Clinical and laboratory observation

Intracranial hemorrhage in newborn and young infants with hemophilia+

Intracranial hemorrhage (ICH) is a severe complication that is relatively common among patients with hemophilia. This systematic review aimed to obtain more precise estimates of ICH incidence and mortality in hemophilia, which may be important for patients, caregivers, researchers, and health policy makers. PubMed and EMBASE were systematically searched using terms related to “hemophilia” and “intracranial hemorrhage” or “mortality.” Studies that allowed calculation of ICH incidence or mortality rates in a hemophilia population ≥50 patients were included. We summarized evidence on ICH incidence and calculated pooled ICH incidence and mortality in 3 age groups: persons of all ages with hemophilia, children and young adults younger than age 25 years with hemophilia, and neonates with hemophilia. Incidence and mortality were pooled with a Poisson-Normal model or a Binomial-Normal model. We included 45 studies that represented 54 470 patients, 809 151 person-years, and 5326 live births of patients with hemophilia. In persons of all ages, the pooled ICH incidence and mortality rates were 2.3 (95% confidence interval [CI], 1.2-4.8) and 0.8 (95% CI 0.5-1.2) per 1000 person-years, respectively. In children and young adults, the pooled ICH incidence and mortality rates were 7.4 (95% CI, 4.9-11.1) and 0.5 (95% CI, 0.3-0.9) per 1000 person-years, respectively. In neonates, the pooled cumulative ICH incidence was 2.1% (95% CI, 1.5-2.8) per 100 live births. ICH was classified as spontaneous in 35% to 58% of cases. Our findings suggest that ICH is an important problem in hemophilia that occurs among all ages, requiring adequate preventive strategies.

Intracranial hemorrhage in the neonatal period is an important clinical problem. Its importance relates to a relatively high frequency of occurrence, accompanied at times by serious neurological sequelae. Over the last decade there have been changes in the relative frequency of intracranial hemorrhage owing to changes in obstetric practice, such as increased vacuum-assisted delivery and reduced rotational forceps, as well as the improved survival of preterm infants with complex intracranial hemorrhagic lesions. Moreover, systematic neuroimaging studies in otherwise asymptomatic term infants have led to a new awareness of the incidence of more clinically benign forms of intracranial hemorrhage. In this chapter, an overview of neonatal intracranial hemorrhage and the basic elements of recognition are presented. Detailed discussion is devoted to subdural hemorrhage, primary subarachnoid hemorrhage, intraventricular hemorrhage of the full-term infant, and certain unusual, miscellaneous examples of neonatal intracranial hemorrhage.

Absolute values of reference ranges for coagulation assays in humans vary within the entire lifespan and confirm the concept of developmental hemostasis. It is known that physiologic concentrations of coagulation factors (F) gradually increase over age: they are lower in premature infants as compared to full-term babies, healthy children or adults. Here we demonstrate in a cohort of 1011 blood donors and in a group of 193 healthy pregnant women, that the process of developmental hemostasis proceeds in adults. During the course of pregnancy F and activation markers steadily increase until delivery with a parallel decrease noticed for protein S. From adolescents, young adults to the elderly there is a further increase of F, reaching significance starting between 35 and 50 years of age compared to younger subjects. Covering the entire lifespan FVIII and von-Willebrand-factor showed the lowest values in carriers of blood group “O”. Apart from pregnancy differences related to gender, pill users, smoking habits or the presence of thrombophilic variants were reported. Laboratory test results should be compared to age-related reference intervals when hemostatic defects are suspected to avoid misclassifications as being “healthy”, prone to “bleeding” or vice versa to “thrombosis”.

The presentation of a neonate with clinical bleeding symptoms commonly causes considerable anxiety to parents and treating physicians. Since inherited coagulation disorders are rare many children with persistently abnormal coagulation screens will have an underlying bleeding disorder. Apart from emergency cases a family history including a bleeding questionnaire is mandatory asking for the onset and/or severity symptoms of hemorrhage prior to laboratory assessment. The absolute values of reference ranges for coagulation assays in neonates and children vary with analyzer and reagent systems, but confirm the concept of developmental hemostasis, showing that physiologic concentrations of coagulation proteins gradually increase and are lower in premature infants as compared to full-term babies or healthy children. The evaluation should include global screening tests and a full blood cell count to rule out thrombocytopenia. As in adults a prolonged PT in neonates reflects decreased plasma concentrations of vitamin-K-dependent factors, whereas the prolonged PTT stems from decreased plasma levels of contact factors. When initial laboratory test results reveal abnormalities, as compared to age-related values, a stepwise diagnostic approach should be followed. In the bleeding neonate or infant that has no laboratory abnormality, FXIII and alpha2-antiplasmin activity should be assessed, and when primary hemostatic defects are suspected, platelet function should be further evaluated. Treatment options of a bleeding neonate vary according to the underlying medical condition.

Haemophilia is a well-known X-linked recessive bleeding disorder related to a deficiency of factor VIII. The aim of the paper is to point out the role of an early diagnosis in cases of intracranial bleeding, especially in neonates and to highlight the bad prognosis.

Three patients were included in the study from our prospective data. All had severe factor VIII deficiency (less than 1%).

The first of them was a newborn without familial history of haemophilia which presented with hypotonia and seizures after a delivery with vacuum. CT showed a subdural haematoma and MRI multiple ischemic lesions. Two months later, he died from a new intracranial haemorrhagic episode resistent to infusion of factor VIII related to development of an anti-factor VIII antiboby. The second neonate had no familial history more and experienced hypothermia and areactive mydriasis because of an acute subdural haematoma. He died eight days later of ischemic lesions in spite of a craniotomy. The third was a 5-month-old boy with a familial history. Physical examination revealed lethargy, seizure and a recent cranial perimeter increase. He underwent a craniotomy with a good result.

The authors stress the need for immediate factor VIII infusion and appropriate neurosurgical work-up. The rapid medical management is mandatory if morbidity and mortality are to be minimized.

L’hémophilie est une maladie récessive liée à l’X, bien connue due à un déficit en facteur VIII. Le but de ce papier était d’insister sur l’intérêt d’un diagnostic précoce dans les cas de saignements intracrâniens chez le nourrisson et de souligner le mauvais pronostic.

Nous avons colligé trois patients à partir de notre banque de données prospective. Tous avaient une hémophilie sévère (taux de facteur VIII < 1 %).

Le premier d’entre eux était un nouveau-né sans notion familiale d’hémophilie, qui présentait une hypotonie avec des crises après un accouchement par ventouse. Le scanner cérébral montrait un hématome sous-dural aigu et l’IRM de multiples lésions ischémiques. Deux mois plus tard, il mourait d’un nouvel épisode hémorragique résistant à la supplémentation en facteur VIII en raison du développement d’un anticorps antifacteur VIII. Le deuxième nouveau-né n’avait pas d’histoire familiale non plus et présentait une hypothermie et une mydriase aréactive unilatérale d’emblée en rapport avec un hématome sous-dural aigu. Il mourait huit jours plus tard malgré une craniotomie. Le troisième était un garçon de cinq mois avec des antécédents familiaux connus. L’examen clinique notait une somnolence, des crises cloniques et une récente augmentation du périmètre crânien. Une craniotomie était réalisée avec un bon résultat.

Les auteurs soulignent la nécessité de supplémentation immédiate en facteur VIII et d’un suivi rapproché neurochirurgical. Une prise en charge rapide est obligatoire pour réduire la morbimortalité.