Raffaella Scandellari

Arterial and venous thrombosis in rare congenital bleeding disorders: a critical review

Summary.  A thorough review of the literature and of personal files has allowed the gathering of 81 patients with rare congenital bleeding disorders and thrombotic phenomena. Sixteen of these patients had congenital afibrinogenemia, eight involved factor V deficiency, 20 factor VII defects, 33 factor XI deficiencies and only one, a factor XIII defect. Altogether 42 patients showed arterial thrombosis (myocardial infarction [MI] in 28 cases; ischemic stroke in 4; arterial occlusion in 8; 2 patients with disseminated intravascular coagulation (DIC)). Ages varied between 13 and 74. Twenty‐two patients were males and 16 females. In four cases, sex was not reported. There were three fatalities: two after a MI and one because of heart failure. With regard to venous thrombosis: 9 patients had pulmonary embolism, 15 patients had deep vein thrombosis, 9 patients had both pulmonary embolism and deep vein thrombosis; 1 patient had superficial vein thrombosis, whereas, 5 cases had an unusual site venous thrombosis (two portal systems, two cerebral sinuses, one inferior vena cava) for a total of 39 cases. Age varied between 3 and 86. In this case, 20 patients were males and 17 were females. In two cases, sex was not reported. There were three fatalities: two because of pulmonary embolism and one because of inferior vena cava thrombosis. The fact that thrombosis has never been described in patients with factor II or factor X seems to underscore the central antithrombotic role that these two factors have in the coagulation system.

Risk factors for thrombosis in patients with immune mediated heparin-induced thrombocytopenia

Abstract. Fabris F, Luzzatto G, Soini B, Ramon R, Scandellari R, Randi ML, Girolami A (University of Padua Medical School, Padova, Italy). Risk factors for thrombosis in patients with immune mediated heparin‐induced thrombocytopenia. J Intern Med 2002; 252: 149–154.

Non-catheter associated venous thrombosis in hemophilia A and B. A critical review of all reported cases

All reported cases of non-catheter induced venous thrombosis in patients with hemophilia A or B have been carefully evaluated. A total of 27 cases were reported,12 patients with hemophilia A and 15 patients with hemophilia B. The age of patients varied between 9 and 67 years. There were 10 cases of deep vein thrombosis, 8 patients with pulmonary embolism accompanied or not by deep vein thrombosis, 5 cases of superficial vein thrombosis. In addition, there were 3 cases of thrombosis in unusual sites (1 retinal central vein thrombosis and 2 portal vein thrombosis). Finally, in one case, venous thrombosis was multiple. There was a fatality in a hemophilia B patient with pulmonary embolism.The most frequent risk or triggering factor in hemophilia A was the administration of Feiba or rFVIIa concentrates in patients with inhibitors. Surgery together with Prothrombin Complex concentrates was the most frequent cause in hemophilia B patients. Congenital associated prothrombotic risk factors were present in two patients.No or very few therapeutic procedures were initiated in these patients but for a suspension or reduction of concentrates infusion. In a few instances low molecular weight heparin was given for a few days. The frequent association of venous thrombosis with infusion of concentrates indicates the need for a careful evaluation of patients about to receive such therapy.

Novel point mutation in a leucine-rich repeat of the GPIbα chain of the platelet von Willebrand factor receptor, GPIb/IX/V, resulting in an inherited dominant form of Bernard-Soulier syndrome affecting two unrelated families: the N41H variant

This reports describes a new variant of heterozygous Bernard-Soulier syndrome with autosomal dominant inheritance. In Italy, a significant proportion of patients with autosomal dominant inheritance of macrothrombocytopenia have been recognized as having heterozygous Bernard-Soulier syndrome carrying the Bolzano-type defect. This condition prompted a systematic review of our out-patients with chronic isolated macrothrombocytopenia. We recognized that the affected members of two unrelated families represented a new variant of heterozygous Bernard-Soulier Syndrome with autosomal dominant inheritance. Sequencing analysis of the GPIbα gene revealed a novel heterozygous mutation, A169C, resulting in an N41H substitution in the protein. This aminoacid belongs to the first leucine-rich repeat of the chain. The molecular modeling suggests that the replacement of the N41 with a histidine (N41H) drastically disturbs the structure of the first portion of GPIbα N-terminal, directly involved in von Willebrand factor binding. As a consequence, platelet aggregation to 1.2 mg/mL of ristocetin is slightly impaired and flow cytometry reveals a reduced binding of monoclonals directed against N-terminal epitopes of the GPIbα.

