Causes of Death Among 379 Patients With Hemophilia: A Developing Country’s Report

Introduction

Inherited hemophilia A and B (HA and HB) are bleeding disorders with an X-linked pattern of inheritance that mainly affects men in all ethnicities worldwide. ¹ The prevalence of HA in developing countries is less than the international average. ² It has been reported that approximately 100 000 individuals with hemophilia live in 77 countries. ³ Individuals with HA and HB possess one of a variety of genetic defects in their factor VIII or IX genes. The hemorrhagic pictures of these afflicted persons can range from mild ecchymosis to fatal bleeding episodes in the central nervous system (CNS) that are nearly compatible with the severity of HA and HB. Although mild cases of HA and HB tend to involve bleeding events right after trauma, surgery, or tooth extraction, patients with moderate HA and HB bleed excessively after simple trauma. However, individuals with any severe type of hemophilia usually exhibit spontaneous bleeding and hemorrhage after minor trauma. Some researchers have proposed that HB may be less severe in their clinical aspects than HA ⁴ including the rates of joint arthroplasty. ⁵

Prior to the 1960s, the hallmark of individuals with hemophilia was the rarity of individuals surviving beyond the age of 60, mainly due to a decrease in life expectancy originating from lethal bleeding episodes. Hemophilia care was revolutionized after the 1970s, with the availability of factor VIII and IX concentrates. However, later the discovery of the hepatitis C virus (HCV) and HIV tragically damaged hopes, and defective concentrate products infected some patients with these blood-borne viruses. In 1986, thanks to the introduction of virally safe coagulation concentrates by the implementation of virucidal methods in the manufacturing process, individuals in the hemophilia community once again began to hope for a long, healthy, and active life. ^{6 –8}

Nowadays, given the improvement in coagulation concentrates, the life expectancy of individuals with hemophilia appears to be equal to that of individuals without hemophilia in developed countries. ^{9 –11} Furthermore, recent findings have demonstrated that prophylaxis regimens decrease bleeding, pain, the frequency and duration of hospitalizations, disability, and quality of life in the hemophiliac population. Several groups of researchers ^12,13 have hypothesized that there is an obvious link between the economic capacity of a country and the availability of the coagulation factors, diagnostic facilities, patients, care levels, and death rates due to bleeding disorders. These parameters can influence the difference in the rate and type of deaths among patients with hemophilia in various countries.

Iran, a large country in the Middle East, has a population of about 80 000 000 and is ranked ninth in the world for having patients with hemophilia. ¹³ Most of these current patients receive on-demand coagulation therapy. Moreover, all patients with bleeding disorders have access to national health insurance and receive relevant coagulation factor concentrates free of charge by the Ministry of Health. Among 31 provinces in the country, nearly all of them have comprehensive hemophilia centers, except for the 2 provinces (Ilam and Chaharmahal-o-Bakhtiari). In the cited provinces without hemophilia centers, patients refer to hemophilia treatment centers in adjacent provinces to access coagulation factor concentrates. The status of blood-borne viruses in patients with hemophilia has been fully addressed in the previous research. ^14,15

Determining the causes of deaths in patients with hemophilia is useful to health-care officials to develop and conduct plans to reduce mortality. Regarding the lack of any data on the causes of death among patients with hemophilia in Iran, it seems it is rational to focus on the causes of death in individuals with HA and HB. Hence, we have conducted this study in order to determine the common causes of death and their spectrum in the Iranian HA and HB populations.

Patients and Methods

We had access to the telephone numbers of 552 inherited bleeding disorder cases (both common and rare bleeding disorders), which included 287 cases with HA. Of these, 143 (49.8%) had severe hemophilia, 59 (20.6%) had the moderate type, and 85 (29.6%) had the mild type. There were 92 cases of HB, in which 43 (46.7%) of them had the severe form, 33 (35.9%) had the moderate form, and 16 (17.4%) had the mild form. ¹⁴ To achieve their goals, in March 2015 in the northeastern region of Iran, an epidemiological retrospective study was carried out on patients with both HA and HB.

The research council and national ethics committee at the Mashhad University of Medical Sciences approved the study’s protocol (no 922108) to determine the number and cause of deaths for those patients with HA and HB. After approval, we conducted a retrospective survey to assess additional information. An interview was carried out by the parents or any adult member of the family, regarding young children with hemophilia. The list of questions included name and family name of the dead patient, type of hemophilia (HA or HB), the severity of the HA and HB, the cause of death, patient’s age at the time of death, and the date of death. Hospital medical records were also referred when family members could not accurately remember and/or when they had doubts to answer to any of their questions.

One researcher collected the telephone numbers of all patients with hemophilia (house, workplace, and cell phone) from their registry of the patients and then called all 379 patients with hemophilia from Ghaem hospital in the Mashhad city (capital of Khorasan Razavi Province) to collect data and record the questions from the questionnaire that was administrated to the respondents. The duration of each call varied according to several factors, including whether the targeted patients were deceased, the level of education of the patients and their families, the presence or absence of the parents at the time of the call, and their recall of the exact answers. In the cases where the family was not certain of date or cause of death, medical records of the relevant patient recruited from 1 of 2 central hospitals (Ghaem and Imam Reza) were referred in order to complete the answers.

