Venous thrombosis in rare or unusual sites: a diagnostic challenge.

Venous thrombosis usually involves the veins of the limbs, most frequently the leg veins. All other venous districts may sometimes be affected by the thrombotic process. Sometimes, the thrombotic occlusion of the veins of a given region show typical signs and symptoms. In other cases, the picture may not be clear and a high degree of clinical suspicion is needed for a correct approach to patient diagnosis and management. Thrombosis of retinal and jugular veins, right heart thrombosis including thrombosis of coronary sinus and thrombosis of the azygos system may be included in this group. In addition, thromboses of umbilical, renal, ovarian, spermatic, and iliac veins also require attention. Finally, the dorsal veins of the penis may also be affected by thrombotic events. The main clinical features of these thromboses are reviewed herein with suggestions for a correct diagnostic approach. The importance of sonography and of other imaging techniques is emphasized. A prompt diagnosis is of paramount importance as most of these thromboses in rare or unusual sites may still cause severe systemic complications (pulmonary embolism, sepsis, and heart failure).

Occurrence of thrombosis in congenital thrombocytopenic disorders: a critical annotation of the literature.

Patients with a low platelet count are prone to bleeding. The occurrence of a thrombotic event in congenital thrombocytopenic patients is rare and puzzling. At least nine patients with Glanzmann thrombasthenia have been reported to have had a thrombotic event, eight venous and one arterial (intracardiac, in the left ventricle). On the contrary, three patients with Bernard-Soulier syndrome have been shown to have had arterial thrombosis (myocardial infarction) but no venous thrombosis. Finally, seven patients with the familiar macrothrombocytopenia due to alterations of the MYH9 gene have been reported to have had thrombosis (five myocardial infractions, one ischemic stroke, one deep vein thrombosis and one portal vein thrombosis). The significance of these findings is discussed with particular emphasis on the discrepancy between venous and arterial thrombosis seen in patients with Glanzmann thrombasthenia and Bernard-Soulier syndrome.

Arterial and venous thromboses in patients with idiopathic (immunological) thrombocytopenia: a possible contributing role of cortisone-induced hypercoagulable state.

Immunological thrombocytopenias, as other forms of thrombocytopenia, are associated with bleeding. Occasionally, these patients manifest thrombotic events. A total of at least 29 patients were reported to have had either arterial (20 cases) or venous (9 cases) thrombosis while platelet count was less than 50 × 10(3)/µL. The most frequent clinical manifestation was a myocardial infarction. Thrombosis occurred in the large majority of patients during prednisone therapy. Patients receiving cortisone or patients with Cushing syndrome show a hypercoagulable state characterized by elevated factor VIII levels, decreased fibrinolysis, and abnormal von Willebrand factor multimers composition. The same is probably true for prednisone-treated patients with thrombocytopenia. However, the 2 conditions are not identical since prednisone is a mainly glycoactive compound, whereas cortisol produced in excess in Cushing syndrome is mainly mineraloactive. The presence of large, young, hyperactive platelets may also play a role. Prednisone-treated patients with thrombocytopenia have to be considered as potentially thrombophilic.

Recombinant FVIIa concentrate-associated thrombotic events in congenital bleeding disorders other than hemophilias.

Recombinant FVIIa concentrate has been originally used in the treatment of hemophilia patients with inhibitors. Recently, its use has been expanded to a variety of off-label indications. Thrombosis is the most important side effect. This may occur especially in off-label use but also in hemophiliacs with inhibitors. The present study investigated the occurrence of thrombosis in congenital bleeding disorders other than hemophilias as gathered from personal files and from the literature. Fifteen patients (seven FVII deficiency, one fibrinogen defect, four FXI deficiency, one von Willebrand disease, and two Glanzmann's Thrombasthenia) have been evaluated. Thrombosis was arterial in eight instances, venous in six, whereas in one case the type of thrombosis was unspecified. In eight cases, associated risk factors were present. Two patients with FXI deficiency had inhibitors. Dosage was variable. There was at least one fatality but in five cases evolution was not reported. The remaining patients recovered with variable sequels.

