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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 10  |  Issue : 3  |  Page : 88-93

Effect of tertiary prophylaxis with low-dose factor VIII in quality of life in adult patients with severe hemophilia A


1 Department of Hematology, Calcutta School of Tropical Medicine and NRS Medical College, Kolkata, West Bengal, India
2 Department of Hematology, NRS Medical College, Kolkata, West Bengal, India

Date of Web Publication14-Nov-2019

Correspondence Address:
Dr. Prakas Kumar Mandal
8C/1/N, Roy Para Road, Kolkata - 700 050, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/joah.joah_37_19

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  Abstract 

BACKGROUND: Hemophilia A, characterized by deficiency of factor VIII (FVIII), is an X-linked bleeding disorder. It is graded as mild, moderate, or severe based on the FVIII level in plasma. Bleeding-related complications are often associated with severe form of the disease. Prophylaxis has now become the standard of care for severe hemophilia A patients.
OBJECTIVES: The study aimed to describe the effect of tertiary prophylaxis with low dose FVIII in quality of life in adult patients with severe hemophilia A.
SUBJECTS AND METHODS: A random 20 adult severe hemophilia A male patients aged 18–40 years with joint deformities, were included for this study. Long-acting recombinant FVIII, Fc Fusion protein (ELOCTATE, Biogen) was then given twice weekly at a dose of 15 IU/Kg/dose twice weekly for 3 months. Results were compared with the previous 3 months records of no prophylaxis. Efficacy was determined in terms of annualized bleed rate (ABR
) and absenteeism from work during this study period. Inhibitor screening was done at regular intervals during prophylaxis.
RESULTS: There was significant decrease in mean ABR along with absenteeism from work during prophylaxis as compared to on-demand therapy (3.6 bleed/year and 9.4 days/year compared to 37.8 bleed/year and 64.7 days/year, respectively). The mean FVIII requirement during prophylaxis (1560 IU/kg) was also less than the on-demand therapy (2150 IU/Kg/year). Majority (85%) had a FVIII trough level of <1%. Only one patient complained of myalgia while on prophylaxis. No inhibitor development was found in any of the individuals.
CONCLUSION: Low-dose recombinant long-acting FVIII prophylaxis can achieve a significantly lower bleeding rate in adult hemophilia A patients along with improved quality of life.

Keywords: Outcome, recombinant factor VIII Fc fusion protein, severe hemophilia A, tertiary prophylaxis


How to cite this article:
Mandal PK, Phukan A, Bhowmik A, Gantait D, Chakrabarti P. Effect of tertiary prophylaxis with low-dose factor VIII in quality of life in adult patients with severe hemophilia A. J Appl Hematol 2019;10:88-93

How to cite this URL:
Mandal PK, Phukan A, Bhowmik A, Gantait D, Chakrabarti P. Effect of tertiary prophylaxis with low-dose factor VIII in quality of life in adult patients with severe hemophilia A. J Appl Hematol [serial online] 2019 [cited 2019 Dec 13];10:88-93. Available from: http://www.jahjournal.org/text.asp?2019/10/3/88/271024


  Introduction Top


Hemophilia A is an X-linked inherited bleeding disorder due to deficiency of coagulation factor VIII (FVIII).[1],[2] The severity of hemophilia is classified depending on the patient's baseline plasma level of FVIII. Coagulation factor levels are often expressed as a percentage of factor activity or as international units (IUs). One IU is the amount of FVIII in 1 mL pooled plasma.[3] Severe hemophilia A is characterized by a FVIII level of <1% (1 IU/dL). The levels of F VIII between 1% and 5% (1–5 IU/dL) result in moderate hemophilia, and levels between 5% and 40% (5–40 IU/dL) are considered as mild hemophilia.[3] The hallmark clinical presentation of severe hemophilia A is excessive bleeding either spontaneously or after trivial trauma in the joints, soft tissue, muscle, or body cavity.

The bleeding-related complications are often seen in severe type of hemophilia A and results in absenteeism from work, increased mortality and morbidity, that finally leads to poor quality of life.[4] Annual cost of on-demand treatment of severe hemophilics is very high.

