effective in treating bleeds. A retrospective analysis from a 10-year-survey in three tertiary medical centers included 34 patients with 55 bleeding episodes who received FEIBA® at a mean dose of 75 U/kg every 8-12 h. Complete bleeding control was achieved in 76 % of the severe and in 100 % in the moderate bleeding episodes [7]. According to the results from the EACH2 registry, FEIBA® as first-line treatment was administered at median initial dosage of 67 U/kg and was effective in 93% of the cases [4]. Treatment was well tolerated, with 4.8% of the patients suffering thrombotic episodes.
The French FEIBHAC registry included 34 patients with AHA who were treated with FEIBA® for a median duration treatment of 4 (2.2-8) days. The mean initial dosage was 75.4 U/kg ± 7.7 U/kg and hemostatic control was achieved in 88% of the bleeding episodes, whereas 6 serious adverse events (either thrombosis or events related to a potentially hypercoagulable state, such as disseminated intravascular coagulation [DIC] and low fibrinogen) were recorded [8].
In a recent Nordic study on 181 patients [9] FEIBA® was used twice as often as NovoSeven® as primary hemostatic treatment and showed superior efficacy. However, bleeds treated with NovoSeven® were more severe and the retrospective nature of the study did not allow for the usage of predefined response criteria. The significance of those results is therefore unclear.
There is no specific laboratory method for monitoring treatment with FEIBA®. The global hemostatic methods, such as thromboelastrography (ROTEM/TEG) and thrombin generation assays (TGA) have shown potential in the follow up and tailoring of treatment [10,11]. ROTEM/TEG is the method most often available in clinical practice and can therefore be used for monitoring the efficacy of treatment with FEIBA®.
Although systemic use of tranexamic acid concomitantly with FEIBA® has been previously not recommended, more recent studies have not shown that there is an increased risk of thrombosis [12]. Administration of tranexamic acid with FEIBA® is therefore not advised against, but it is recommended, whenever possible, to maintain an interval of six hours between administration of the products.
According to the results of one study [13], administration of low dose FEIBA® to 15 patients for a mean of 20.5 ± 17.6 days following remission after initial treatment, led to lower rates of bleeding relapse compared to the rest of the cohort (n=41) which did not receive prophylactic treatment. The authors reported no thromboembolic events. However, due to the small size of the cohort, no recommendation on secondary prophylaxis following remission can be given.
rFVIIa (NovoSeven®)
The optimal dosage of NovoSeven® in AH has not been defined. A dose of 90 µg/kg every 2-3 hours until hemostasis is achieved, is generally recommended to patients with congenital hemophilia with inhibitors.
Sumner et al. [10] reviewed 139 patients with AH who were treated with NovoSeven® at 124 non- surgical and 57 surgical situations. The dose regimens and length of treatment were similar for all patients with administration either as bolus injection (46-150 µg/kg at 2-24 h intervals) or continuous infusion (8-50 µg/kg/h). Most patients were treated for < 7 days. The overall clinical response was evaluated as excellent or effective in 74.7 % and partially effective in 13.7 %. Ten thrombotic events were recorded.
In the EACH2 registry, the median initial dosage of NovoSeven® was 90 µg/kg (84.71-102.86) at an initial interval of 3 hours, and a median number of 12 dosages/patient. Out of the 174 patients, 5 suffered a thrombotic complication (2.9%) [4].
A recent, single-centre study from China on 165 patients reported the usage of NovoSeven® to 13 patients, of which an overwhelming majority (12/13) achieved good hemostatic control. Since aPCC was not available in this area, no patients received FEIBA® [14].
Generally, tranexamic acid is added during treatment with NovoSeven®.
Factor Concentrates
FVIII concentrates may be useful in patients with FVIII autoantibodies. FIX concentrates may be useful in patients with FIX autoantibodies, which only occur rarely.
The success of treatment with factor concentrates is dependent on, above all, the inhibitor titre but also the severity and localization of the bleeding. Factor concentrates are generally not effective in patients with high antibody titres (>5-10 BU).
For AHA, recombinant factor VIII is recommended [1,4]. For a newly diagnosed patient with a moderate or severe bleeding, a high bolus dose of 100-200 U FVIII/kg may be used. Alternative dosages suggested by other studies are 20 U of factor concentrate for each BU, with an additional 40 U/kg and 90 U/kg every 2-3 hours [15] until bleeding control. According to the results of the EACH2 trial, the incidence of thromboembolic complications in patients treated with rFVIII was 2.9% [1]. FVIII and FIX concentrates may be administered intermittently or as continuous infusion.
