M. Franchini

Thrombotic adverse events to coagulation factor concentrates for treatment of patients with haemophilia and von Willebrand disease: a systematic review of prospective studies.

Summary.  Thrombotic adverse events (AEs) after clotting factor concentrate administration are rare but the actual rate is unknown. A systematic review of prospective studies (1990–2011) reporting safety data of factor concentrates in patients with haemophilia A (HA), haemophilia B (HB) and von Willebrand disease (VWD) was conducted to identify the incidence and type of thrombotic AEs. In 71 studies (45 in HA, 15 HB, 11 VWD) enrolling 5528 patients treated with 27 different concentrates (20 plasma‐derived, 7 recombinant), 20 thrombotic AEs (2 HA, 11 HB, 7 VWD) were reported, including two major venous thromboembolic episodes (both in VWD patients on prolonged replacement for surgery). The remaining thrombotic AEs were superficial thrombophlebitis, mostly occurring at infusion sites in surgical patients and/or during concentrate continuous infusion. The overall prevalence was 3.6 per 103 patients (3.6 per 104 for severe AEs) and 1.13 per 105 infusions, with higher figures in VWD than in haemophilia. Thrombotic AEs accounted for 1.9% of non‐inhibitor‐related AEs. Thrombosis‐related complications occurred in 10.8% of patients with central venous access devices (CVADs) reported in six studies, the risk increasing with time of CVAD use. Data from prospective studies over the last 20 years suggest that the risk of thrombotic AEs from factor concentrate administration is small and mainly represented by superficial thrombophlebitis. These findings support the high degree of safety of products currently used for replacement treatment.

Disseminated Intravascular Coagulation in Hematologic Malignancies

Disseminated intravascular coagulation (DIC) significantly contributes to the bleeding and thrombotic complications in patients with hematologic malignancies. As shown in other cancer settings, an underlying condition of activation of the coagulation system leading to a prothrombotic state of chronic or subclinical DIC is detectable. A variety of disease- or treatment-related factors may affect this condition, enhancing the risk of thrombosis or of bleeding and further triggering mechanisms of DIC in this setting. An overt DIC is diagnosed in approximately 15% of patients with acute leukemia, and bleeding manifestations prevail over thrombosis, with the highest and most harmful clinical impact in acute promyelocytic leukemia (APL). Pathogenic mechanisms include a series of intrinsic properties of malignant cells, able to directly activate the coagulation system or to stimulate prothrombotic effects by the host cells. Moreover, chemotherapy or concomitant infections play an important concurrent role. In this review the coagulation abnormalities, clinical manifestations, and the presently known pathophysiologic mechanisms of DIC in patients with hematologic malignancies are discussed, focusing on the most extensively studied condition of APL. Current approaches and open issues for the management and treatment of these patients are also reviewed.

Understanding inhibitor development in haemophilia A: towards clinical prediction and prevention strategies

Summary.  Inhibitor development, because of its impact on patients’ morbidity and quality of life, is presently the most serious complication of haemophilia A treatment. The identification of several genetic and non‐genetic risk factors may be used for the stratification of inhibitor risk and the definition of prevention strategies, particularly for patients with a high‐risk genetic profile. The most extensively studied genetic factor is the type of F8 mutation, i.e. large deletions, nonsense mutations and inversions, which are associated with a higher risk of inhibitor development. This is the basis for the increased risk in patients with inhibitor family history; however, concordance family studies showed that factors other than F8 mutations are involved. An emerging role is investigated for polymorphisms of immune‐regulatory genes that may increase (IL‐10 and TNF‐α) or reduce (CTLA‐4) inhibitor risk and whose heterogeneous ethnic distribution may correlate to the higher inhibitor risk in non‐caucasian patients. A role for FVIII haplotypes, particularly in black haemophiliacs, has been recently proposed. Recent studies report an increased inhibitor risk for initial intensive treatments (surgery or severe bleeds requiring high‐dose and/or prolonged treatment, presence of danger signals), whereas regular prophylaxis (absence of danger signals) exerts a protective effect. A clinical score including the type of F8 mutation, family history of inhibitors and intensive treatment has been recently validated for predicting inhibitor risk. Because of the lack of useful data regarding the role of different types of FVIII concentrates, the stratification of risk in patients starting replacement treatment together with the careful evaluation of indications, doses and duration of treatment at first exposures and further efforts for overcoming barriers to early implementation of prophylaxis are encouraged, particularly for patients with a predictable high inhibitor risk.

Poor predictive value of contemporary bleeding risk scores during long-term treatment of venous thromboembolism. A multicentre retrospective cohort study.

