What are inhibitors?

Inhibitors in haemophilia are antibodies that develop in response to the infused coagulation factor treatment when the immune system sees it as a foreign protein. This is a normal way the body detects and neutralizes potential threats, e.g. pathogens. When the infused coagulation factor becomes the target of that response, it is eliminated and thus, the replacement therapy stops working.
 
Incidence of inhibitors in people with haemophilia:

  • Haemophilia A: 25% to 50% develop inhibitors
  • Haemophilia B: 1,5% to 5% develop inhibitors
  • Women are also affected: 5% to 10% of type 3 VWD patients develop inhibitors
  • In moderate and mild haemophilia, inhibitors often neutralise the body’s own factor alongside with the infused factors, turning haemophilia from mild or moderate into severe.

 
Inhibitor development

  • Previously Untreated Patients (PUPs) are at the highest risk to develop inhibitors, especially within the first 150 exposure days (EDs) to a clotting factor concentrate(CFC);
  • A lifelong threat remains for Previously Treated Patients (PTPs), especially in connection with ageing, surgery, intensive treatment and change of treatment product.

 

Heterogeneity
In patients with severe haemophilia, the risk of developing inhibitors levels off after 50 exposure days. However, in mild and moderate haemophilia patients, the increasing number of exposure days can cause the risk of developing inhibitors to increase as well.
 

Prevalence

  • Approximately 1/3 of the patients develop so-called “transient” inhibitors that disappear without treatment.
  • In approximately 1/3 of patients, inhibitors can be treated with immune tolerance induction (ITI) therapy or patients can be “tolerised”.
  • In approximately 1/3 of patients, inhibitors are persistent and high titre. Those patients can be eventually reassessed for ITI.
  • If it is not possible to detect inhibitors in the tests, it does not mean that they have disappeared. The only way to check is to expose the patient to the coagulation factor concentrate again.

 
Risk factors
Some of the Previously Untreated Patients (PUPs) are at a higher risk of inhibitor development. The risk factors are:

  • Genetic (which coagulation factor, VIII or IX, is deficient; severity; type of gene mutation; family history; ethnicity; immune response);
  • Treatment (frequency and intensity of exposure to CFCs, context, type and structure of the product used).

The development of inhibitors at any moment in life is related to risk factors, such as ageing, surgery, intensive treatment and change of treatment product.
 
Clinical implications
Development of inhibitors can lead to life-threatening situations, irreversible joint damage and dramatically reduce the quality of life of the patients, both in the short and in the long term. Compared to haemophilia patients with no inhibitors, those with inhibitors are likely to experience:

  • More frequent and recurrent joint and muscle bleeding;
  • More severe bleeding without any traceable cause that may be life threatening;
  • Greater haemarthropathy in a larger number of joints;
  • More physical impairment and mobility difficulties;
  • Lower quality of life;
  • Higher impact of the condition on the family, social environment and school/ work.

 
Those affected by an inhibitor need to have prompt access to optimum treatment and multidisciplinary care delivered by trained experts.
 

Diagnosing inhibitors

  • Activated partial thromboplastin time (APTT) assay – a blood test that detects reduced activity of intrinsic pathway coagulation factors (including FVIII and FIX).
  • Bethesda assay (with Nijmegen modification) – a blood test that measures the titre or strength of inhibitor (lower than 5 Bethesda Units (BU) is a low-titre inhibitor; higher than 5BU is a high-titre inhibitor).
  • Routine testing is not always applicable. Tests should be carried out based on clinical symptoms, closely linked to the risk factors.
  • Relatively high percentage of false results, both negative (up to 5%) and positive (up to 32%), can be possible.
  • The state-of-the-art testing methodology/equipment is not always available in the local haemophilia treatment centre (HTC). In this case, the patient could ask to be referred to a laboratory in an expert centre, such as one of the certified European Haemophilia Comprehensive Care Centres (EHCCC) or European Haemophilia Treatment Centres (EHTCs).

 
More resources
There are some resources for further reading available on the websites of the WFH, the Canadian Hemophilia Society and the National Hemophilia Foundation of the USA.