The rough data were entered into IBM SPSS Statistics 20 for Windows (SPSS Inc, Chicago, Illinois). The χ² test for independence was used to evaluate the relationship between HA and HB, as well as the cause of death, the severity of HA and HB, and the severity of HA and CNS bleeding. We categorize the causes of deaths, according to the International Classification of Diseases Version 10.

Results

Overview

Overall, among the 379 male cases of HA and HB, there were 46 deaths (the proportion of deaths was 12.1%). Among the 46 deaths, 30 hemorrhagic episodes (spontaneous and traumatic bleedings) were the main cause of deaths (65%). Additionally, 32 deaths (69.5%) occurred in those with the severe type of HA and HB; thus, the mortality rate was affected by the severity of the HA and HB (the P value = .01). Twelve deaths occurred in children aged below 10 years (26%) and 10 deaths occurred in males who were aged more than 50 years (21%; Figure 1). The leading infectious disease as a primary or associated reason for fatality was HCV, which was the cause of death in 5 (10.8%) cases, whereas HIV was the cause of death in 3 (6.51%) cases. Additionally, the overall mortality rate in patients with HA was approximately 7-fold higher than that for patients with HB with 40 (86.9%) death episodes in patients with HA versus 6 episodes (13%) in patients with HB (Figure 2).

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Figure 1.

The overall total number of deaths that have occurred in both hemophilia A and B in various age-groups with 5-year intervals.

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Figure 2.

The numbers of happened deaths in hemophilia A and B and their subtypes.

We did not encounter any patient who died due to the existence of inhibitors against coagulation factors VIII or IX. The mortality trend (due to the severity of the disease and age at which death occurred) has been shown in Figure 1. Additionally, the age range with the lowest mortality rate for severe HA and HB was 26 to 40 years. The lowest mortality age period for moderate and mild types of the diseases was 26 to 60 years in their region.

Hemophilia A

Among these patients, 40 (13.9%) deaths occurred in previous years (Figure 2). The youngest fatality with hemophilia was a 3-month-old neonate, and the oldest was a 60-year-old man. The mean of age of death was 17.17 years. The earliest death happened 64 years ago, and the most recent occurred 2 years ago. The mean time between deaths was 30.05 years. The death episodes can be divided according to the severity of HA as follows: 30 (75%) death episodes for the severe type, 6 (15%) episodes in the moderate type, and 4 (10%) episodes for the mild type. The causes of death included 11 (27.5%) episodes of CNS bleeding, 6 (15%) cases of posttrauma bleeding, 6 (15%) cases of various cancers (including 2 cases of lung cancer and 1 case each of hepatoma, brain tumor, larynx tumor, and ocular tumor), 4 (10%) cases of cirrhosis of the liver, 6 (15%) cases due to various uncontrolled bleeding, 3 (7.5%) cases due to HIV infection, 2 cases due to unknown causes, 1 (2.5%) case due to heart problems, and 1 (2.5%) case due to uncontrolled postsurgery bleeding. Although, among the 11 deaths that were secondary to CNS bleeding, 9 (81.8%) deaths occurred in severe patients with HA, and there was not a relationship between the severe type of HA and the frequency of CNS bleeding (P value = .540). Additionally, of the 11 events that were due to CNS bleeding, 7 (63.6%) episodes occurred due to posttrauma to the head, and 4 (36.3%) episodes occurred spontaneously (Figure 3). As expected, the mortality rate was higher in severe, moderate, and mild types, respectively (Figure 2). The highest death rates for severe HA cases was during childhood and after 45 years of age. Beside this, the mortality trend (Figure 4) shows that deaths are declining starting from about 2000 to now. Given that a hemophilia center has been established in their region in about 1990, there are no records of patients with hemophilia before that time at the center. After that time, new diagnostic facilities have provided a better diagnostic tool for patients with bleeding disorders. The lower death episodes before 2000 may be due to undiagnosed cases with hemophilia and a lower number of patients. Figure 4 also shows that after 2000, death trend tends to decrease despite the increasing number of patients in the group of individuals with hemophilia. It may be influenced by some factors, including better access to coagulation factor concentrates.

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Figure 3.

The causes and number of deaths in 6-year-interval periods in patients with hemophilia A and B.

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Figure 4.

The death trend in hemophilia A and B during the past decades.

Discussion and Conclusion

This retrospective study was carried out to evaluate the mortality rate in patients with HA and HB living in the northeast Iran (Khorasan Razavi Province), in order to mask the lack of any contribution in this geographic area in the medical literature regarding mortality rate in hemophilia. In the current study, 379 patients with hemophilia (287 patients with HA patients and 92 patients with HB) were interviewed and 46 episodes of death were identified in patients with hemophilia. Traumatic and spontaneous hemorrhagic events were the main causes of death.