Factor replacement therapy with either plasma derived or recombinant FVIII is highly effective in controlling bleeding but has its limitations. Whether it is used for prophylaxis or on demand therapy, the hemostatic action has a finite time for its effectiveness; the therapy frequently requires repeat dosing.[5] The long-acting recombinant FVIII (with extended half-life) has remarkably changed the paradigm in hemophilia treatment.[6] With the availability of long-acting FVIII, there is increased patient adherence to prophylaxis due to reduction in repeated venous puncture. In case of tertiary prophylaxis of hemophilia, treatment is initiated after the onset of joint disease to prevent further joint damage and thus improve the quality of life.[3] A successful prophylaxis in hemophilia depends on various factors such as onset of prophylaxis, adherence to treatment, trough level of FVIII, and drug pharmacokinetics.[3]

Objectives

  1. To describe the characteristics of adult hemophilia patients
  2. To assess the effect of tertiary prophylaxis with low-dose FVIII in quality of life in adult patients with severe hemophilia A
  3. To assess the effect of long-acting recombinant FVIII Fc fusion protein in adult patients with severe hemophilia A.



  Subjects and Methods Top


The study was a prospective study conducted over a period of 6 months. A random 20 adult severe hemophilia A male patients were included for this study. All the patients were followed up in the institution on regular basis and those who are on regular follow-up for last 6 months were considered for randomization. Twenty patients were randomized over a period of 1 month and then followed up. The inclusion and exclusion criteria for the study were as follows:-

Inclusion criteria

  • Individuals with the age range of 18–40 years
  • All severe hemophilia A with FVIII of <1% without any inhibitors (Bethesda unit (BU) <0.5).


Exclusion criteria

  • Patients who already received long-acting recombinant FVIII earlier
  • Patients with detectable inhibitor level (BU >0.5) at the beginning of study
  • Previous history of hypersensitivity reaction with any FVIII concentrate.


Before starting prophylaxis, the individuals were followed up for a period of 3 months to determine their baseline characteristics such as the overall bleed rates, frequency of joint bleeds, and absenteeism from work and were recorded. All the individuals were screened for the presence of FVIII inhibitor before starting prophylaxis. Any bleeding episodes during this initial 3 months period were managed with long-acting recombinant FVIII replacement. The doses were determined as per the guidelines of World Federation of Hemophilia.[3] It is a prospective study, and the 3 months' reports are multiplied by factor 4 and we got the annualized factor consumption. The on-demand FVIII required during this period is then calculated as annualized factor consumption in terms of IU/kg/year. All the individuals were screened for the presence of FVIII inhibitor before starting prophylaxis.

None of the patients had received recombinant FVIII earlier. Long-acting recombinant FVIII, ELOCTATE (Fc Fusion protein) was then given intravenously twice weekly (Monday and Thursday) in the morning at a fixed dose of 15 IU/Kg/dose for next 3 months. Only for 2 patients [Table 1], patient number 3 and 10], there was difficulty with venous access; for them, butterfiy needle were used. All the patients were adherent to treatment protocol and used to attend the center on regular basis. Among them, 6 patients were trained on self-infusion.
Table 1: Demographic profile of the patients included in the study (n=20)

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The efficacy of the long-acting FVIII in the tertiary prophylaxis of adult severe hemophilia A patients is determined by annualized bleed rate (ABR) and absenteeism from work. The mean ABR and mean joint bleed rates were calculated. Total amount of FVIII needed during prophylaxis was also calculated. The results after 3 months of prophylaxis were noted and compared with their previous 3 months records of “on demand therapy.” Bleeding episodes were self-reported. If any bleeding occurred during prophylaxis, it was controlled by therapeutic dose as per the standard guideline.[3]

FVIII trough level testing was done for each and every patient who was on prophylaxis. The FVIII trough level for each patient was measured at least on three occasions during prophylaxis; samples were collected just before the next dose prophylaxis on Monday with a wash-out period of 96 h.

Patients were also looked for the development of any adverse reaction during the period of prophylaxis. Inhibitor screening was done in each and every patient at the end of 3 months of prophylaxis and as and when clinically indicated.