Considerations on a tentative classification of FVII deficiency suited for practical clinical purposes.

Adequate classifications of disorders are of paramount importance in the management of congenital bleeding disorders. Classification of congenital FVII deficiency should be simple, based on few tests using thromboplastins of different origin. The first thromboplastin to be used is a rabbit brain preparation since it has been proven that this is the one that, overall, yields the lowest activity level. This is particularly so since molecular biology techniques have supplied important information with regard to the structure-function relation but have failed to supply a satisfactory classification of the defect. Mutations in the same domain have yielded different forms of FVII deficiency. Furthermore, molecular biology techniques are time consuming and are not feasible in every laboratory. A classification of FVII deficiency based on clinical, clotting, and immunological assays is proposed. This classification is suited for practical clinical purposes and may represent a useful preparatory basis for molecular biology studies.

A cluster of factor XI-deficient patients due to a new mutation (Ile 436 Lys) in northeastern Italy.

A new mutation (Ile 436 Lys) was found in a cluster of patients in northeastern Italy. The mutation was present in five patients at the homozygote level and in one patient as a compound heterozygote with an already known mutation namely Glu 117 stop. All these patients showed a mild bleeding tendency mainly associated with deliveries or surgery. The first two patients were two sisters, and their parents were consanguineous. The third patient was the only homozygote in the family, and parents apparently were not consanguineous. The fourth and fifth patients were a brother and a sister, and in this case too, parents were not consanguineous. The sixth patient, a compound heterozygote, negated also the existence of consanguinity between his parents. There were also seven heterozygotes among the family members of the patients homozygous for this new mutation (Ile 436 Lys). Finally, there were two heterozygotes for the Glu 117 stop mutation in the family of the sixth patient. The heterozygotes, regardless of the mutation, were asymptomatic. The Ile436Lys mutation is characterized by low factor XI activity and antigen, namely is a cross-reaction material negative form. Molecular modeling indicates that the Ile436Lys mutation causes a large conformational change within the 432-442 loop. No relation could be traced among the different families; however, all their ancestors were autochthonous of the same two small towns. Furthermore, no Jewish ancestry could be found. The close geographical area in which all these patients were found and the absence of the same mutation in the general population of the area strongly suggests a founder effect and that the mutation is responsible for the defect. The compound heterozygosis with the Glu 117 stop mutation, common among Jews, was not surprising because of the past strict ties of the Republic of Venice with the Middle East.

Thrombotic events in MYH9 gene-related autosomal macrothrombocytopenias (old May-Hegglin, Sebastian, Fechtner and Epstein syndromes).

Congenital macrothrombocytopenia are a group of disorders which may be due to mutations in the MYH9 gene. This gene linked to chromosome 22 encodes for the nonmuscle heavy chain IIA that is expressed in platelets and in other tissues. In the past these disorders were known as May-Hegglin anomaly, Sebastian, Fechtner and Epstein syndromes. The main common feature is the presence of thrombocytopenia with large platelets. The evaluation of all reported cases indicates that thrombotic events appear to occur only in patients with May Hegglin variants. Whether this is due to the higher prevalence of this variant as compared with the others or to a specific difference is still unknown. However, the occurrence of thrombotic events in only one of these conditions may be used as a new tentative differentiability feature.

Worldwide diffusion of FVII Arg304Gln coagulation defect (FVII Padua).

FVII Padua is a Type 2 defect owing to an Arg304Gln substitution in exon 8. The defect was originally discovered in an isolated valley in northeastern Italy. Subsequently, it was described in several other countries of the Mediterranean basin and Middle East. Recently, several proven or suspected cases have been described among Afro-Americans in the USA. This study has demonstrated the existence of at least a two-founder effect for this FVII abnormality, Mediterranean countries, and USA Afro-Americans. Patients are usually asymptomatic or only paucisymptomatic. The defect is characterized by low FVII activity when rabbit brain thromboplastins are used in the assay system. On the contrary, FVII levels are normal when ox-brain thromboplastins are used. FVII antigen is always normal.