Emanuela Bonamigo

Comparative incidence of thrombosis in reported cases of deficiencies of factors of the contact phase of blood coagulation

Thrombotic manifestations occurring in patients with coagulation defects have drawn considerable attention during the last decade. It concerned mainly patients with hemophilia, vW disease or FVII deficiency. Occasional reports involved also the deficiencies of the contact phase of blood coagulation, mainly FXII deficiency. The purpose of the present study was to evaluate the comparative incidence of thrombosis in all reported patients with FXII, Prekallikrein and Kininogens deficiencies. Out of the reported 341 cases with these conditions that could be tracked there were 43 cases with thrombosis. More specifically, there were 32 patients with FXII deficiency who also had a thrombotic event (16 arterial and 16 venous). As far as Prekallikrein deficiency is concerned, there were nine cases with thrombosis (five arterial and four venous). Finally, two patients with Total or High molecular weight Kininogen deficiencies had also a thrombotic manifestation (one arterial and one venous). The thrombotic manifestations were M.I. 11 cases; ischemic stroke 9 cases; peripheral arteries 3 cases; deep vein thrombosis with or without pulmonary embolism 17 cases; thrombosis in other veins 3 cases. Congenital or acquired associated prothrombotic risk factors were present in 33 out of 36 cases. In three cases the existence of associated risk factors was excluded whereas in the remaining seven patients no mention is made in this regard. This study clearly indicates that the severe in vitro coagulation defect seen in these conditions does not protect from thrombosis.

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

Abstract 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 Glanzmanns 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.

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.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.

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.

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.

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 × 103/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.

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

Abstract 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.

Activated FVII levels in factor VII Padua (Arg304Gln) coagulation disorder and in true factor VII deficiency: a study in homozygotes and heterozygotes

Abstract Congenital FVII deficiency is usually subdivided into two forms: type I and type II. Type I is characterized by a concomitant deficiency of FVII activity and FVII antigen (true deficiency). Type II is characterized by a discrepancy between FVII activity which is always low and FVII antigen which may be normal, near normal, or reduced. Thromboplastins of different origins may show a discrepant behaviour towards type II FVII deficiencies. The abnormal factor VII present in these forms may, in fact show, different levels of activity, according to the thromboplastin used in the assay system. Typical of these variants is the Arg304Gln mutation (know as FVII Padua). In this variant, FVII level is low when rabbit brain thromboplastin is used, whereas the level is perfectly normal when ox-brain thromboplastin is employed. Intermediate levels are obtained if human placenta or human recombinant is used. Since ox-brain thromboplastin is very sensitive to activated FVII, the normal FVII levels obtained in FVII Padua could be due to abnormally high circulating levels of activated FVII. The purpose of the present paper was to investigate the level of activated FVII present in homozygotes and heterozygotes with FVII Padua. For comparison, a group of patients with type I or ‘true’ deficiency was also investigated. A group of 21 normal patients served as controls. The activated FVII level found in FVII Padua was 8·4 and 41·0 mU/ml for homozygotes and heterozygotes, respectively. The level found in homozygous true deficiency was unassayable, whereas that found in heterozygotes was 36·2 mU/ml. The level found in the control population was 64·9 mU/ml in agreement with other reports. The low levels of activated FVIIa found in homozygotes with FVII Padua indicate that the normal FVII activity found with ox-brain thromboplastin cannot be attributed to higher than normal circulating levels of FVIIa.

Ox Brain versus Rabbit Brain Thromboplastin Assays Are the Best Tool for a Preliminary Diagnosis of the Arg304Gln Factor VII Defect (FVII Padua)

Factor VII (FVII) deficiency, the most frequent defect among the rare bleeding disorders, is commonly divided into type I and type II. In the former, there is a concomitant decrease in FVII activity and antigen. In the latter, there is a clear discrepancy between activity which is low and antigen which is normal or nearly normal. FVII Padua (Arg304Gln) is characterized by different reactivity towards different tissue thromboplastins. FVII levels were assayed by the use of different tissue thromboplastins, namely rabbit brain, human placenta, human recombinant and ox brain thromboplastin, in 6 homozygous patients. Cases reported in the literature were also evaluated. Ox brain thromboplastins yielded normal values, whereas human tissue or recombinant human thromboplastins yielded only slightly higher levels of activity than those obtained with rabbit brain reagents. The ox brain versus rabbit brain ratio was about 22, whereas the ratio for human placenta or human recombinant versus rabbit brain thromboplastin was only about 5. The FVII antigen versus rabbit brain, human tissue and ox brain activity ratios were 24.8, 4.3 and 1.1, respectively. These results indicate that the ox brain versus the rabbit brain thromboplastin ratio supplies a wider difference than the one between human tissue and rabbit brain. The antigen/ox brain activity ratio of 1.1 fully confirms this assertion.

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).