Very high doses of FVIII concentrate should be avoided, as a risk of developing thrombosis cannot be entirely excluded, especially in elderly patients.
Porcine FVIII
Porcine plasma FVIII (pFVIII) concentrate is also available (Obizur®) and has been shown to be effective in increasing FVIII:C even at dosages 100 U/kg [16]. Due to its different sequence from human FVIII, porcine FVIII concentrate has lower risk of inactivation by inhibitors. Its main advantage is the possibility to monitor treatment response by routinely used FVIII:C measurements, although discrepant results in OSA and CSA assays that are not consistent, have been reported. There is also a significant variability in the response to the product, mainly dependent on pre-existing pFVIII antibodies and the appearance of such under treatment. In the initial study that led to registration of the product, a loading dose of 200 U/kg was used. In patients without anti-pFVIII, FVIII reached supra-therapeutic levels (>400 IU/dL) while patients with antibodies had normal or sub-therapeutic levels of FVIII [16]. This study also demonstrates that FVIII levels do not rise as rapidly in the first 24 h in patients with a pre-existing anti-pFVIII antibody as in those without, but therapeutic levels could still be achieved. To predict the response of therapy it is thus, advisable that an assay to measure anti-pFVIII is available. However, by using a lower loading dose (100 U/kg) and measure the FVIII in vitro recovery, the adequate dose of subsequent doses can be calculated. A practical limitation is the high number of vials needed per dose (28 vials to achieve a dose of 200 U/kg in a 70 kg person [17]).
Tranexamic acid
Tranexamic acid (Cyklokapron®, Tranon®) is an efficient inhibitor of fibrinolysis. It may be useful in prevention of bleeds in AHA, both as mono therapy in minor bleeds and as a concomitant treatment. Tranexamic acid should be avoided in bleeds from the urinary tract. Caution is advisable when treating patients with significant cardiovascular comorbidities. Rare cases have been reported with thrombotic microangiopathy, using bypassing agents in conjunction with tranexamic acid. There are no available data on the use of tranexamic acid in patients treated with emicizumab.
Desmopressin
Desmopressin (Octostim®, Minirin®) is a synthetic analogue of vasopressin, whichstimulates an endogenous release of FVIII, VWF and t-PA (tissue plasminogen activator). It has shown some effect in the treatment of minor bleeds [15] and could be considered as second line treatment if no other hemostatic agents are available to patients with low inhibitor titre (<5 BU) and minor bleeding episodes. However, due to inferior efficacy [4], it should not be used as first-line treatment.
Emicizumab (Hemlibra®)
Emicizumab, known as Hemlibra®, is a bispecific antibody that bridges FIXa to FXa independently of the presence of neutralizing antibodies against Factor VIII. In recent years, several case reports have described the use of emicizumab in AHA to efficiently prevent bleeding with few thromboembolic complications [18,19]. In Japan, the indication to use Hemlibra® in AHA was approved in 2022, based on the AGEHA study; JapicCTI-205151. In this study, the dosage of emicizumab differed from that given in congenital hemophilia A with the aim of reaching steady state (>30 µg/mL) and bleeding control more quickly. Even if the study only contained 12 patients (the oldest 92 years old), the authors concluded that the dosage regimen and completion criteria may have a favorable benefit-risk profile [20]. One asymptomatic venous thrombosis was incidentally detected. Further two open-label, single-arm, multicenter, phase 2-studies have been initiated, using the same dosing regimen: one in Europe (in Germany and Austria: The GTH-AHA-EMI trial) and one in North America. In contrast to the Japanese study, IST was discontinued in the European study during the 12-week treatment period [21]. The findings from the study on 47 patients (median age 76 years), indicated that emicizumab effectively prevented bleeding with low number of thromboembolic events, severe infections, and fatalities. Additionally, it suggested that IST could be deferred while patients are receiving emicizumab. The authors meant that this would be a benefit for high-risk patients, allowing them to wait starting IST until fit enough. One ischemic stroke occurred in week 20 (emicizumab was continued off-label because of low factor VIII activity at week 12). The patient had end-stage renal failure and a history of coronary artery disease. The North American study is still ongoing (NCT05345197).
Emicizumab does not have an approved indication from the European Medicines Agency for preventing bleeds in patients with AHA. Even so, the GTH-AHA Working Group has published consensus recommendations (based on experts from 16 hemophilia centers in Germany and Austria) to provide guidance to physicians on the use of emicizumab in AHA that follows the results from the clinical trials [22].
