Tapering and discontinuation of thrombopoietin receptor agonists in immune thrombocytopenia: Real-world recommendations.

Thrombopoietin receptor agonists (TPO-RAs) are currently indicated for continuous treatment of chronic primary immune thrombocytopenia (ITP). However, there is growing evidence that TPO-RAs can also trigger sustained response in 10-30% of cases after treatment tapering and discontinuation. Therefore, at least for selected responding patients, it might be rational to plan TPO-RA interruption to exploit off-treatment response. Intriguingly, complete or partial responses with TPO-RAs are frequently observed when treatments are initiated early, suggesting that unknown immune-related mechanisms may be involved in this phenomenon. The sustained responses observed after interruption of TPO-RAs may be interpreted as a recovery of immunological tolerance; thus, the re-establishment of immunological equilibrium might be primarily responsible for the observed off-treatment effect. Importantly, these findings may indicate that anticipated TPO-RA usage can lead to improved responses, and that optimized tapering and interruption in selected patients can furthermore improve prognoses. On the base of this rationale, a series of real-life considerations have been generated by a panel of Experts to elucidate possible novel criteria and modalities to identify subgroups of patients who can benefit from tapering and/or discontinuation of TPO-RAs. Towards this aim, the results of a survey of ITP experts are herein reported, reflecting a snapshot of current real-life experience on early discontinuation of TPO-RA-based therapy. The present manuscript also highlights the importance of future translational studies on novel prognostic and predictive biomarkers that can stratify patients and facilitate the clinical choice for second-line treatment of ITP.

Safety of vitamin K antagonist treatment for splanchnic vein thrombosis: a multicenter cohort study.

BACKGROUND: The treatment of splanchnic vein thrombosis (SVT) is challenging, due to the increased risk of bleeding and potentially life-threatening complications. Current recommendations are based on evidence from the treatment of venous thrombosis in usual sites, but small observational studies in SVT population suggest that the bleeding risk may offset the benefit of anticoagulant treatment in this setting. The aim of this study was to evaluate the safety of vitamin K antagonists (VKAs) in SVT patients. METHODS: We retrospectively included SVT patients treated with VKAs followed by 37 Italian anticoagulation clinics, until June 2013. The primary outcome was the incidence of major bleeding (MB), according to the ISTH definition, during VKA treatment. Vascular events, including both arterial and venous thrombosis, and mortality were also documented. RESULTS: Three hundred and seventy-five patients were included (median age 53 years; 54.7% males). During a median VKA treatment duration of 1.98 years, 15 MB events occurred, corresponding to an incidence rate of 1.24 (95% confidence interval [CI], 0.75-2.06) per 100 patient-years. Gastrointestinal bleeding represented 40% of all MB events. At multivariate analysis, the presence of esophageal varices emerged as independent predictor of MB (hazard ratio 5.4; 95% CI, 1.4-21.1). The incidence rate of vascular events on treatment was 1.37 (95% CI, 0.84-2.23) per 100 patient-years and the mortality rate was 0.83 (95% CI, 0.44-1.54) per 100 patient-years. CONCLUSIONS: Selected SVT patients followed by anticoagulation clinics for the management of VKA treatment show a low rate of major bleeding and vascular events.

Accuracy of a portable prothrombin time monitor (Coagucheck) in patients on chronic oral anticoagulant therapy: a prospective multicenter study.