Associated prothrombotic conditions are probably responsible for the occurrence of thrombosis in almost all patients with congenital FVII deficiency. Critical review of the literature

The occasional occurrence of thrombosis in patients with congenital bleeding disorders has received considerable attention during the past decade. Myocardial infarction, ischemic strokes and venous thromboembolism have been reported in hemophilia A or B patients, in von Willebrand disease and, also, in rare coagulation disorders, especially in factor VII (FVII) deficiency. To explain the relatively high frequency of thrombotic phenomena, mainly venous, seen in the last condition, it was speculated that a special form or variant of FVII deficiency could exist. The presence of associated prothrombotic risk factors has been occasionally reported to be present in these patients but the matter has never been duly evaluated and emphasized. The purpose of the present paper was to evaluate if the clinical setting in which thrombosis appeared in these patients could explain the occurrence of the thrombosis. All reported cases of thrombosis seen in patients with FVII deficiency have been analyzed and the presence of associated risk factors recorded. Out of a population of 33 documented cases, the presence of prothrombotic risk factors was reported in 30 instances. In two of the remaining cases, no mention is made about associated risk factors. In the last case they were explicitly excluded. The critical evaluation of the literature suggests that the occurrence of thrombosis in FVII deficiency may be due to common prothrombotic risk factors. As a consequence it may be only stated that FVII deficiency does not protect from thrombosis.

Arterial thrombosis in young women after ovarian stimulation: case report and review of the literature

Both venous and arterial thrombosis have been described in women after ovarian stimulation and/or hyperstimulation for infertility management. The ratio between venous and arterial thrombosis in this condition is about 2 or 3 to 1, contrary to what seen during pregnancy or oral contraception where it is 5 or 10 to 1. An accurate perusal of the literature and of personal files has yielded 34 cases of arterial thrombosis after assisted reproductive technologies (ART) which entailed ovarian stimulation. There were 15 cases of ischemic strokes; 7 cases of carotid and/or vertebral artery occlusion; 6 of aorta and peripheral vessel thrombosis, 2 of mesenteric artery occlusion, 3 with myocardial infarction and 2 with intracardiac thrombosis. Associated risk factors were as follow: smoking in 4 women; antiphospholipid antibodies in 2; decrease in protein S in 1. Furthermore, polycystic ovaries were present in two women. Ovarian hyperstimulation was obtained with several protocols which included human chorionic gonadotropin (HCG) in all but a few instances. Age of women varied between 22 and 41 with an average of 32. Nineteen women were pregnant at the time of thrombosis. Only seven of these 19 pregnancies were brought to term with fetal survival. Abortion was spontaneous in 5 cases and therapeutic in the additional 7. There were two maternal fatalities.

Platelet response to Helicobacter pylori eradication therapy in adult chronic idiopathic thrombocytopenic purpura seems to be related to the presence of anticytotoxin-associated gene A antibodies

The aims of this study were to assess the prevalence of Helicobacter pylori infection in chronic idiopathic thrombocytopenic purpura adult patients and investigate the platelet response after eradication. To minimize the confounding effect of concomitant idiopathic thrombocytopenic purpura therapies, patients were eligible for the prospective study if they had 20–100 × 109/l platelets, and no requirement for treatment for thrombocytopenia or no change of doses of ongoing medications for at 3 months before inclusion.Helicobacter pylori infection was assessed in 62 patients using a stool antigen test, and the infection was present in 52% of patients. Immunoglobulin G antibodies against the cytotoxin-associated gene A protein were detected in 53% of infected patients. All patients underwent sampling for specific platelet autoantibodies, 37.5% of H. pylori-positive and 33% of H. pylori-negative patients had detectable platelet autoantibodies. Sixteen eligible H. pylori-positive patients were submitted to the eradication therapy and followed in the prospective study. We considered 14 H. pylori-negative patients as control group. Platelet response was defined as an incremental increase above 50% from baseline platelet count. A positive response was observed in 43% patients after 6 months of follow-up. Eradicated responder and nonresponder patients were comparable for all main clinical features but not for anticytotoxin-associated gene A antibodies (83 vs. 12.5%, P = 0.026).Given the good cost–benefit ratio, we believe that all idiopathic thrombocytopenic purpura patients should be screened for H. pylori infection and eradication treatment should be considered, particularly for patients who are also found positive for anticytotoxin-associated gene A antibodies.