Recommendations for emicizumab treatment in AHA
Treatment regimen with subcutaneous emicizumab (Hemlibra®) 150 mg/ml follows the protocol of the AGEHA study: 6 and 3 mg/kg on days 1 and 2, then 1.5 mg/kg once weekly.
Lower or less frequent maintenance doses have been used in case reports after control of acute bleeding had been obtained with FVIII bypassing agents and may be considered if clinically motivated.
If bypassing agent aPCC (FEIBA®) has been used to treat bleeds before treatment start, this must be stopped 48 hours before emicizumab treatment.
In case of bleeding, bolus doses of rFVIIa (NovoSeven®) are administered.
Due to lack of data in previous trails, it is suggested to avoid concomitant use of tranexamic acid with emicizumab. If used, high precaution is warranted as this is an elderly population with high cardiovascular morbidity.
Treatment with emicizumab may be discontinued when remission is achieved.
There is no restriction regarding the initiation of IST.
Pregnant and breastfeeding women cannot be treated with emicizumab. For other contraindications, see also GTH-AHA-EMI trial (NCT04188639) before treatment start.
If emicizumab is initiated, it is important to ensure that the patient provides informed consent for off-label treatment.
For interference with laboratory assays, see paragraph 2.4 Specialized laboratory methods.
Local treatment
Immobilization of a limb may help to relieve pain and stabilize the clot. This should, however, be merely a temporary measurement since immobilization in combination with administration of (primarily) bypassing agents could increase the risk for thrombosis.
Ice bags on towels can be applied on muscle hematomas. Fibrin glue, spongostan and similar products can be used locally, e.g. after tooth extractions. Tranexamic acid can be administered locally, for example to treat epistaxis or oral bleeds. A solution of lidocainhydroklorid + nafazolin (⍺-adrenergic vasoconstrictor) may be used in mucous membrane bleeds. Rigorous and repeated clinical evaluations of the bleeds in order to assess progress or regress are required.
Pre- and perioperative management
Surgery or other invasive procedures should be avoided in patients with AH until the inhibitor is eradicated because of the risk of uncontrollable bleeds. If surgery is inevitably necessary, it should be undertaken with rigorous precautions. The surgeon must be familiar with operations on hemophilia patients and thorough surgical hemostasis should be applied.
Since there are no large studies on the pre- and perioperative management of patients with AH, recommendations are often extrapolated from studies on patients with congenital hemophilia with inhibitors. Bypassing agents are considered as first-choice agents for pre- and perioperative prophylactic treatment in patients with acquired hemophilia. The dosages are similar to those required for bleeding control and it is generally recommended to maintain the perioperative dosage for 48-72 hours for major surgery, followed by tapering down [23]. If bypassing agents are not available, administration of rFVIII/IX concentrate, intermittently or as a continuous infusion, would be efficient treatment if the levels of FVIII/IX are increased after injection (a test dosage should be administered prior to surgery in order to evaluate the effect). Porcine FVIII may also be considered after evaluating the in vitro recovery.
Factor concentrates or bypassing agents should be administered as soon as possible in severe manifestations associated with bleeding to avoid complications such as ileus or compartment syndrome, thus rendering invasive procedures unnecessary.
Recommendations for treatment of bleeding
Treatment of bleeding in patients with acquired hemophilia is optimally carried out at a specialist center or, if referral is not possible, following early consultation with a coagulation expert.
First line treatment:
Bypassing agents are recommended for severe bleeds.
Choice of agent depends primarily on availability and clinical experience. Upon treatment failure with one agent, it is recommended to use the other. When switching treatments, an interval of at least 3 hours (when switching from NovoSeven® to FEIBA®) and 6 hours (when switching from FEIBA® to NovoSeven®) is recommended. Combination treatment can be considered if monotherapy is inefficient.When reimbursed, emicizumab can be considered as prophylaxis for bleeding in patients with a bleeding phenotype as off-label use (for recommendations see Emicizumab (Hemlibra®).
Factor VIII concentrates in high dosages can be used as first line treatment in patients with AHA, if bypassing agents are not available and especially in patients with low antibody titres and if daily measurement of FVIII is possible.
Tranexamic acid can be used as concomitant treatment both in patients receiving bypassing agents and factor concentrates. In mild bleedings, tranexamic acid can be used as monotherapy or in combination with desmopressin.
Second line treatment:
Either factor concentrates or bypassing agents can be used as second line treatment, depending on the medication used as first line treatment.
Porcine FVIII is recommended if adequate bleeding control is not achieved on treatment with bypassing agents.