BLEEDING IN PATIENTS WITH HEMOPHILIA. CME#2

BLEEDING IN PATIENTS WITH HEMOPHILIA

Hemophilia includes bleeding epitomized by limb- or life-threatening bleeding symptoms, such as hemarthrosis, soft-tissue bleeding, muscle hematomas, retroperitoneal and intracerebral hemorrhage, and postsurgical bleeds. To some degree, the type and the site of bleeding are age dependent (owing to characteristic developmental milestones, such mouthing of objects and mobility) and severity of disease dependent. Neonates with severe hemophilia most commonly present with bleeding after circumcision but may also present with intracranial hemorrhage. In toddlers, bleeding from minor mouth injuries and intracranial and extracranial hemorrhages may occur after minor injuries. As the toddler starts to become more mobile, bleeding into soft tissues, such as buttock hematomas and muscle and joint hemorrhages, may become evident.

Kulkarni and colleagues [1]analyzed infants younger than 2 years of age and found that of 580 children with hemophilia studied, nearly 60% were diagnosed within 3 days of birth, 75% in the first month of life, and 90% by 8 months of age. The diagnosis was established earlier in infants whose mothers were known carriers (median, 1 day) or who had a documented family history (median, 2 days) than in those who presented with bleeding (median, 7 days) or whose maternal carrier status was unknown (median, 152 days). Postcircumcision bleeding was the most common site of first bleed (27.4%), followed by head bleeds in 17% (of which 36.4% had an intracranial hemorrhage).[[1]

Because hemophilia A and B are X-linked conditions, the disease occurs in males and is transmitted by females who may be heterozygous for the gene mutation. Historically, it was assumed that carriers were asymptomatic for bleeding; however, it recently has come to light that many carriers do experience bleeding symptoms. Hemophilia A and B carriers, even those with normal hemostatic levels (>40%), have an increased bleeding tendency, including prolonged skin bleeding, heavy menstrual bleeding, oral bleeding, and excessive bleeding after dental procedures and surgery.[2-4].  Additionally, Sidonio and colleagues[5] showed that carriers of FVIII or FIX deficiency enrolled in the Universal Data Collection project had a reduced mean joint range of motion compared with historic controls from the Normal Joint Study. The data from this study suggest that subclinical bleeding may occur as early as adolescence.

1. Kulkarni R, Soucie JM, Lusher J, et al. Sites of initial bleeding episodes, mode of delivery and age of diagnosis in babies with haemophilia diagnosed before the age of 2 years: a report from The Centers for Disease Control and Prevention's (CDC) Universal Data Collection (UDC) project. Haemophilia. 2009;15:1281-1290. Abstract
2. Olsson A, Hellgren M, Berntorp E, Ljung R, Baghaei F. Clotting factor level is not a good predictor of bleeding in carriers of haemophilia A and B. Blood Coagul Fibrinolysis. 2014;25:471-475. Abstract
3. Paroskie A, Oso O, Almassi B, DeBaun MR, Sidonio RF Jr. Both hemophilia health care providers and hemophilia a carriers report that carriers have excessive bleeding. J Pediatr Hematol Oncol. 2014;36:e224-e230. Abstract
4. Plug I, Willemse J, Rosendaal FR. Bleeding in carriers of hemophilia. Blood. 2006;108:52-56. Abstract
5. Sidonio R F, Mili FD, Li T, et al. Females with FVIII and FIX deficiency have reduced joint range of motion. Am J Hematol. 2014;89:831-836. Abstract

Hemophilia management guidelines CME .#1

INTRODUCTION

Hemophilia A and B are X-linked recessive disorders of coagulation characterized by deficiency of Factor VIII (FVIII) and Factor IX (FIX). Across all ethnic groups, the prevalence of hemophilia A is estimated to be 1 in 5000 males, and that of hemophilia B is 1 in 30,000.[ 1] It is estimated that hemophilia affects approximately 400,000 individuals in the world. Hemophilia A is more common than hemophilia B and represents 80% to 85% of the total hemophilia population. This article reviews the latest understanding of hemophilia and the significant progress that has been made in diagnosis and management during the past several decades.

CLASSIFICATION OF SEVERITY

The severity of disease is classified based on the residual plasma levels of circulating FVIII and FIX. The disease is classified as follows: severe if levels are <1%, moderate for levels of 1% to 5%, and mild for levels between 5% to 40% of normal.^[2] There are some limitations to this classification in that it does not recognize the clinical heterogeneity in bleeding observed in individuals with levels <1%.

It has been observed that 10% to 15% of patients with severe hemophilia as defined by factor levels may have a milder clinical profile.^[3] Additionally, this classification may not distinguish between the bleeding profiles of hemophilia A and B.^[4] Based on inpatient hospital admissions, factor consumption, and rates of joint arthroplasty, some reports suggest that hemophilia B may have a milder bleeding phenotype than hemophilia A,^[5-7] although a more recent study demonstrated that age at first bleed, age at first joint bleed, and age at first factor exposure were similar in patients with hemophilia A vs B.^[8] An additional issue that is unresolved is the classification of individuals with levels of 40% to 50%. Another important point that the current classification does not consider is the potential discrepancy between the 1- and 2-stage assays for FVIII (FVIII levels were lower with the 1-stage assay) in some patients with mild hemophilia A.^[9]

Despite these limitations, the current classification is widely accepted, and there is good correlation between age at diagnosis, age at first bleed/first joint bleed, and age at first treatment and the classification of disease severity based on circulating factor levels in most patients.^[ 10] In general, individuals with mild hemophilia bleed only in response to trauma, such as that experienced during surgery, tooth extractions, or major injuries, whereas patients with moderate hemophilia bleed excessively after relatively minor trauma, and those with severe hemophilia may bleed spontaneously or after trivial trauma.