Homozygous FVII deficiencies with different reactivity towards tissue thromboplastins of different origin.

The reagents most frequently used for FVII activity assay are obtained by rabbit brain or human placenta. In recent years, human recombinant thromboplastins have received great attention. FVII activity in FVII deficiency is usually low, regardless of the thromboplastin used. There are a few exceptions to this rule. These are represented by FVII Padua (Arg304Gln), FVII Nagoya (Arg304Trp), and FVII (Arg79Gln). In these three instances, clear discrepancies were noted in the FVII activity depending on the thromboplastin used. This indicates that at least two areas of FVII are involved in tissue binding, namely an epidermal growth factor domain of the light chain (Arg79Gln) and the catalytic domain (Arg304), controlled by exons 4 and 8, respectively. Since these three variants are cross reactive material positive, namely they are Type 2 defects, all other variants with normal antigen should be investigated by a panel of at least three tissue thromboplastins (rabbit brain, human tissue or human recombinant, and ox brain derived) in order to obtain a satisfactory classification.

Persistent validity of a classification of congenital factor X defects based on clotting, chromogenic and immunological assays even in the molecular biology era.

An adequate classification of congenital bleeding disorders is of great importance in clinical practice. This is true also for factor X (FX) deficiency. This defect is classified in two forms: type I (cases with low activity and antigen) and type II (cases with low activity and variable levels of antigen). The introduction of molecular biology techniques has allowed a classification based on the site of mutation (propeptide, Gla-domain, catalytic domain etc.) or on the type of mutation (missense, nonsense, deletion etc.). However, with a partial exception for defects in the Gla-domain, no site or type of mutation yields a constant and/or typical phenotype. Due to these difficulties, a classification based on clotting, chromogenic or immunological assays is still the most suited for clinical purposes. A satisfactory classification that takes into account recent advances of FX deficiency could read today as follows: • Type I (cross-reacting material (CRM) negative) (Stuart like) • Type II (CRM positive with inert protein) (Prower like) • Type III (CRM positive with disreactive protein) 1. Defects in all activity systems but for RVV activation (Friuli like) 2. Defects only or predominantly in the extrinsic-Xase system (Padua like) 3. Defects only or predominant in the intrinsic-Xase system (Melbourne like) 4. Defects with discrepant (high) chromogenic assays. Finally, type IV should be added to include cases of FX deficiency associated with FVII deficiency usually due to chromosome 13 abnormalities. By using this nosographic approach, all reported cases of FX deficiency can be adequately allocated to one of these groups.

Unexplained discrepancies in the activity--antigen ratio in congenital FX deficiencies with defects in the catalytic domain.

Studies on molecular biology have considerably enhanced our understanding of congenital coagulation disorders but have failed so far to supply tools for an adequate classification of defects. In fact, mutations in the same domain may give rise to different phenotypes. Conversely, mutations in different domains, controlled by different exons, may cause similar patterns. The 37 kindreds with congenital factor X (FX) deficiency, known to have a defect in the catalytic domain, have been evaluated in an attempt to investigate the genotype-phenotype relation. Discrepant results were obtained because about half kindreds showed a type I pattern, namely a concomitant decrease in FX activity and antigen. The other half showed a type II pattern, namely a decrease in FX activity with a normal or near normal FX antigen. In a few instances, the allocation of the kindred either to type I or to type II defect could not be reached, due to the lack of information about the antigen. The comparison of the kindreds in which the same mutation has been discovered by different investigations is not always possible also for lack of information. The study analyzes the need to have a multipronged approach to the study of congenital FX deficiency. The indication of a mutation in a given domain does not provide clear information about the phenotype.

Hemospermia in patients with congenital coagulation disorders: a study of three cases.

Hemospermia is usually a symptom of urological relevance, however it may have also a medical and hematological significance and has been reported in congenital or acquired bleeding disorders. Because of this symptom's negative psychological impact on the patient, it is likely that the condition is underplayed and therefore underdiagnosed. During the years 1967-2003 we had the opportunity to see 3 patients with hemospermia on a congenital bleeding disorder: a patient with hemophilia A, another with prothrombin deficiency and finally a patient with von Willebrand disease type I. All patients were heterosexual. In all instances the course was benign since it required administration of substitution therapy on only 2 occasions. Rest and abstinence from sexual activity appeared to be helpful. The first patient had other signs and symptoms compatible with the diagnosis of urethritis due to Escherichia coli and he underwent a course of antibiotic therapy. The other 2 cases appeared to be idiopathic since no associated condition was found. Urinary cytology, rectal examination, prostate sonography and prostate-specific antigen were normal in all cases. The rarity of hemospermia in congenital bleeding disorders remains unexplained, although the strong perineal and sphincter muscles may exercise a compressive hemostatic effect which could prevent or reduce bleeding.

Control of ovulation-induced hemoperitoneum by oral contraceptives in a patient with congenital hypoprothrombinemia and in another with congenital factor V deficiency.

Hemoperitoneum is a serious and often life-threatening bleeding manifestation. This is particularly true for women who carry congenital bleeding disorders. We describe here a hemoperitoneum occurring in 1 patient with congenital prothrombin deficiency and another with congenital factor V deficiency. Both patients have been followed by us for many years. The patient with prothrombin deficiency underwent laparoscopy but was treated consecutively with whole blood, plasma transfusions and 1,000 units of prothrombin complex concentrates. Response was good and she was then placed on oral contraceptives (OC) which prevented any recurrence. The patient with factor V deficiency presented several episodes of ovulation-related bleeding which required hospitalization and fresh frozen plasma transfusions. On the fifth occasion, the patient had to undergo surgery, and a left oophorectomy was carried out. After this last episode, she was also placed on OC which were very effective in preventing further recurrences. Both patients tolerated the medications very well which, in addition, were able to control menometrorrhagia with a consequent decrease over time in transfusional needs. OC are the treatment of choice in congenital bleeding disorders to control both the menorrhagia and, more importantly, ovulation-related hemoperitoneum.

Congenital FX deficiency combined with other clotting defects or with other abnormalities: a critical evaluation of the literature.

The presence of more than one congenital clotting defect in a given patient is a rare event but not an exceptional one. Combined defects of factor X (FX) are very rare because congenital isolated FX deficiency is by itself very rare. A perusal of personal files and of the literature has yielded 12 families with FX deficiency in which an association with another clotting factor deficiency was found. The associated defects were factor VII (FVII) or factor VIII (FVIII) or factor XII (FXII) deficiency. By far the most frequently associated was with FVII. Two forms of this association were found. In the first form there is casual association of both FVII and FX deficiency in the proband with independent recessive segregation of the two defects in other family members. The second form is because of abnormalities in chromosome 13 (deletions, translocations and so on) involving both FX and FVII genes. These genes are known to be very close and located on the long arm of chromosome 13 at about 13q34. In this form the hereditary pattern is autosomal dominant. Isolated FX deficiency and, more frequently, combined FX + FVII deficiency appear also associated with coagulation-unrelated abnormalities (carotid body tumours, mitral valve prolapse, atrial septal defect, ventricular septal defect, thrombocytopenia absent radius (TAR) syndrome, mental retardation, microcephaly and cleft palate). Diagnosis of a combined clotting defect could be difficult on the basis of global tests. For example, both isolated FX deficiency and combined FX + FVII deficiency yield a prolongation of basal PTT and PT. Only specific assays could allow one to reach the correct diagnosis. In cases of casual association with other defects, it is also important to study family members, as the two defects should segregate independently.