16 Because each person with OI may have a different skeletal or extra-skeletal focus that causes fatigue, or in which fatigue may cause additional impairment, it is important to determine the extent of fatigue in OI compared to people without OI. Understanding the extent of fatigue in OI can be a valuable resource for quality of life interventions. Bleeding tendency In addition to clinically distinctive features, there are a number of complaints that are consistently mentioned by OI patients but are not clearly reflected in the literature. One notable complaint among these is frequent bruising. Frequent bruising can be a symptom of an underlying bleeding tendency 59. In well-known coagulation disorders, such as von Willebrand disease and haemophilia, an essential part of the coagulation cascade does not function properly 60 (Figure 1). Alongside the major known coagulation abnormalities, there is also a wide range of less obvious problems that can cause a mild bleeding tendency in both the coagulation cascade and the collagen in the vessel wall 61. Mild bleeding tendency is a well-known phenomenon in collagen disorders other than OI, such as Ehlers-Danlos. Bleeding tendency in Ehlers-Danlos is caused by a malfunction of fibrillin, which together with elastin forms an elastic fibre. These elastic fibres, together with other structures, form the basic meshwork for the connective tissue matrix 61. This connective tissue matrix has a direct interaction with coagulation factors and also provides strength to the capillary structure, protecting it from tearing during shearing forces. A similar mechanism could be underlying in OI. Diagnosing a mild bleeding tendency in OI can be a difficult task. In fact, bleeding problems occur frequently in the normal population without an increased bleeding tendency. Bleeding symptoms occur sequentially, sometimes with long intervals. Patients with a mild bleeding disorder may not consider the number of bleedings they experience as abnormal, as there is usually an inherited disorder at the basis of their disease. If several family members suffer from bleeding problems, it is less obvious that the bleedings are abnormal. In general practice, certain bleeding symptoms, such as heavy menstrual blood loss and epistaxis, are very common and are only recognized at a late stage as a manifestation of an underlying coagulation disorder. In coagulation disorders such as von Willebrand’s disease, the time lag to diagnosis is reported to be as long as 16 years 62. If a mild bleeding tendency is suspected, it remains extremely difficult to find an underlying explanation because not all the components of the complex coagulation cascade can be tested. This is why recent reviews emphasize the importance of a detailed bleeding history and family history 59,63. In OI, research into bleeding tendency began in the 1950s and was aimed at finding an explanation for the frequent bruising and significant bleeding tendency in OI as was reported in various case
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