  Results Top


A total of 20 adult hemophilia A patients were included in the study. As shown in [Figure 1], the age of presentation and diagnosis ranged from 2 months to 10 years and number of joints involved from two to a maximum of six joints. As shown in [Table 1] against patient number 12 and 18, they presented and diagnosed late at the age of 8 years and 10 years, respectively, but had large number (five) of joint involvement. Majority of them had single target joint, but many others had more than one target joint. Only two patients skipped single dose during the study period. The average frequency of bleed in these patients was three times per month during the initial 3 months' period before starting the tertiary prophylaxis. Most of the patients had two to three episodes of bleed per month while some patients had recorded a bleed rate of four to five times per month. The mean overall ABR of the patients before staring prophylaxis was 37.8 bleed/year. However, after starting prophylaxis in these patients, the ABR was found to improve significantly. The mean ABR became only 3.6 bleed/year compared to 37.8 bleed/year found in the on-demand arm [Table 2]. The standard deviation of ABR in the 'prophylaxis' arm and 'off prophylaxis' arm were 0.788 and 3.213 with difference of standard deviation of 3.485 as shown in [Figure 1]. The bleeding characteristics were found to be almost similar in both the arms. Most of the bleeds were joint bleed in both the prophylaxis and on-demand arms. The mean joint ABR was also significantly improved, which was found to be 3.4 bleed/year in the “prophylaxis” arm compared to 36 bleed/year in the “on-demand” arm. Significantly, a total of eight patients (35%) experienced not a single bleeding episode during the 3 months' prophylaxis period.
Figure 1: Comparison of mean and standard deviation of annualized bleed rate of two arms

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Table 2: Outcome of “tertiary prophylaxis” versus “on demand” therapy of factor VIII

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A fixed low dose of FVIII 15 IU/kg/dose was used as prophylaxis in the study. As shown in [Table 2], the mean FVIII used during prophylaxis was found to be lower (1560 IU/Kg/year) as compared with the FVIII used during the on-demand period (2150 IU/Kg/year); however, the difference was not statistically significant.

The significant lower incidence of bleed during the prophylaxis period was also refiected in their quality of life. The mean absenteeism from work was found to be 9.4 days/year during prophylactic period. Whereas, it was 64.7 days/year during the on-demand arm [Table 2]. The standard deviation of absenteeism in the 'prophylaxis' arm and 'off prophylaxis' arm were 2.221 and 2.524 with difference of standard deviation of 3.531 [Table 2].

On further analysis of the FVIII trough level, it was revealed that 85% of the patients had a trough level of <1% [Figure 2], although majority of the patients in the cohort were nonbleeders.
Figure 2: Plasma trough level of factor VIII “on” and “off” prophylaxis

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Adverse reaction in the form of Grade 2 myalgia was documented only in one patient during the prophylactic period that subsided after short course of analgesics (acetaminophen). No patient had showed any clinical signs of inhibitor development also. None of the patient developed any detectable level of inhibitor (>0.5 BU) during and at the end of 3 months of prophylaxis.


  Discussion Top


In this study, for both prophylaxis and on-demand therapy, long-acting recombinant FVIII, ELOCTATE (Fc Fusion protein) was used for FVIII replacement therapy. Fusion of a biologically active protein to the Fc domain of human IgG facilitates binding of the protein to the neonatal Fc receptor (Fc Rn). Fc Rn is expressed in many cell types throughout life. Once the Fc-fusion protein binds to Fc Rn, it becomes protected from lysosomal degradation. When Fc-fusion proteins and IgG are taken up from circulation into cells by endocytosis, they interact with Fc Rn endosomes and are redirected back to plasma. This naturally occurring recycle pathway prolongs the half-lives of various biologics, including recombinant FVIII.[6] So with this product, patient has the option of lengthening the interval between infusions. It ultimately leads to both less frequent infusions and greater adherence to prophylaxis. Similar extended half-life products are now under study with PEGylation of recombinant FVIII.[7]

Decreasing the bleeding rate is the primary aim of prophylaxis in hemophilia patient. Prophylaxis results in a reduction in the frequency of hemarthrosis which protect joints from the development and progression of arthropathy. It also prevents bleed in the muscles, brain, genitourinary system, and other vital sites leading to improvement in the morbidity and mortality associated with the disease. In this study, we have achieved a statistically significant decrease in the mean overall ABR in the prophylactic period (3.6 bleed/year) compared to that of on-demand therapy (37.8 bleed/year) while comparing in the same patients. Other studies have also achieved a similar or more significant decrease in ABR with FVIII prophylaxis in both children and adult patients. However, in other studies, a higher dose of long-acting FVIII was used with a target to keep the FVIII level >1%.[7],[8] However, despite low dose of prophylaxis in our study, a significant overall improvement in bleed rate could be achieved. As shown in [Table 2], the mean FVIII used during prophylaxis was found to be lower as compared to the on-demand arm. Although the difference was not statistically significant, it indicates that the cost of the therapy can be reduced in long run. It is to be considered a very significant achievement considering the financial issues of resource constrains countries in the world, who cannot afford adequate supply of FVIII for regular use.

