Unusual Disorders of Hemostasis

Functional deficiencies of Hageman factor (Hage-man trait), plasma prekallikrein (Fletcher trait), and high molecular weight kininogen (Fitzgerald, Flaujeac, or Willimas trait) are all asymptomatic, although in each case a major defect in clotting is found in the laboratory. These disorders occur with equal frequency in both sexes, and are recessive traits, meaning that they must be inherited from both parents. Hageman trait and deficiencies of plasma prekallikrein and high molecular weight kininogen are all rare, and data concerning their prevalence are available only for Hageman trait, which, in Ohio, occurs in about 1 in 500,000 individuals. By contrast, a disproportionately high number of cases of Hageman trait have been reported from the Netherlands. No racial predilection for Hageman trait or deficiency of high molecular weight kininogen had been described, but deficiency of plasma prekallikrein appears to be more frequent in blacks and in individuals of Mediterranean extraction.

Hageman trait is a heterogeneous disorder; in most families, the plasma appears to be deficient in Hageman factor, but plasma in a few contains a nonfunctional variant of this clotting factor. A similar heterogeneity had been observed in plasma prekallikrein deficiency, with the plasma of those patients of Mediterranean origin containing a nonfunctional variant of plasma prekallikrein.

The hereditary deficiency of plasma thromboplastin antecedent (PTA or factor XI deficiency) is also inherited in an autosomal recessive manner. The hemorrhagic symptoms are usually mild; in women, excessive menstrual bleeding may be troublesome. Nearly all reported cases have been those of Ashkenazi (i.e., eastern European) Jews or Japanese, although cases in individuals of American black, Arabic, Italian, German, Yugoslav, Dutch, Scandinavian, English, Korean, and Asiatic Indian heritage have also been recognized. In Israel, as many as 0.1 to 0.3 percent of Ashkenazi Jews may be affected, and 5.5 to 11 percent may be heterozygous carriers. Similarly, in Ohio, at least 0.3 percent of Ashkenazi Jews have PTA deficiency, and at least 3.4 percent are heterozygotes.

Hereditary deficiencies of factor VII, Stuart factor (factor X), proaccelerin (factor V), and prothrombin are rare, and no racial or geographic distribution is yet apparent. An estimate of one case of factor VII deficiency per 100,000 has been made. A still rarer syndrome, the combination of factor VII deficiency and Dubin-Johnson syndrome (the latter a disorder of billirubin metabolism) has been described in Is raeli Jews of Sephardic origin, the patients coming from Iran, Iraq, and Morocco.

In each of these disorders, the deficiency appears in both sexes and is inherited as a recessive trait, and in a number of instances the parents have been consanguineous. In general, the basic nature of these functional deficiencies is variable. In some instances, the plasma of the affected individuals appears to be deficient in the factors, as shown in functional assays. In others, the plasma contains an incompetent variant of the supposedly missing factor. For example, patients functionally deficient in prothrombin may either be truly deficient in this protein, or their plasma may contain one or another variant, nonfunctional form of prothrombin (congenital dysprothrombinemia). A similar variability in the nature of functional deficiencies of factor VII and Stuart factor (factor X) has been detected. In one variant of factor X deficiency, first observed in patients in the village of Friuli in northeast Italy, Stuart factor could not be detected in the usual functional assays, but behaved normally when the venom of Russell's viper was added to the patients' plasma.

The symptoms of deficiencies of factor VII, Stuart factor, and proaccelerin (the last called parahemophilia) are variable, some individuals having hemorrhagic episodes comparable to those of severe hemophilia, whereas others are spared except in the event of severe trauma. In women, excessive menstrual bleeding may be a serious problem.

Disorders of fibrin formation are of peculiar interest. Patients with congenital afibrinogenemia (who have no detectable fibrinogen in plasma) may bleed excessively from the umbilicus at birth, and thereafter from injuries or surgical procedures. In addition, they may exsanguinate from relatively minor vascular injuries, and menorrhagia may be disastrous; yet they may have little in the way of spontaneous bleeding. Fortunately, cogenital afibrinogenemia is a rare recessive disorder, detected in both sexes, and only about 150 cases have been recorded to date. Often the parents are consanguineous. A milder form, congenital hypofibrinogenemia (in which the plasma contains small but measurable amounts of fibrinogen), has also been described in about 30 families, and some investigators believe that this is the heterozygous state for congenital afibrinogenemia, meaning that these individuals have inherited the abnormality from but one parent. In still other families, the concentration of fibrinogen in plasma is normal or only moderately decreased, but the fibrinogen is qualitatively abnormal. This disorder, congenital dysfibrinogenemia, occurs in both sexes and in successive generations; that is, it is inherited as a dominant trait. The affected individuals may be asymptomatic, detected only by chance, or they may suffer mild bleeding problems. Paradoxically, they may also sustain thrombosis. Over 100 families with dysfibrinogenemia have been described, and the molecular defect in each family is almost always unique.

Fibrin-stabilizing factor (factor XIII) deficiency is similarly rare; perhaps 100 cases have been described thus far. In some, plasma appears to be deficient in fibrin-stabilizing factor, and in others, plasma contains a nonfunctional variant of this agent. Patients with fibrin-stabilizing factor deficiency have severe bleeding problems beginning with the umbilicus at birth. The patients may die of central nervous system hemorrhage, and in women spontaneous abortion is frequent. Some evidence suggests that affected males are sterile.

Little information is available concerning a racial or geographic predilection for any of these disorders of fibrin formation, but the prevalence of fibrin-stabilizing factor deficiency in the United Kingdom is said to be 1 in 5 million.

Another disorder of great interest is the hereditary deficiency of alpha-2-antiplasmin. In this disease, which is inherited as a recessive trait, patients may have symptoms suggestive of severe classic hemophilia. Bleeding apparently results from the rapid dissolution of clots by plasmin, whose proteolytic activity is unchecked because of the deficiency of alpha-2-plasma inhibitor. Too few cases have been recognized to determine whether there is a geographic predilection for this disorder, but it has been reported in Japan, the Netherlands, Norway, the United States, and Argentina.

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