Intracranial Hemorrhage: A Devastating Outcome of Congenital Bleeding Disorders—Prevalence, Diagnosis, and Management, with a Special Focus on Congenital Factor XIII Deficiency

Abstract

Intracranial hemorrhage (ICH) is a medical emergency. In congenital bleeding disorders, ICH is a devastating presentation accompanied with a high rate of morbidity and mortality. The prevalence of ICH is highly variable among congenital bleeding disorders, with the highest incidence observed in factor (F) XIII deficiency (FXIIID) (∼30%). This life-threatening presentation is less common in afibrinogenemia, FVIII, FIX, FVII, and FX deficiencies, and is rare in severe FV and FII deficiencies, type 3 von Willebrand disease and inherited platelet function disorders (IPFDs). In FXIIID, this diathesis most often occurs after trauma in children, whereas spontaneous ICH is more frequent in adults. About 15% of patients with FXIIID and ICH die; the bleeding causes 80% of deaths in this coagulopathy. Although in FXIIID, the bleed most commonly is intraparenchymal (> 90%), epidural, subdural, and subarachnoid hemorrhages also have been reported, albeit rarely. As this life-threatening bleeding causes neurological complications, early diagnosis can prevent further expansion of the hematoma and secondary damage. Neuroimaging plays a crucial role in the diagnosis of ICH, but signs and symptoms in patients with severe FXIIID should trigger replacement therapy even before establishment of the diagnosis. Although a high dose of FXIII concentrate can reduce the rate of morbidity and mortality of ICH in FXIIID, it may occasionally trigger inhibitor development, thus complicating ICH management and future prophylaxis. Nevertheless, replacement therapy is the mainstay of treatment for ICH in FXIIID. Neurosurgery is performed in patients with FXIIID and epidural hematoma and a hemorrhage diameter exceeding 2 cm or a volume of ICH is more than 30 cm. Contact sports are not recommended in people with FXIIID as they can elicit ICH. However, a considerable number of safe sports and activities have been suggested to have more benefits than dangers for patients with congenital bleeding disorders, and are hence suitable for these patients.

Expression and CpG island methylation pattern of MMP-2 and MMP-9 genes in patients with congenital factor XIII deficiency and intracranial hemorrhage

“…Forty patients with congenital FXIII deficiency including 20 patients with ICH and 20 without ICH were recruited, as case and control groups, respectively. Diagnosis of ICH was done based on general clinical presentations of ICH and neuroimaging, as described previously (2). Clinical manifestations of the patients were assessed by an expert staff as well as a physician by physical examination and a structural questionnaire, at time of disease diagnosis, and six-month regular intervals.…”

“…It is activated in the final phase of the coagulation cascade and cross-links fibrin chains, resulting in a stronger clot. FXIII is a multifunctional protein with pleiotropic roles in mediating a wide variety of physiological and pathological processes including the wound healing, angiogenesis, embryo implantation, neoplasm, and cerebrovascular diseases [1,2].…”

Impact of Exercise/Sport on Well-being in Congenital Bleeding Disorders

“…This most often occurs following trauma in children, which is different to adults who experience spontaneous intracranial hemorrhage. 25,26,50 This lifethreatening complication makes it necessary that patients with severe FXIII deficiency are treated with primary prophylaxis. 25,36 Fortunately, FXIII has a long half-life; therefore, a FXIII concentrate administration every 4 to 6 weeks is sufficient to reach adequate levels of circulating FXIII and to prevent spontaneous bleeds.…”

“…However, it is mandatory to choose a safe sport, avoiding contact sports. 50 The rare bleeding disorders differ by the site and severity of bleeding. Currently, a specific clotting factor concentrate is not always available for all patients with rare bleeding disorders, with prophylaxis not always clearly recommended or available.…”

Editorial Compilation VI

“…Congenital FXIII deficiency is an extremely rare hemorrhagic disorder associated with a high rate of morbidity and mortality, including a high rate of intracranial hemorrhage. 20 The disorder is more frequent in Iran, especially in Khash, a city in the southeast of the country. As identified in the current report, the prevalence of FXIII deficiency in this city is 1 homozygote per 500 population (which is 4,000 times higher than the worldwide prevalence), with 3.5% heterozygotes.…”