A portable prothrombin time (PT) monitor allows patients on oral anticoagulant therapy (OAT) to measure their PT at home. The purpose of the study was to evaluate the accuracy and precision of a portable PT monitor (Coagucheck, Roche Diagnostics, Mannheim, Germany) as compared with laboratory methods. The prospective study was conducted in four centers of the Italian Federation of Anticoagulation Clinics. A one-month instruction phase was followed by a six-month surveillance phase. Seventy-eight subjects on stable OAT (48 men, 30 women, age range: 18-75) were selected on a volunteer basis. Dual measurements of INR values were performed in each subject both from finger capillary blood by the monitor and from venous blood by the Anticoagulation Clinic laboratory in three instruction sessions. The mean difference (bias) of the monitor INR results when compared with the average of laboratory INR and monitor INR results was -0.025 (limits of agreement-LA: -0.84/+0.81 INR units). The mean bias was -0.0675 (LA: -0.37/+0.23), +0.018 (LA: -0.39/+0.35), and +0.039 (LA: -0.49/+0.55), respectively, for INR values lower than 2.0, between 2.0 and 3.0, and greater than 3.0. The overall precision coefficient of monitor INR was 0.370, while it was 0.23, 0.46, 0.29, and 0.21, respectively, in Centers 1, 2, 3, and 4. The overall variation coefficient was 6.5% while it was 3.7%, 8.5%, 4.7%, and 4.9%, respectively, in Centers 1, 2, 3, and 4. Coagucheck has an acceptable level of accuracy for INR values in the range between 2.0 and 3.0. A wide variation in monitor performance was found among centers.

[Arg506 --> Gln mutation of coagulation factor V (factor V Leiden) and transient cerebral ischemia at a young age in 3 members of the same family]. / Mutazione Arg506 --> Gln del fattore V della coagulazione (fattore V Leiden) ed ischemia cerebrale transitoria in giovane età in tre membri della stessa famiglia.

The Arg506 --> Gln coagulation factor V mutation (factor V Leiden) is the most frequent inherited abnormality of blood coagulation which predisposes to venous thromboembolism. Its association with an increased risk of arterial thrombosis is uncertain. We describe 3 members of the same family (a woman and her 2 children) who were heterozygous for the Arg506 --> Gln mutation and who presented cerebral transient ischemic attacks (TIA) at a young age. The patients (with the exception of one smoker) had no risk factors for TIA and no abnormality of the coagulation system other than the Arg506 --> Gln mutation. The observation of the mutation and TIA in 3 members of the same family may suggest the hypothesis of an association between the mutation and arterial thrombosis. This hypothesis must be interpreted with caution, due to the absence of objective instrumental findings in patients with TIA and to the high prevalence of the Arg506 --> Gln mutation in the general population.

Oral surgery in patients on oral anticoagulant therapy: a randomized comparison of different intensity targets.

OBJECTIVE: To evaluate whether or not it is possible to perform oral surgery in patients on oral anticoagulant therapy (OAT) without stopping treatment. STUDY DESIGN: A prospective randomized open-label study was designed to evaluate the outcome of oral surgery in patients on OAT, operated upon in conditions of reduced international normalized ratio (INR), compared with patients maintained in their usual therapeutic ranges of the prothrombin time INR. The INR target in the group with reduced OAT was 1.8, and the INR target of the group without reduced OAT was 2.5 or more in carriers of artificial valves. RESULTS: One hundred thirty-one patients on OAT were randomized to reduced anticoagulation or to full anticoagulation, and 511 teeth were extracted by the same surgeon. Mild bleeding, but excessive enough to warrant adoption of supplementary local hemostatic measures, was observed in 10 cases (15.1%) in the reduced dosage group and in 6 cases (9.2%) in the unmodified dosage group, which was a nonsignificant difference. There were no thrombotic complications in either group. CONCLUSIONS: This randomized study shows that, using simple measures for local hemostasis, it is not necessary to reduce OAT in patients undergoing routine dental extractions.

P-Glycoprotein Expression in Acute Myeloid Leukaemia Cells at Diagnosis: Its relationship to Daunorubicin or Idarubicin Induction Therapy and Survival.

