Short summary

Haemolytic anaemia is defined as anaemia due to shortened survival of red blood cells (RBCs).

In spite of the potential for negative health effects of the disorder, epidemiological studies of the long-term morbidity and mortality of chronic haemolytic anaemia are scant.

We will use these registries to track nationwide cohorts of patients with chronic haemolytic anaemia and compare their long-term morbidity and mortality with that of the general population.

The proposed studies will provide important novel insights into the health consequences of chronic haemolytic anaemia, to the benefit of this patient group.

Rationale

Haemolytic anaemia and haemolytic disorders are severe congenital and acquired chronic diseases that have a major impact on the patients' quality of life, morbidity, and mortality. The prevalence of particular types of haemolytic disorders varies geographically. With growing migrant populations, the prevalence of particular types of haemolytic diseases in the Western world has changed over time and these disorders have become a global challenge for health systems and economies. 

The red blood cell (RBC) or erythrocyte has a lifespan of approximately 120 days. Although a shortening of the RBC lifespan below 100 days is considered pathological, anaemia does not arise until the lifespan is below 50 days, or even 25 days, below which limit the bone marrow no longer can compensate with increased production of RBCs. In conditions with such a short RBC lifespan, chronic anaemia will arise. Pathological haemolysis can be detected by different blood tests - although no single test exists to establish the diagnosis. Chronic anaemia causes tissue hypoxia and stress to cardiac function, and also inflicts negatively on the function of others organs. Individuals with anaemia will most often suffer from fatigue, dyspnoea, impaired working ability and impaired cognitive performance. Moreover, anaemia has been reported to worsen prognosis and increase the cost of treatment of other diseases. However, it is important to recognize that haemolysis may also inflict negatively on health even when there is no anaemia. In such cases, haemolysis can lead to release of haemoglobin, which exceeds the corresponding concentration of the scavenging proteins haptoglobin and hemopexin, thus leading to extracellular haemoglobin. The extracellular haemoglobin scavenges nitric oxid (NO), and evokes an inflammatory vascular response leading to vasoconstriction, inflammatory processes, and a deregulated antithrombotic system. The decreased blood flow in combination with the increased inflammatory reaction also result in increased adhesion of red and white blood cells to the vascular wall. All these events may contribute to decreased oxygenation of tissues and thrombosis. 

The morbidity and mortality associated with certain diseases with chronic haemolysis has been previously investigated, e.g., paroxysmal nocturnal haemoglobinuria, sickle cell anaemia, and thalassemia. However, no previous epidemiological studies have investigated the morbidity and mortality of patients with haemolytic disorders in unselected populations. Furthermore, no population-based studies of the prevalence of haemolytic disorders exist. 

Another research area, which has received even less attention, are the possible health consequences of haemolysis without anaemia, e.g., in patients with milder haemolytic disorders such as hereditary spherocytosis, a disorder which is a relatively frequent haemolysis diagnosis in Denmark. The proposed studies will address the abovementioned gaps in our knowledge regarding patients suffering from chronic haemolysis, with or without anaemia. We recently demonstrated that identification of patients with chronic haemolytic anaemia in the Danish National Patient Registry is feasible and the validity of the coded diagnoses, both overall, and within specific haemolysis disorders, is sufficiently high for register-based studies. 

We intend to exploit the possibilities provided by this and other nationwide Danish registries to conduct a series of studies in which we will describe the epidemiology of chronic haemolytic anaemia in terms of prevalence, morbidity and mortality.

Description of the cohort

We will identify a cohort comprising all patients with a first-ever diagnosis coding of haemolysis through the Patient Registry. A matched cohort from the general population will be identified through the Civil Registration System.

Data and biological material

We will link information from the following registries for the purposes of our study:

• The Danish Civil Registration System (CRS)

• The Danish National Patient Register (Patient Registry) and Danish Psychiatric Central Research Register (DPCRR)

The Patient Registry contains information on all hospital contacts to public hospitals (inpatient data since 1977 and outpatient data since 1995). Data recorded in the Patient Registry include the CRN, dates of hospital outpatient visits, hospital admission and discharge dates, and up to 20 diagnoses coded by physicians according to the International Classification of Diseases, 8th revision (ICD-8) during 1977-1993 and 10th revision (ICD-10) thereafter.

• Cause-of-Death Registry (CDR)

The CDR contains information data on underlying and immediate causes of death for all deaths in Denmark since 1970.35 The cause of death will be grouped into categories based on ICD-8 diagnosis codes from 1970-1994 and ICD-10 diagnosis codes thereafter. We will retrieve information on immediate and underlying causes of death and date of death.

• Danish National Prescription Registry (Prescription Registry)

The Danish National Prescription Registry contains information on all prescription drugs dispensed at Danish community pharmacies since 1994. For each prescription along with the CRN, a full account of the dispensed product, including the anatomical therapeutic chemical (ATC) code is recorded.

• Statistics Denmark

We will use annually updated information from registries held by Statistics Denmark to establish each study subjects' educational level and income as proxies for socioeconomic status. 

Collaborating researchers and departments

Department of Neurology, Odense University Hospital

• Consultant, professor David Gaist, Ph.D.

Department of Psychiatry, Odense University Hospital

• Consultant, professor Kjeld Andersen, Ph.D. 

•  Adjunct Sören Möller, Ph.D.

Publications associated with the project

Positive predictive value of diagnosis coding for hemolytic anemias in the Danish National Patient Register Hansen DL, Overgaard UM, Pedersen L, Frederiksen H. Clinical Epidemiology. 2016 June 24;8:241-52. doi: 10.2147/CLEP.S93643. eCollection 2016.