The most common cause of death, in the group under survey, was spontaneous or posttrauma bleeding due to CNS. Given that the majority of the patients in the current group were an on-demand infusion of the relevant coagulation factors, ¹⁴ it seems prophylaxis regimens may be a useful therapeutic regimen in the prevention of CNS bleeding and deaths.

Many factors such as the availability of coagulation concentrates, self-knowledge of the bleeding disorder, ability for self-injection of the coagulation factors, age of the patients, the levels of awareness of the family about the entity of hemophilia disorder and bleeding symptoms, knowledge of the family about the way of infusing the coagulation concentrates, the quality of health services, and some other factors may influence the morbidity and the mortality rates in the patients with hemophilia.

The finding has shown that 6 (6.5%) deaths in the HB group in comparison with 40 (13.9%) deaths in the HA group is compatible with the recent report of Mannucci and Franchini who reported HB is less severe than HA. ⁴ The P value was .058, and the relationship was not statistically approved.

It has been ascertained that prophylactic therapy used in the early treatment of hemorrhagic episodes in patients with hemophilia is an effective method for the prevention of bleeding episodes. ^{16 –18} There were noticeable numbers of the fatal spontaneous CNS bleeding events in the surveyed patients with hemophilia. This may be due to limited access to the coagulation factor concentrates in their country in the past decades. The trend of deaths (both in causes of death and the number of occurred death; Figures 1 and 3) has shown a decrease in the number of deaths in the current decade that can reflect the better availability of coagulation concentrates despite the rising number of diagnosed cases in recent years. Cancer, as a cause of death, has been detected in recent years (Figure 3), and this may be due to the increase in life expectancy for patients with hemophilia in recent years, and improvement in detection techniques of cancer in the recent decade may be another influencing factor.

The existence of the inhibitor against any coagulation factor does not merely increase the rate of the hemorrhagic episodes, but it can exacerbate the intensity of the bleeding episodes and make control of the bleeding more complicated. ¹⁹ There are limited numbers of patients with hemophilia and inhibitors under prophylactic therapy, and the majority of patients with hemophilia are on-demand regimens in their region. ¹⁴ The on-demand approach program may cause fatal hemorrhagic episodes, subsequent episodes, and more cost for the patients with hemophilia and the health-care system.

A survey on 717 Dutch patients with hemophilia has revealed that individuals with hemophilia have a protection against ischemic heart disease, whereas it has been reported there are more cancer-related mortalities. ²⁰ There were 6 episodes of death due to various cancers, whereas in the current survey, there was only death due to heart problems. This may be relevant somehow to the fluctuation in the pattern of deaths among developed and developing countries. Given the numbers of patients, some of the conclusions about cancer and ischemic heart disease may not be statistically significant. A cohort with a large number of patients is needed to obtain meaningful insights.

These findings further support the several important considerations needed for better management of hemophilia care in the developing countries. First, fatal bleeding episodes (CNS bleedings) can be decreased noticeably by prophylaxis regimens. This requires improved resources to be devoted to hemophilia care centers by health providers and legislators. Second, given that traumatic bleeding was the most noticeable cause of death, it seems awareness of the patients and their families about the leading cause of bleeding episodes is a necessity. Educational programs seem beneficial for children and their parents to teach patients to void dangerous and traumatic situations.

The higher rate of death in childhood in their region may be due to many sporadic cases with no family history of hemophilia that might not be diagnosed at the early age of life. Among the current group under survey, there was an undiagnosed boy who died due to postcircumcision bleeding about 60 years ago. Second, in childhood, affected children do not have a complete understanding of hemophilia and its consequences, so they may further encounter hemorrhagic episodes. At older ages, multifactors, including hypertension, may facilitate the bleeding. Prophylaxis treatment regimens may be very useful in such situations, but owing to budget limitations, it is a problematic issue in the developing countries.

The very low number of deaths caused by cirrhosis and HIV is really an interesting finding in this survey. Although transmission of blood-borne viruses occurs in the multifactorial process, ²¹ some factors including cultural matters, lifestyle patterns, and scrutiny in the selection of blood donors may be among reducing causes of blood-borne infections. ²²

Most of the patients with hemophilia in their region are on-demand therapy, except the restricted cases who have an inhibitor against factor VIII. It has been shown that the development of inhibitors to factor VIII or IX in patients with hemophilia makes the control of bleeding episodes more difficult to manage and may increase the mortality rate in severe hemophilia cases. ²³ The patients with hemophilia in their region mainly have a low titer of inhibitors. ¹⁹ None of deceased patients with hemophilia in the current survey developed inhibitors; hence, none of the deaths can be attributable to the development of inhibitors. It is certain that the total 46 deaths, that have been reported here, is not the actual number of deaths among the hemophilia group in the region. In their study, we encounter the following limitations:

The authors only had access to the telephone numbers of 379 cases with HA and HB. There were other cases with HA and HB; however, their contact numbers have been changed and so we could not interview them. According to this, there may be other deaths that have been missed due to no access to the telephone number of all patients with hemophilia in the region.

In spite of these observations, it seems the rate of deaths can be decreased by better education and support programs.