We investigated the expression of P-glycoprotein (P-gp) in 50 adults with de novo diagnosed acute myeloid leukaemia (AML) and the relationship between presence of P-gp in leukaemic cells and efficacy, as remission induction and survival rate, of two different anthracyclines, daunorubicin (DNR) and idarubicin (IDR). We found that 30 out of 50 patients (60%) were negative (Group 1) and 20 (40%) were positive (Group 2) for P-gp expression evaluated by mean of MRK16 MoAb using a cut-off of 10% positive cells. Thirty-five out of 50 patients (70%) obtained complete remission (CR); depending on P-gp expression, the CR rate was 80% for group 1 and 45% for group 2 (p lt; 0.005). The median duration of overall survival was 20 months for patients in Group 1 as compared with 10 months for patients of Group 2 (p < 0.005). Regarding the anthracycline used, no significant difference in CR was observed in patients of Group 1 (75% of CR with DNR vs. 90% with IDR); Group 2 obtained 40% of CR with DNR vs. 70% with IDR (p < 0.005). The median duration of overall survival (OS) with the two regimens was comparable in Group 1, while it was significantly longer in patients of Group 2 treated with IDR compared with DNR regimen (p < 0.005). These results confirm the prognostic value of P-gp expression in AML at first appearance and we suggest that idarubicin could be a valid anthracycline drug in the treatment of AML to be evaluated as potential drug of choice in patients with primary or drug-induced multidrug resistance.

Optimising local therapy during oral surgery in patients with von Willebrand disease: effective results from a retrospective analysis of 63 cases.

Bleeding after dental extractions is very frequent in patients with von Willebrand disease (vWD) and in the past often necessitated transfusions with factor VIII/von Willebrand factor concentrates (vWFc). To evaluate the benefits of a standard local therapy on bleeding complications during oral surgery, 63 consecutive patients with vWD were analysed retrospectively. All types of vWD were included: type 1 (n=31), type 2 (n=22) and type 3 (n=10). All the patients had dental extractions or periodontal surgery at the same hospital by the same oral surgeons. All cases had been given tranexamic acid (TA) before and for 7 days after surgery. As additional local therapy fibrin glue (FG) was used during surgery in several patients. Additional systemic therapies were: desmopressin (DDAVP, 0.3 microg kg-1) and fVIII/vWF concentrates (vWFc, 40 U kg-1) given as a single dose before surgery. The 29 subjects (46%) treated locally did not bleed. Among the remaining cases, 24 (38%) were given DDAVP as additional systemic therapy and 6 (9.5%) received vWFc. There was bleeding after surgery in only two cases who had been given local FG (type 2 B) or systemic vWFc (type 3), but bleeding was stopped with an additional local application of FG. Our data suggest that a standard local therapy with TA and FG with DDAVP can prevent bleeding complications during oral surgery in the majority of patients (84%) with vWD and reduce the need for concentrates, with all their possible complications and high costs.

P-Glycoprotein Expression in Acute Myeloid Leukaemia Cells at Diagnosis: Its relationship to Daunorubicin or Idarubicin Induction Therapy and Survival; Malignancy.

We investigated the expression of P-glycoprotein (P-gp) in 50 adults with de novo diagnosed acute myeloid leukaemia (AML) and the relationship between presence of P-gp in leukaemic cells and efficacy, as remission induction and survival rate, of two different anthracyclines, daunorubicin (DNR) and idarubicin (IDR). We found that 30 out of 50 patients (60%) were negative (Group 1) and 20 (40%) were positive (Group 2) for P-gp expression evaluated by mean of MRK16 MoAb using a cut-off of 10% positive cells. Thirty-five out of 50 patients (70%) obtained complete remission (CR); depending on P-gp expression, the CR rate was 80% for group 1 and 45% for group 2 (p < 0.005). The median duration of overall survival was 20 months for patients in Group 1 as compared with 10 months for patients of Group 2 (p < 0.005). Regarding the anthracycline used, no significant difference in CR was observed in patients of Group 1 (75% of CR with DNR vs. 90% with IDR); Group 2 obtained 40% of CR with DNR vs. 70% with IDR (p < 0.005). The median duration of overall survival (OS) with the two regimens was comparable in Group 1, while it was significantly longer in patients of Group 2 treated with IDR compared with DNR regimen (p < 0.005). These results confirm the prognostic value of P-gp expression in AML at first appearance and we suggest that idarubicin could be a valid anthracycline drug in the treatment of AML to be evaluated as potential drug of choice in patients with primary or drug-induced multidrug resistance.