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.

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.

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 outpatients 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.

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.

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.Background. As reported by major clinical series in the literature, about 2% of patients receiving unfractionated heparin (UFH) develop immunemediated (type II) heparin-induced thrombocytopenia (HIT) that may be complicated in 30-75% of cases by a paradoxical thrombotic syndrome (HITTS), either arterial or venous. HITTS carries relevant rates of mortality and morbidity, amongst which cerebral and/or myocardial infarction and limb amputations. It is unclear as yet why some patients suffer from isolated thrombocytopenia (HIT), whilst others have HITTS. The aim of the present study was to look for clinical and laboratory features related to the occurrence of HITTS. Patients and methods. We retrospectively analysed the clinical records of 56 patients with proven HIT, as diagnosed on clinical grounds and by in vitro demonstration of immunoglobulin (IgG)/ IgM against the PF4/heparin complex. Thirty-four patients (61%) had HITTS (19 venous thrombosis, seven arterial thrombosis, five arterial and venous thrombosis, two skin necrosis, one diffuse intravascular coagulation), whereas 22 had uncomplicated HIT. Amongst HITTS patients, two had limb amputation, five had recurrent thrombosis and seven died.Amongst HIT patients three died from causes unrelated to HIT. Results. No significant difference in sex, age, previous exposure to heparin, UFH route of administration or dose, duration of therapy, time of onset of thrombocytopenia and platelet count recovery, nor antiheparin/PF4 antibodies subtype (IgG or IgM) was detected when comparing HIT and HITTS. In contrast, in the HITTS group a higher prevalence of orthopaedic surgery (15 of 34 vs. 2/22; P ¼ 0.01), a significantly lower platelet count nadir (43 ± 32 vs. 75 ± 63 · 10 9 /L; P ¼ 0.01) and a significantly higher titre of antiheparin/PF4 antibodies, expressed as optical density of enzyme-linked immunosorbent assay (ELISA); (1989 ± 1024 vs. 1277 ± 858; P ¼ 0.009), were observed in comparison with the HIT group. Amongst HITTS patients, the prevalence of venous thrombosis was significantly higher in orthopaedic patients and in those being treated for venous thromboembolism (18/24 vs. 1/9 patients, v 2 8.4, P ¼ 0.004), whilst arterial thrombosis (ART) occurred more often in heparin treatment for arterial disease (3/4 vs. 4/29 patients, v 2 4.6, P ¼ 0.03). Conclusions. Orthopaedic surgery, the severity of thrombocytopenia and high antiheparin/PF4 antibodies titre are adverse prognostic or concurrent factors in the development of HITTS.