The bleeding characteristics were found to be almost similar in both the arms. Most of the bleeds were joint bleed in both the prophylaxis and on-demand arms. The mean joint ABR was also significantly improved with prophylaxis. It was found to be 3.4 bleed/year in the prophylaxis arm compared to 36 bleed/year in the on-demand arm. Studies from literature also showed similar pattern of bleeding in hemophilia prophylaxis regimens.[8] Significantly, a total of 8 patients (35%) experienced not a single bleeding episode during the 3 months of prophylaxis period.

The FVIII infusion was given regularly on Monday and Thursday in the morning hours which was found to be convenient for the patients. By giving Monday and Thursday dose, the maximum working days of the weeks were also covered in the patients resulting in improved productivity in them.

Besides the dose and the frequency of FVIII infusions, the individual pharmacokinetic is responsible for determining the time spent below a certain factor level and the trough FVIII level. Therefore, patients receiving the same factor dosage and regimen of infusions may show largely variable FVIII trough levels.[9] In this study, the trough level was checked after a wash-out period of 96 h. The samples were collected in the Monday morning considering the last prophylactic dose was received on Thursday morning. Interestingly, maximum number of patients, i.e. around 85% had FVIII trough level of <1%. However, despite such low FVIII trough level, a good control of bleeding episodes was achieved in most of the patients in this study. So the exact level of factors required to prevent break through bleeding is still needed to find out. On merely <1%, clotting factor concentration cannot always correlate well with the frequency of bleeding in an individual. Hence, more accurate measures and good knowledge of drug pharmacokinetics are needed to detect the actual FVIII level, which is adequate to prevent spontaneous bleeding in severe hemophilia patients.

During the prophylaxis period, there is a significant improvement in quality of life in the patients. There improvements can be expressed in terms of decrease in joint pain and joint pain related morbidity, decrease in absenteeism from work, and decrease in psychological fear of repeated bleed. There was also improvement in school attendance of the collegegoing students. Patients were able to maintain a normal daily routine works and also take part in some of the social activities. Aznar et al.[10] reported similar positive results achieved in their studies. The present study showed, the absenteesm from work during prophylaxis was 9.4 days/year compared to 64.7 days/years while they were on demand therapy. They were able attend their works regularly. As a result, quality and standard of life has automatically improved in these patients during prophylaxis. Again due to on regular prophylaxis, the patients can maintain their regular routine. School absenteeism has also decreased in the schoolgoing students.

As shown in [Table 2], FVIII requirement during prophylaxis in this study was indeed less than the amount of FVIII required for on-demand therapy, as also shown in studies by Aznar et al.[10] This may be due to the use of low fixed dose of factor in this study. FVIII dose used as prophylaxis in this study was 15 IU/kg/dose. The mean FVIII needed during prophylaxis was 1560 IU/Kg/year compared to 2150 IU/Kg/year on the “on demand arm.” This may be considered as an important outcome of this study as adequate FVIII availability is always an issue in most of the developing countries. Study by Collins et al.[11] used a much larger dose of FVIII for prophylaxis. As a result, there is greater requirement of FVIII during prophylaxis compared to on-demand therapy; thus, it incurs very high cost of therapy. Hence, in this study, with very minimum amount of FVIII, we were able to control bleeding in maximum number of patients. The total FVIII requirement during prophylaxis period, including both prophylactic dose and dose needed for break through bleed, was still low in the prophylactic arm.

As reported by Mahlangu et al.[6], the common side effects reported with long-acting recombinant FVIII were arthralgia and malaise. In our study, we have documented myalgia only in a single patient. That was of Grade 2 myalgia and responded to a short course of analgesic. No other side effect was noted in any patient during study period. A larger study population and a long-term study might help to establish the actual incidence of various side effects with these long-acting recombinant factors.

Inhibitor screening was done in all of the patients at the end of prophylaxis. Development of detectable level of inhibitor (>0.5 BU) was not seen in any of the cases at the end of this study. All bleeding during prophylaxis period were well controlled with FVIII infusion, and so, no patients needed inhibitor screening during that period. Some of the limited studies in literature also have found the same results.[7] However, these results cannot be interpreted as significant as the study period is very short. As per available literatures, most other studies had studied over a period of 6 months. Sidharthan et al. from South India studied with low-dose secondary/tertiary prophylaxis in children with hemophilia and showed a similar kind of promising result with FVIII prophylaxis.[12] In countries with financial constraints, there is inconsistency in regular and adequate supply of factors. Low-dose prophylaxis can be a feasible option to cover maximum number of patients with limited supply of factors. It definitely improves the quality of life in adult patients with less long-term complications. The results obtained from this study were really encouraging to us. The compliance was very good; this may be because of repeated counseling of the patients and close proximity of residence to healthcare facility. However, low number of patients, short-term of study, and institution-based prophylaxis are the limiting factors of the study.


