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CHAPTER 123 hemorrhagic events. Prophylaxis is the treatment of choice and can prevent

HEMOPHILIA A AND disabling joint disease and other hemorrhagic events such that patients can
expect a relatively normal life span provided that adequate replacement ther-
HEMOPHILIA B apy is available. For patients with inhibitors, factor VIIa and factor VIII inhibitor
bypassing activity can be used to “bypass” the factor VIII or factor IX deficiency.
Both disorders are good candidates for gene therapy that may eventually lead
to their cure.
Miguel A. Escobar and Nigel S. Key

HEMOPHILIA A (CLASSIC HEMOPHILIA,
SUMMARY
FACTOR VIII DEFICIENCY)
Hemophilias A and B are the only two bleeding disorders inherited in a
sex-linked fashion. The gene for both disorders is on the long arm of the DEFINITION AND HISTORY
X-chromosome. Both disorders appear as otherwise clinically indistinguish- Hemophilia A is an X-linked hereditary disorder caused by defective
able hemorrhagic diseases of mild, moderate, or life-threatening severity. In synthesis of factor VIII. Hemophilia A is less common than von Wille-
the most-severe form, both hemophilias A and B are characterized by mul- brand disease (VWD; Chap. 126), but it is more common than other
tiple bleeding episodes into joints and other tissues leading to chronic crip- inherited clotting factor abnormalities. The estimated incidence of
hemophilia A is one in every 5000 to 7000 live male births. It occurs in
pling hemarthropathy and internal organ hemorrhage unless treated early or all ethnic groups in all parts of the world. 1
prophylactically with factor VIII or IX concentrates, respectively. Even though Sex-linked hemophilia was recognized at least as early as the
phenotypically similar, both diseases are genetically heterogeneous with more 2nd century, when a rabbi correctly deduced that sons of hemophilic
than 1000 mutations leading to the absence of or dysfunctional factor VIII or carriers were at risk for bleeding following circumcision. In the 19th
2
IX molecules that do not support normal thrombin generation nor adequate century, several authors noted the sex-linked inheritance pattern of the
fibrin clot formation. disease and ascribed the hemorrhagic episodes to delayed blood coag-
3
Despite similarities in hemorrhagic symptoms, there are major differences ulation. Morawitz developed the classic theory of blood coagulation,
between hemophilias A and B. Hemophilia A is about five times more common which recognized two major reactions: (1) conversion of prothrombin
than hemophilia B, and is caused by defects in the factor VIII gene, a large to thrombin by a tissue substance that Morawitz termed thrombokinase,
4
186-kb gene with 26 exons. A common mutation results from inversion and and (2) conversion of fibrinogen to fibrin by thrombin. In 1911, Addis
crossing over of intron 22 during meiosis. This mutation leads to severe hemo- demonstrated that thrombin formed more slowly in hemophilic blood
than in normal blood and that the defect could be corrected by small
philia, and because no factor VIII protein is made, these patients are prone amounts of normal plasma. However, he incorrectly theorized that
to developing antibody inhibitors to therapeutically administered factor VIII hemophilia resulted from prothrombin deficiency. As protein purifi-
that neutralize its coagulant function, making adequate therapy problem- cation techniques improved throughout the 1930s and 1940s, throm-
atic. Approximately 20 percent of severely affected hemophilia A patients bokinase was resolved into several distinct components. Brinkhous
5
develop such inhibitors, whereas only 3 percent or fewer of severely affected demonstrated that the prothrombin content of hemophilic plasma was
hemophilia B patients develop inhibitors against factor IX. About one-third of normal and that the basic defect in hemophilia was the delayed con-
the mutations in hemophilias A and B arise de novo at CpG “hotspots.” These version of prothrombin to thrombin. The defect could be corrected by
mutations are apt to occur in the germ cells of a maternal grandfather whose a fraction of normal plasma containing the antihemophilic factor, later
6
daughters will be carriers and whose grandsons will have a 50 percent chance named factor VIII. In 1947, Pavlovsky observed that when blood from
of having hemophilia. one patient with hemophilia was transfused into another patient with
Replacement therapy is available for both hemophilia A and hemophilia B a similar clinical phenotype, the prolonged clotting time in the recipi-
ent was corrected. At the time, Pavlovsky did not recognize that he was
patients. Safe, effective, and highly purified factor VIII and factor IX concen- dealing with two different types of hemophilia. This fact was recognized
trates derived from plasma or made by recombinant technology are available by Aggeler and coworkers in 1952, when they described a patient defi-
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for prophylactic therapy to prevent bleeding episodes or prompt treatment of cient in “plasma thromboplastin component”, a blood clotting factor
different from factor VIII. A deficiency of “plasma thromboplastin
component,” later termed factor IX, was identified as the cause of hemo-
philia B. A month later, Biggs and colleagues described a similar patient
whose surname was Christmas, thus the synonym “Christmas disease.”
8
Acronyms and Abbreviations: AAV, adeno-associated virus; aPTT, activated partial Hemophilias A and B are the only two hereditary clotting factor defects
thromboplastin time; BT, bleeding time; BU, Bethesda unit; CGA, cytosine, guanine, inherited in a sex-linked pattern, and they are clinically indistinguish-
adenine; CJD, Creutzfeldt-Jakob disease; COX, cyclooxygenase; CRM, cross-reacting able, although data suggest that on the whole, hemophilia B may be less
material; CT, computerized tomography; DDAVP, 1-desamino-8-d-arginine vaso- severe than hemophilia A. However, in an individual patient, the dis-
9
pressin, desmopressin; DVT, deep vein thrombosis; EACA, ε-aminocaproic acid; FEIBA, orders cannot be distinguished without a specific assay for factor VIII
factor VIII inhibitor bypassing activity; GLA, γ-carboxyglutamic acid; Ig, immunoglob- or IX.
ulin; PT, prothrombin time; PTC, plasma thromboplastin component (factor IX); RFLP, In 1964, a proposal to organize the growing number of coagulation
restriction fragment length polymorphism; TCT, thrombin clotting time; VWD, von factors into a cascade or waterfall mechanism was put forth by Davie
Willebrand disease; VWF, von Willebrand factor. and Ratnoff and by Macfarlane. 10,11 In this scheme, each zymogen clot-
ting factor was sequentially activated to a protease that subsequently

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