Comprehensive Pediatric Care of Rare Bleeding Disorders

Muriel Giansily-Blaizot; Jean-François Schved

Pediatr Health. 2010;4(2):209-217.

Abstract and Introduction

Abstract

Although less common than hemophilia or von Willebrand disease, inherited rare bleeding disorders, comprising afibrinogenemia and deficiencies in factors II, V, VII, X, XI, XIII or V plus VIII combined, or in vitamin K-dependent coagulation factors, may lead to severe bleeding episodes such as recurrent hemarthroses and neonatal intracranial or gastrointestinal hemorrhage. Consanguinity significantly increases the risk of the occurrence of all rare bleeding disorders that are associated with an autosomal recessive pattern of inheritance. Each of the disorders is characterized by a wide interindividual variation in clinical phenotype and a large mutational spectrum with no clear correlation between the phenotype and genotype. Replacement therapy relies on specific molecules or concentrates (afibrinogenemia, factor VII, XI and XIII deficiencies), on a mixture of different concentrates that are otherwise known as a prothrombin complex, which contains factors II, VII, IX and X, or on fresh frozen plasma. International consensus guidelines for treatment modalities are progressing; however, guidelines for prophylaxis, especially in pediatric patients, are lacking.

Introduction

Inherited rare bleeding disorders (RBD), including afibrinogenemia and deficiencies in factor (F) II, V, VII, X, XI, XIII or V plus VIII combined, or in vitamin K-dependent coagulation factor (VKDC), generally represent 5% of all inherited coagulation disorders^[1] with slight variations occurring between countries depending, in particular, on the prevalence of consanguinity in different racial groups. In that way, RBDs differ from hemophilia A and B where the prevalence appears to be similar in all races. The prevalence of RBDs ranges from one in 3,000,000 individuals for the rarest (VKDC or FXIII deficiency) to one in 300,000 individuals for the most common (FVII or FXI deficiencies) homozygous or compound heterozygous forms. All of the above disorders are transmitted in an autosomal recessive manner, implying that the heterozygous carriers are asymptomatic. This is true for the combined FV plus FVIII and VKDC defects where heterozygotes have normal clotting factor levels. Contrary to this, heterozygous carriers for the single deficiency RBDs generally display reduced levels of their respective factor. Those individuals are usually asymptomatic, but symptomatic heterozygous carriers have been widely reported with the FXI deficiency^[2] and mild bleeding features might also be observed in FII-, FVII- or FX-deficient heterozygotes.^[3–5] Nevertheless, the autosomal recessive trait implies that the risk of presenting with a RBD is increased where consanguineous marriages are common, explaining the aforementioned variable incidences between countries. In addition, there may be no preceding family history to suggest the diagnosis and an affected child may be part of a kindred with very few affected individuals – heterozygous patients usually being asymptomatic. As bleeding symptoms in children manifest in a manner that is distinct to those in adults, pediatricians and neonatalogists need to be aware of these differences and thoroughly investigate every unexpected bleeding event that presents early in life, since it may potentially represent early markers of severe inherited bleeding disorders. Indeed, the most severely affected patients often present with life-threatening hemorrhages within a few days of birth, including intracranial hemorrhages (ICHs) or gastrointestinal hemorrhages. Inadequate or delayed treatment of such neonatal bleeding may increase the risk of mortality or significant long-term disability. Later in life, recurrent joint bleeding may lead to the development of chronic arthropathy. Emphasis should be placed on early diagnosis, replacement treatment and prophylaxis. Two entire issues of the journals Haemophila (2008) and Seminars in Thrombosis and Hemostasis (2009) are devoted to the RBDs and are recommended for supplementary information.