Pregnancy and oral contraceptives in factor V deficiency: a study of 22 patients (five homozygotes and 17 heterozygotes) and review of the literature

Summary.  Information on the effect of pregnancy or oral contraceptives (OC) in congenital factor V (FV) deficiency is scanty. The personal investigation of five homozygous and 17 female heterozygous showed that patients with severe deficiency bleed considerably at the time of delivery. However, bleeding can be controlled properly by administration of fresh frozen plasma with excellent foetal outcome. The safe level for adequate haemostasis seems around 25% of normal. On the contrary, heterozygote patients show no significant postpartum bleeding and therefore need no substitution therapy. Oral contraceptives were taken and well tolerated by four of our homozygous patients and appear to be beneficial because they cause a decrease in menometrorrhagies thereby improving the anaemia and decreasing transfusional needs. One patient took hormonal replacement therapy with no undue effects. No thrombosis was noted in the propositae during oral contraceptive therapy. The review of the literature has allowed the gathering of information on 20 additional pregnancies. The foetal outcome was satisfactory in every instance. Excessive bleeding was noted in 11 pregnancies. In seven of the remaining pregnancies, no undue bleeding was noted thanks to appropriate substitution therapy. In the remaining two pregnancies no bleeding was noted and no substitution therapy was given. No data are apparently available in the literature about the use of OCs in FV deficiency.

Congenital factor X deficiencies with a defect only or predominantly in the extrinsic or in the intrinsic system : A critical evaluation

Congenital Factor X deficiency is commonly classified as type I, in which there is a concomitant decrease of activity and antigen (CRM negative), and in type II, in which activity is low but antigen is normal or near normal (CRM positive). During the past decades it was shown that type II was by itself very heterogeneous. It was shown in fact that some forms showed a defect in all three assay systems (extrinsic, intrinsic, and RVV dependent), whereas others showed a defect only in two of the three systems. Molecular biology analysis, whenever available, has failed so far to supply clear explanations for these discrepancies. The purpose of the present article was an attempt to correlate the clotting activities seen in these two defects with other clotting, chromogenic, immunological assays, and molecular biology results. There are in the literature 10 families that show a predominant defect in the extrinsic system, and four families that show a predominant defect in the intrinsic system. All patients showed a normal, near normal, or reduced level of antigen that is always definitively higher than the clotting counterpart. Molecular biology studies revealed mutations in different exons, namely 2, 4, 5, 6, and 8. These mutations in different exons do not allow any clear genotype‐phenotype conclusions, but indicate that mutations in different exons may give rise to the same phenotype. The study underlines the importance of a multipronged evaluation of all cases with Factor X deficiency. In fact only by this approach can an acceptable classification of the defect be reached. Am. J. Hematol., 2008.

Heparin-Induced Thrombocytopenia in Patients with Philadelphia-Negative Myeloproliferative Disorders and Unusual Splanchnic or Cerebral Vein Thrombosis

Background: Philadelphia-negative myeloproliferative disorders (Ph-MPD) are common causes of unusual splanchnic or cerebral vein thrombosis, which is treated with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). Heparin-induced thrombocytopenia (HIT) is a dangerous potential complication of this therapy, but it has rarely been reported in Ph-MPD. Patients and Methods: We retrospectively reviewed clinical records of 29 patients with Ph-MPD who have been treated with UFH or LMWH for unusual splanchnic or cerebral vein thrombosis (3 cerebral sinus, 6 portal and 20 hepatic vein). The goal of the study was to determine the occurrence of new thrombotic events during heparin therapy secondary to HIT (HITT). Results: During heparin therapy, 5 out of the 29 patients (17%) developed a new thrombotic episode (pulmonary embolism) with a high clinical probability of HIT based on the 4 T’s score even though not all the patients developed ‘true’ thrombocytopenia. A diagnosis of HIT was established in 2 patients (6.8%) through the presence of heparin-related antibodies. Conclusions: Ph-MPD patients on heparin warrant careful monitoring and HIT has to be suspected whenever platelet counts drop or a new thrombosis is detectable.