Bleeding is a common and feared complication of oral anticoagulant therapy. Several prediction models have been recently developed, but there is a lack of evidence in patients with venous thromboembolism (VTE). The aim of this study was to validate currently available bleeding risk scores during long-term oral anticoagulation for VTE. We retrospectively included adult patients on vitamin K antagonists for VTE secondary prevention, followed by five Italian Anticoagulation Clinics (Cuneo, Livorno, Mantova, Napoli, Varese), between January 2010 and August 2012. All bleeding events were classified as major bleeding (MB) or clinically-relevant-non-major-bleeding (CRNMB). A total of 681 patients were included (median age 63 years; 52.0% female). During a mean follow-up of 8.82 (± 3.59) months, 50 bleeding events occurred (13 MB and 37 CRNMB), for an overall bleeding incidence of 9.99/100 patient-years. The rate of bleeding was higher in the first three months of treatment (15.86/100 patient-years) than afterwards (7.13/100 patient-years). The HAS-BLED showed the best predictive value for bleeding complications during the first three months of treatment (area under the curve [AUC] 0.68, 95% confidence interval [CI] 0.59-0.78), while only the ACCP score showed a modest predictive value after the initial three months (AUC 0.61, 95%CI 0.51-0.72). These two scores had also the highest sensitivity and the highest negative predictive value. None of the scores predicted MB better than chance. Currently available bleeding risk scores had only a modest predictive value for patients with VTE. Future studies should aim at the creation of a new prediction rule, in order to better define the risk of bleeding of VTE patients.

Non-ABO red blood cell alloantibodies following allogeneic hematopoietic stem cell transplantation

Summary:Immune-mediated hemolysis is a well-recognized occurrence which complicates the period following a bone marrow transplant (BMT). However, although many studies have investigated the hemolytic anemia following ABO-incompatible BMT, data regarding the occurrence of alloantibodies against red blood cell (RBC) antigens other than ABO in patients undergoing hematopoietic stem cell transplantation are limited. In this review, we briefly analyze the most important non-ABO red blood cell (RBC) antigen systems involved in the development of post-BMT alloimmune hemolytic anemia, paying particular attention to the pathogenic mechanisms and the clinical significance of the alloantibodies involved. Among the non-ABO RBC antigens, RhD antigen is the one most frequently implicated in the development of post-BMT alloimmune hemolytic anemia. Although less frequent than hemolysis following transplants with ABO incompatibility, non-ABO-incompatible allograft hemolysis may severely complicate the post-BMT period creating difficult clinical management issues. For this reason, we advise careful pre-transplant donor and recipient checks for the most important RBC antigen systems and close post-BMT immunohematological monitoring in those patients undergoing allogeneic hematopoietic stem cell transplant with RBC antigen incompatibility.

Tyr2105Cys mutation in exon 22 of FVIII gene is a risk factor for the development of inhibitors in patients with mild/moderate haemophilia A.

Summary.  We report the case of a patient with mild haemophilia A, due to a Tyr2105Cys mutation in exon 22 of the C1 domain, who developed a high‐titre factor VIII inhibitor (maximum titre 1600 BU) with recurrent severe haemorrhages and fatal intracranial bleeding. Based on published data, it appears that although this mutation occurs rarely in patients with mild or moderate haemophilia A, it is frequently associated with the development of high‐titre inhibitors.

Efficacy of desmopressin as surgical prophylaxis in patients with acquired von Willebrand disease undergoing thyroid surgery

Coagulation abnormalities may occur in patients with thyroid diseases. We report on 14 patients undergoing thyroid surgery for a thyroid disease with an alteration of coagulation parameters resembling von Willebrand disease. Subcutaneous desmopressin was first tested and then used successfully in these patients as surgical prophylaxis, with no side‐effects or bleeding complications during or after surgery. This study highlights the need for coagulation studies in patients with thyroid diseases undergoing thyroid surgery. Subcutaneous desmopressin may be used in these patients in order to prevent a surgically related bleeding risk.

Thrombin generation assay: a useful routine check-up tool in the management of patients with haemophilia?

