The risk of recurrent deep venous thrombosis is similar among carriers of factor V Leiden and patients without this mutation. Carriers of both factor V Leiden and the G20210A prothrombin mutation have an increased risk of recurrent deep venous thrombosis after a first episode and are candidates for lifelong anticoagulation.

Deficiency of the naturally occurring anticoagulant proteins, such as antithrombin, protein C and protein S, and activated protein C resistance due to the factor V Leiden gene mutation is associated with inherited thrombophilia. So far, no direct comparison of the thrombotic risk associated with these genetic defects is available. In this study, we wish to compare the lifetime probability of developing thrombosis, the type of thrombotic symptoms, and the role of circumstantial triggering factors in 723 first-and second-degree relatives of 150 index patients with different thrombophilic defects. We found higher risks for thrombosis for subjects with antithrombin (risk ratio 8.1, 95% confidence interval [CI], 3.4 to 19.6), protein C (7.3, 95% CI, 2.9 to 18.4) or protein S deficiency (8.5, 95% CI, 3.5 to 20.8), and factor V Leiden (2.2, 95% CI, 1.1 to 4.7) than for individuals with normal coagulation. The risk of thrombosis for subjects with factor V Leiden was lower than that for those with all three other coagulation defects (0.3, 95% CI, 0.1 to 1.6), even when arterial and superficial vein thromboses were excluded and the analysis was restricted to deep vein thrombosis (0.3, 95% CI, 0.2 to 0.5). No association between coagulation defects and arterial thrombosis was found. The most frequent venous thrombotic manifestation was deep vein thrombosis with or without pulmonary embolism (90% in antithrombin, 88% in protein C, 100% in protein S deficiency, and 57% in factor V Leiden), but a relatively mild manifestation such as superficial vein thrombosis was common in factor V Leiden (43%). There was a predisposing factor at the time of venous thromboembolism in approximately 50% of cases for each of the four defects. In conclusion, factor V Leiden is associated with a relatively small risk of thrombosis, lower than that for antithrombin, protein C, or protein S deficiency. In addition, individuals with factor V Leiden develop less severe thrombotic manifestations, such as superficial vein thrombosis.

Inherited resistance to activated protein C (APC) has been recently recognized as a novel cause underlying venous thrombophilia. In most cases APC resistance is due to a single point mutation in the factor V gene leading to a replacement of Arg506 with Gln (factor V Leiden). Factor V Leiden allele is present in about 5% of the Caucasian individuals (Europeans, Jews, Israeli Arabs, and Indians) and is virtually absent in Africans, Asians, and races with Asian ancestry such as Amerindians, Eskimos, and Polynesians; this suggests a single origin of the mutation, which has been proven by haplotype analysis. A low prevalence of the mutation (1%) was noticed in African-Americans for recent racial admixture. Factor V Leiden presents not a major role as risk factor for arterial thrombosis, while it is present in 18% of Caucasian patients with venous thrombosis. This high incidence prevalence mirrors the incidence in the corresponding general populations and can be even higher in some areas according to the ethnic background. Conversely, factor V Leiden is usually not found in non-Caucasian thrombotic patients; this could give reason of the lower incidence of venous thrombotic disease in Africa and Asia in comparison with Europe. Therefore, screening for factor V Leiden is suggested for all Caucasian individuals with previous venous thrombosis; inclusion criteria for the screening should not be stringent because clinical manifestations associated with the mutant genotype can be also mild or secondary to circumstantial risk factors or manifesting at advanced age. Factor V Leiden can act also as concurrent risk factor in individuals with deficiency of natural inhibitors or mild hyperhomocysteinemia. So far, screening for the mutation in individuals with no history of thrombosis is recommended only for relatives of proband patients identified as carriers; the available data do not justify indiscriminate screening before risk situations such as oral contraceptives intake, pregnancy, or high-risk surgery.

Key Points• TCRab 1 /CD19 1 -depleted haplo-HCT is associated with a reduced incidence of graft failure in patients with hemoglobinopathies.• The major challenges of haplo-HCT in hemoglobinopathies are delayed immune reconstitution and associated morbidity and mortality.We examined outcomes of haploidentical hematopoietic cell transplantation (haplo-HCT) using hydroxyurea, and azathioprine. The median follow-up among surviving patients was 3.9 years.The 5-year probabilities of overall survival (OS) and disease-free survival (DFS) were 84% and 69%, respectively. The incidence of graft failure was 14%. We compared outcomes to a historical group of 40 patients with hemoglobinopathies who received CD34 1 -selected grafts (CD34 group). The median follow-up of surviving patients for the CD34 group was 7.5 years. The 5-year probabilities of OS and DFS were 78% and 39%, respectively. The CD34 group had a significantly higher incidence of graft failure (45%) than the TCR group (14%) (P 5 .048). The incidences of grades 2 to 4 acute graft-versus-host disease (GVHD) in the TCR and CD34 groups were 28% and 29%, respectively, and 21% and 10% (P 5 .1), respectively, for extensive chronic GVHD. Viral reactivation was common in both groups. The overall incidence of posttransplant lymphoproliferative disorders for the entire group was 16%. Among all patients, 5 developed autoimmune hemolytic anemia or thrombocytopenia, with the overall cumulative incidence of 11%. The 2 groups showed suboptimal CD4 1 recovery within the first 6 months of transplantation with no significant difference between groups. These data demonstrate that TCRab 1 /CD19 1 -depleted grafts are associated with a reduced incidence of graft failure, but delayed immune reconstitution and associated morbidity and mortality remain a significant challenge.