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CHAPTER 124 coagulation, such as fibrinogen, prothrombin, and factors V, V+VIII,
Rare congenital deficiencies of plasma proteins involved in blood
INHERITED DEFICIENCIES OF VII, X, XI, and XIII, generally lead to lifelong bleeding disorders. These
disorders have been described in most populations with an incidence
COAGULATION FACTORS II, V, varying from one case in 500,000 for factor VII deficiency, to one case
in 2 to 3 million for prothrombin and factor XIII deficiency. How-
1,2
ever, their relative frequency varies among populations, being higher in
V+VIII, VII, X, XI, AND XIII regions where consanguineous or endogamous marriages are common,
partly as a result of increased high frequencies of specific mutant genes
in these inbred populations. Two large surveys were made by the
3–8
World Federation of Hemophilia (WFH; www.wfh.org) and the European
Flora Peyvandi and Marzia Menegatti* Network of the Rare Bleeding Disorders (EN-RBD; www.rbdd.eu), with
the aim of collecting epidemiologic data and providing information to
hemophilia organizations and treatment centers to reduce and prevent
SUMMARY complications of bleeding. Data collected by these surveys showed that
factor VII and factor XI deficiencies are the most prevalent rare bleeding
Rare bleeding disorders (RBDs), accounting for the 3 to 5 percent of patients disorders (RBDs), each accounting for approximately one-third of all
with abnormal hemostasis, include the nonhemophilia inherited deficiencies RBDs, while the rarest disorders are factor II (prothrombin) deficiency
and combined deficiency of factors V and VIII (Table 124–1). The sever-
of the coagulation factor II (prothrombin), factor V, combined factor V/VIII, ity of bleeding manifestations in affected patients is variable. The most
factor VII, factor X, factor XI, factor XIII, and fibrinogen. The prevalence of typical symptom, common to all RBDs, is bleeding from the mucosal
RBDs is variable, both the relative frequency among the different factors and tracts or at the site of invasive procedures; life- and limb-endangering
frequency in different regions of the world. The genetic transmission of these symptoms, such as umbilical cord and central nervous system bleeding,
disorders is usually autosomal recessive. Bleeding manifestations caused by recurrent hemarthroses, and soft tissue hematomas, occur with higher
these inherited deficiencies are of variable severity and usually related to the frequency only in some severe deficiencies. 9–15 Although heterozygotes
extent of the decreased activity of the particular coagulation factor. Usually, for the coagulation factor deficiencies usually do not manifest a bleed-
only homozygous and compound heterozygous patients are symptomatic, ing tendency, some cases of postdelivery and post–dental-extraction
although occasionally heterozygotes display a bleeding tendency. On the bleeding in heterozygotes for factor X deficiency have been reported. 16
whole, the most typical symptom, common to all RBDs, is the occurrence
of mucosal bleeding, while life-endangering bleeding, such as the central LABORATORY DIAGNOSIS
nervous system or umbilical cord bleeding, are more frequent only in the
some deficiencies, such as afibrinogenemia and severe factor XIII and factor The complexity of blood coagulation and the large number of proteins
X deficiencies, characterized by very low or undetectable coagulant activity. and nonprotein substances involved necessitate that a global test be
used to simply and reproducibly assess its function: the screening tests
Treatment of patients affected with the various coagulation factor deficiencies such as prothrombin time (PT) and activated partial thromboplastin
could be (1) on demand for spontaneous bleeding episodes, (2) after surgical time (aPTT) are the first step in evaluating patients reporting a clin-
procedures, and (3) for prevention (prophylaxis). Because of the rarity of these ical and family history of bleeding. The PT interrogates the extrinsic
disorders and the technical limitations of laboratory testing and the lack of coagulation pathway, its prolongation is indicative of the deficiency of
specific concentrates, a unified, evidence-based therapeutic approach to many factor VII; a normal aPTT is highly dependent on the intrinsic coagu-
such patients is not always clear. To overcome these limitations, new strate- lation pathway, so that its prolongation is indicative of deficiencies of
gies, such as the creation of global partnerships and networking between factors XI, VIII, IX, and XII. However, all patients homozygous or com-
treatment centers, have been developed to increase our knowledge and create pound heterozygous for factor XI deficiency have aPTT values longer
17
platforms for researchers and clinicians to exchange information. than 2 SD above the normal mean, while heterozygotes substantially
overlap the normal range. 17,18 Consequently, screening of patients for a
hemostatic abnormality prior to surgery (which is recommended for
Jewish patients because of the high prevalence of factor XI deficiency)
identifies patients with severe factor XI deficiency. The prolongation
Acronyms and Abbreviations: aPTT, activated partial thromboplastin time; of both the PT and aPTT indicates the lack of a factor belonging to
COPII, coat protein complex II; EGF, epidermal growth factor; ELISA, enzyme-linked the common pathway, including prothrombin, factor V or factor X.
immunosorbent assay; ERGIC, endoplasmic reticulum–Golgi intermediate com- However, patients with factor X deficiency harboring mutations that
partment; FFP, fresh-frozen plasma; GGCX, γ-glutamyl carboxylase; Gla, γ-carbox- cause a defect only in the tissue factor (TF) pathway will only display
yglutamic acid; LMAN, mannose-binding lectin; MCFD, multiple combined-factor a prolonged PT and their aPTT will be normal. Other patients who
deficiency; PAR, protease-activated receptor; PCC, prothrombin complex concen- carry mutations that only affect the intrinsic pathway activity of factor
19
trate; PPH, postpartum hemorrhage; PT, prothrombin time; TAFI, thrombin-activat- X, will exhibit a normal PT and prolonged aPTT. Abnormal results
able fibrinolysis inhibitor; TF, tissue factor; TT, thrombin time; VKORC1, vitamin K of either of these screening tests should be followed by mixing studies
epoxide reductase–oxidase complex. where equal amounts of patient plasma and normal plasma are mixed
and retested; the relevant test time is normalized in patients with factor
deficiencies, but is not corrected or only minimally corrected in patients
* The authors would like to thank Dr. U. Selighson and Dr. O. Salomon who wrote with factor inhibitors. In case of correction, specific coagulation assays
the chapter “Inherited Deficiencies of Coagulation Factors II, V, VII, X, XI, and are then performed to make the diagnosis of the specific factor defi-
XIII and Combined Deficiencies of Factors V and VIII and of the Vitamin K– ciency. To evaluate fibrinogen deficiency, all coagulation tests that
Dependent Factors” contained in the previous edition of this book. depend on the formation of fibrin as the end point are necessary; hence,

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