  Conclusion Top


With tertiary prophylaxis even with a low dose, there is significant decrease in bleeding episodes despite a very low FVIII trough level. There is also a significant improvement on quality of life in terms of decreased joint pain-related morbidities and decrease in absenteeism from work. With the use of low fixed dose FVIII, mean factor consumption during prophylaxis was significant low, giving great hope to the patients with low socioeconomic status from countries with resource constraints.

Acknowledgment

The factor support to the patients included in the study was received from World Federation of Hemophilia Humanitarian Aid through Hemophilia Federation of India. Biogen Inc., Cambridge, MA 02142, donated the product (leveled as-Humanitarian use only; not for Resale) to the WFH.

Financial support and sponsorship

The factor support to the patients included in the study was received from World Federation of Hemophilia (WFH) humanitarian aid through Hemophilia Federation of India (HFI). Biogen Inc., Cambridge, MA 02142, donated the product (levelled as- Humanitarian use only; not for Resale) to the WFH.

Confiicts of interest

There are no confiicts of interest.

 
  References Top

1.
Hoyer LW. Hemophilia A. N Engl J Med 1994;330:38-47.  Back to cited text no. 1
    
2.
Mannucci PM, Tuddenham EG. The hemophilias – From royal genes to gene therapy. N Engl J Med 2001;344:1773-9.  Back to cited text no. 2
    
3.
Srivastava A, Brewer AK, Mauser-Bunschoten EP, Key NS, Kichen S, Llinas A, et al. Guidelines for the Management of Hemophilia. 2nd ed. Canada: Blackwell Publishing Ltd.; 2012. p. 41-7.  Back to cited text no. 3
    
4.
Ragni MV. Targeting antithrombin to treat hemophilia. N Engl J Med 2015;373:389-91.  Back to cited text no. 4
    
5.
Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, Kilcoyne R, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med 2007;357:535-44.  Back to cited text no. 5
    
6.
Mahlangu J, Powell JS, Ragni MV, Chowdary P, Josephson NC, Pabinger I, et al. Phase 3 study of recombinant factor VIII fc fusion protein in severe hemophilia A. Blood 2014;123:317-25.  Back to cited text no. 6
    
7.
Wynn TT, Gumuscu B. Potential role of a new PEGylated recombinant factor VIII for hemophilia A. J Blood Med 2016;7:121-8.  Back to cited text no. 7
    
8.
Sommer JM, Moore N, McGuffie-Valentine B, Bardan S, Buyue Y, Kamphaus GD, et al. Comparative field study evaluating the activity of recombinant factor VIII fc fusion protein in plasma samples at clinical haemostasis laboratories. Haemophilia 2014;20:294-300.  Back to cited text no. 8
    
9.
Collins PW, Blanchette VS, Fischer K, Björkman S, Oh M, Fritsch S, et al. Break-through bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment for severe hemophilia A. J Thromb Haemost 2009;7:413-20.  Back to cited text no. 9
    
10.
Aznar JA, García-Dasí M, Pérez-Alenda S, Marco A, Jaca M, Moret A, et al. Secondary prophylaxis vs. On-demand treatment to improve quality of life in severe adult haemophilia A patients: A prospective study in a single centre. Vox Sang 2014;106:68-74.  Back to cited text no. 10
    
11.
Collins P, Faradji A, Morfini M, Enriquez MM, Schwartz L. Efficacy and safety of secondary prophylactic vs. on-demand sucrose-formulated recombinant factor VIII treatment in adults with severe hemophilia A: Results from a 13-month crossover study. J Thromb Haemost 2010;8:83-9.  Back to cited text no. 11
    
12.
Sidharthan N, Pillai VN, Mathew S, Sudevan R, Viswam D, Joseph C, et al. Low dose secondary/tertiary prophylaxis is feasible and effective in resource limited setting in South India for children with hemophilia. Blood 2016;128:2336.  Back to cited text no. 12
    


    Figures

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    Tables

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