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Table 1. Phenotypical and molecular characteristics and treatment modalities of each rare bleeding disorder.
Factor deficiency	Clinical features	PT	APTT	TCT	Mutational spectrum	Treatment	Ref.
Afibrinogenemia	Large heterogeneity Usual onset at neonatal period: bleedings of the umbilical cord, GI bleedings and ICHs Onset at a later age is possible (beware of spleen ruptures)	↑	↑	↑	Higher incidence of mutations in the FGA gene (compared with the FGB and FGG genes) There are two common mutations in Europeans in FGA: c.510 + 1G>T and 11-kb deletion	Fibrinogen factor concentrates either on-demand or in prophylaxis in cases of neonatal bleeding events	^[8]
Hypo-fibrinogenemia	Usually asymptomatic	Fibrinogen levels of approximately 1.0 g/lTCT is the most sensitive assay			Heterozygotes for afibrinogenemia mutations	Hypodysfibrinogenemia patients may sometimes need replacement therapy during surgery	^[8]
FII	FII:C <20%: spontaneous hemorrhage (ICHs and hemarthrosis) FII:C >20%: heterogeneous and moderate bleeding	↑	↑	N	Large heterogeneity^†	PCC or FFP	^[3–6]
FV	FV:C <20%: oral cavity bleedings (60%), epistaxis hematomas and hemarthroses (25%); ICHs and GI bleeding events are extremely rare FV:C >20%: heterogeneous, mucous membrane bleeding or asymptomatic	↑	↑	N	Up to 50 FV mutations have been reported (Tyr1702Cys is recurrent in Italy)^‡	FFP or platelets	^[29]
FV plus VIII	Provoked skin and mucous membrane bleeding events	↑	↑	N	Mutations have been found in LMAN 1 in two thirds of mutations Mutations have been found in MCFD 2 in a third of mutations	On-demand treatment with sources of both FV and FVIII In the absence of recommendations, hemostatic levels of 30 and 20% should be used for FVIII and FV, respectively	^[16]
FVII	Wide heterogeneity with a poor relationship between FVII:C levels and bleeding tendency ICHs (7%), hemarthroses (22%) and epistaxis (83%)	↑	N	N	Large heterogeneity, up to 250 mutations reported^§	Treatment is on-demand or prophylactic for early diagnosed patients and those with severe bleeding (newborns and children) using recombinant activated FVII or FVII concentrates when available; alternative therapy includes PCCs	^[30]
		Possibility of different FVII:C levels when measured with thromboplastins derived from various species (e.g., R304Q, R79Q and G331D FVII variants)
FX	The most severe rare bleeding disorder FX:C <2%: life-threatening CNS or GI hemorrhage 2% < FX:C < 15%: severe bleeding events, hemarthrosis and hematomaFX:C >20%: asymptomatic (70% of all cases) and provoked bleeding	↑	↑	N	Large heterogeneity (Gly[-20]Arg and Gly380Arg are recurrent in Latin America)^†	Freeze-dried FIX and FX concentrates (in some countries) or PCC or FFP	^[5,23]
FXI	Injury-related bleeding events Increased risk when local fibrinolytic potential is high (urogenital tract and oral cavity)	N	↑	N	See the Factor XI Deficiency Mutation Database^¶	FXI concentrates	^[2,31]
FXIII	Umbilical stump bleeding (80%), ICHs (30%), hematomas (27%) and impaired wound healing (14–29%)	Nx	N	N	Mutations have been found in both FXIII-A and FXIII-B genes^#	FXIII concentrate	^[7]
		Special screening test or FXIII activity assay
VKDC	Large heterogeneity ranging from fatal ICHs at birth to provoked hemorrhagic manifestations in childhood associated with antibiotic therapy leading to decreased gut vitamin K production	↑ Diagnosis can be delayed owing to the routine administration of vitamin K1 to newborns	↑	N	Mutations have been found in both VKORC1 and GGCX genes	Large heterogeneity in the responsiveness to oral or even parenteral vitamin K1 Where ineffective, factor replacement is mandatory (PCC or FFP)	^[32]

Percentage values in the 'Clinical features' column refer to the prevalence of the bleeds.
^†See the Coagulation Serine Protease Mutation Database.^[33]
^‡Mutation database available on request from h.l.vos@lumc.nl.
^§Mutation database available on request from m-giansily@chu-montpellier.fr.
^¶The Factor XI Deficiency Mutation Database is available at ^[102].
^#See the FXIII Registry Database.^[103]
↑: Prolongation of the corresponding clotting test. APTT: Activated partial thromboplastin time; C: Coagulant activity; F: Factor; FFP: Fresh frozen plasma; GGCX: γ-glutamyl carboxylase; GI: Gastrointestinal; ICH: Intracranial hemorrhage; LMAN 1: Leguminous mannose-binding lectin gene; MCFD 2: Multiple coagulation factor deficiency gene 2; N: Clotting test within normal ranges; PCC: Prothrombin complex concentrate; PT: Prothrombin time; TCT: Thrombin clotting time; VKORC1: Vitamin K epoxide reductase unit 1.

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