Summary.  Severity assessment of patients with haemophilia A (HA) is traditionally based on FVIII activity (FVIII:C). Clinical phenotype of HA patients often differs between individuals with the same FVIII:C determined with clotting and chromogenic assays. The aim of this study was to assess the influence of the FVIII:C on thrombin generation (TG) assay parameters both in vitro and ex‐vivo postinfusion plasma. For in‐vitro approach, influence of FVIII:C was evaluated on TG parameters in several dilutions of a normal plasma pool with commercial FVIII‐depleted‐plasma (FVIIIDP) and in others experiments, adding increasing amounts of different commercial FVIII concentrates (Fanhdi, Haemate‐P, Hemofil‐M and Kogenate Bayer) to FVIIIDP. In a series of 50 postinfusion samples, from HA patients of different severity, we assayed TG and FVIII:C (chromogenic and clotting). In vitro experiments, the 50% of maximum TG peak (TGMP) was achieved using only 5% FVIII:C and the TGMP was obtained with 40% of normal VIII:C. Impaired response compared with normal plasma was found in FVIIIDP using addition of increasing amounts of different commercial FVIII concentrates. An overall good correlation between the two FVIII assays was observed (y = 0.9115x − 0.273, r = 0.975, P < 0.001); TGMP and the Lag‐Phase‐Time (LPT) provided some discrepant results when compared with the total range of FVIII:C measurements. In contrast, correlations for TGMP, LPT and endogenous thrombin potential were improved in samples restricted to FVIII:C <5%. We conclude that TG parameters tentatively could be a tool to tailor the global haemostatic capacity in haemophilic patients.

Preoperative autologous blood donation by elderly patients undergoing orthopaedic surgery

To assess the feasibility of a programme of predeposit in elderly patients undergoing elective orthopaedic surgery.

Treatment for patients with type 3 von Willebrand disease and alloantibodies: a case report

Alloantibodies that bind von Willebrand factor (VWF) and form circulating immune complexes develop in approximately 8–14 per cent of patients with type 3 von Willebrand disease (VWD) who received multiple transfusions, especially in carriers of null mutations [1]. As these antibodies may lead to immune complex-mediated, life-threatening anaphylactic reactions, concentrates containing VWF are generally contraindicated in these patients [2]. We report the case of a patient with type 3 VWD and anti-VWF alloantibodies who was managed with recombinant factor VIII (rFVIII). The patient, a 35year-old female, was previously described on the occasion of her first life-threatening anaphylactic reaction that occurred in May 1993, following the infusion of a FVIII/VWF concentrate (Haemate P; CLS Behring, Marburg, Germany) [3]. On that occasion, she was successfully treated for the first time with rFVIII. From January 1994 to November 2005, the patient was treated with rFVIII (boluses of 5000 U followed by 1500 U h by continuous infusion until the resolution of bleeding) on the occasion of eight haemorrhagic episodes (three episodes of renal colicky pain with macrohaematuria, three episodes of abdominal pain because of haemorrhagic follicular rupture, one episode of menorrhagia and a haematoma of the right arm). Overall, 432 000 IU of rFVIII (144 000 IU of Kogenate and 288 000 IU of Recombinate) were used, the mean number of hours of rFVIII treatment per episode being 36 (range: 12–72) and the mean number of IU of rFVIII infused per episode being 54 000 (range: 23 000–113 000). In all the occasions, treatment was effective in stopping bleeding and no drugsrelated adverse reactions occurred. In December 2005, the patient was retreated for menorrhagia with Recombinate at the usual dosage and a diffuse skin rash appeared after the bolus infusion. Recombinate was immediately stopped, and the cutaneous reaction rapidly regressed. However, it was necessary to restart this rFVIII product (after steroid premedication) because of persistent menorrhagia, but on this occasion, the infusion was uncomplicated (a total of 36 000 IU of Recombinate was administered over 24 h). No blood components were transfused during the bleeding episode. A control of the anti-VWF antigen (VWF:Ag) titre performed in January 2006 showed an increased level (150 U mL) compared with historical controls of the same patient, while the next consecutive blood samples (March and June 2006) documented the progressive decrease of anti-VWF:Ag towards the trough value of 10 U mL. Figure 1 shows the anti-VWF:Ag course. Thus, it can be hypothesized that traces of VWF, responsible for the anamnestic antibody response, were present in the final formulation of Recombinate as a result of the production process, because the VWF gene is co-expressed with the FVIII gene in the cell culture system used for manufacturing this rFVIII [4]. There is limited but favourable experience reported in the literature on the use of rFVIII in type 3 VWD patients with alloantibodies [3]. However, as the half-life of the infused FVIII in the absence of its carrier VWF is very short (1–2 h) in these patients, rFVIII must be administered at very large doses by continuous infusion in order to maintain haemostatic levels of FVIII. Other positive experiences have been reported with the use of the bypassing agent recombinant activated factor VII (rFVIIa) [5]. Correspondence: Massimo Franchini, MD, Servizio di Immunoematologia e Trasfusione – Centro Emofilia, Ospedale Policlinico, Piazzale L.Scuro, 10-37134 Verona, Italy. Tel.: +0039 45 812 3610; fax: +0039 45 812 3612; e-mail: massimo.franchini@azosp.vr.it