Lucio Lo Coco

Patients requiring interruption of long-term oral anticoagulant therapy: the use of fixed sub-therapeutic doses of low-molecular-weight heparin.

Summary.  Introduction: We tested the efficacy and safety of fixed doses of low‐molecular‐weight heparin (LMWH) in patients requiring interruption of vitamin‐K antagonist (VKA) because of invasive procedures. Methodology: Preoperatively, patients discontinued VKA for 5 ± 1 days; in those at low risk for thrombosis, LMWH was given at a prophylactic dosage of 3800 UI (nadroparin) or 4000 UI (enoxaparin) anti‐factor (F) Xa once daily the night before the procedure. In patients at high risk for thrombosis, LMWH was started early after VKA cessation and given at fixed sub‐therapeutic doses (3800 or 4000 UI anti‐FXa twice daily) until surgery. Postoperatively, LMWH was reinitiated 12 h after procedure while VKA was reinitiated the day after. Heparin was continued until a therapeutic INR value was reached. The primary efficacy endpoints were the incidence of thromboembolism and major bleeding from VKA suspension (because of surgery) up to 30 ± 2 days postprocedure. Results: A total of 328 patients (55.4% at low risk and 44.6% at high risk for thrombosis) were enrolled; 103 (31.4%) underwent major surgery and 225 (68.6%) non‐major invasive procedures. Overall, thromboembolic events occurred in six patients (1.8%, 95% confidence interval 0.4–3.2), five belonging to the high‐risk group and one belonging to the low‐risk group. Overall, major bleeding occurred in seven patients (2.1%, 95 confidence interval 0.6–3.6), six patients belonged to the high‐risk group and one belonged to the low‐risk group; most of the events occurred in the high‐risk group during major surgery. Conclusion: LMWH given at fixed sub‐therapeutic doses appears to be a feasible and safe approach for bridging therapy in chronic anticoagulated patients.

Relapsing or refractory idiopathic thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: the role of rituximab

Idiopathic thrombotic thrombocytopenic purpura–hemolytic uremic syndrome (TTP‐HUS) is a rare disease responsive to treatment with plasma exchange (PE) but with a high percentage of relapse or refractory patients. A severe deficiency of ADAMTS‐13 (<5% of normal activity), congenital or caused by an autoantibody, may be specific for TTP and it has been proposed that severe ADAMTS‐13 deficiency now defines TTP. B cells play a key role in both the development and the perpetuation of autoimmunity, suggesting that B‐cell depletion could be a valuable treatment approach for patients with idiopathic TTP‐HUS. This review of the literature focuses on the role of rituximab, a chimeric monoclonal antibody directed against CD20 antigen expressed by B lymphocytes, in patients with relapsing or refractory TTP‐HUS with or without ADAMTS‐13 deficiency, suggesting that rituximab may produce clinical remission in a significant proportion of patients. Rituximab therapy reduces plasma requirement and avoids complications related to salvage‐immunosuppressive therapy. In conclusion, rituximab provides an effective, well‐tolerated, and safe treatment option for patients with idiopathic TTP‐HUS, thus giving an alternative approach to the current treatment based on PE.

Leukocyte count, diabetes mellitus and age are strong predictors of stroke in a rural population in southern Italy: an 8-year follow-up

Stroke incidence rates in the Mediterranean area are higher compared to northern European countries. In this study, we present the 8-year prospective data from a small rural Sicilian town. This population, consisting of 1351 subjects (622 males and 729 females), is homogeneous for ethnic background with traditional healthy dietary habits and shows low cholesterol mean levels. We found that the risk of stroke was significantly associated with the record of at least one previous neurological symptom (PNS), such as lack of strength, loss of vision or speech or possible drop attacks, and high hematocrit in males, and to high body mass index (BMI) and waist-hip ratio (WHR), diabetes, hypertension, high leukocyte count in females. We also documented age-related differences: stroke was associated in younger subjects (age<65 years) with diabetes, high BMI, high uric acid levels and in older patients (age>/=65 years) with high WHR, hypertension, diabetes, PNS, leukocyte count and hematocrit above the 95th percentile. Multivariate analysis demonstrated an independent association between stroke and age, diabetes, leukocyte count, hypertension and PNS. In conclusion, in this rural Sicilian population, the incidence rate of stroke is 1.72 cases per 1000/year in the subjects between 40 and 75 years of age. The risk factors associated with stroke are different in younger and older subjects. Leukocyte count, as an expression of an undergoing inflammatory process, may have a relevant role at least in the elderly.

Optimal Duration of Low Molecular Weight Heparin for the Treatment of Cancer-Related Deep Vein Thrombosis: The Cancer-DACUS Study

PURPOSE We evaluated the role of residual vein thrombosis (RVT) to assess the optimal duration of anticoagulants in patients with cancer who have deep vein thrombosis (DVT) of the lower limbs. PATIENTS AND METHODS Patients with active cancer and a first episode of DVT treated with low molecular weight heparin (LMWH) for 6 months were eligible. Patients were managed according to RVT findings: those with RVT were randomly assigned to continue LMWH for an additional 6 months (group A1) or to discontinue it (group A2), and patients without RVT stopped LMWH (group B). The primary end point was recurrent venous thromboembolism (VTE) during the 1 year after disconinuation of LMWH, and the secondary end point was major bleeding. Analyses are from the time of random assignment. RESULTS Between October 2005 and April 2010, 347 patients were enrolled. RVT was detected in 242 patients (69.7%); recurrence occurred in 22 of the 119 patients in group A1compared with 27 of 123 patients in group A2. The adjusted hazard ratio (HR) for group A2 versus A1 was 1.37 (95% CI, 0.7 to 2.5; P = .311). Three of the 105 patients in group B developed recurrent VTE; adjusted HR for group A1 versus B was 6.0 (95% CI, 1.7 to 21.2; P = .005). Three major bleeding events occurred in group A1, and two events each occurred in groups A2 and B. The HR for major bleeding in group A1 versus group A2 was 3.78 (95% CI, 0.77 to 18.58; P = .102). Overall, 42 patients (12.1%) died during follow-up as a result of cancer progression. CONCLUSION In patients with cancer with a first DVT, treated for 6 months with LMWH, absence of RVT identifies a population at low risk for recurrent thrombotic events. Continuation of LMWH in patients with RVT up to 1 year did not reduce recurrent VTE.

Residual vein thrombosis for assessing duration of anticoagulation after unprovoked deep vein thrombosis of the lower limbs: The extended DACUS study

The safest duration of anticoagulation after idiopathic deep vein thrombosis (DVT) is unknown. We conducted a prospective study to assess the optimal duration of vitamin K antagonist (VKA) therapy considering the risk of recurrence of thrombosis according to residual vein thrombosis (RVT). Patients with a first unprovoked DVT were evaluated for the presence of RVT after 3 months of VKA administration; those without RVT suspended VKA, while those with RVT continued oral anticoagulation for up to 2 years. Recurrent thrombosis and/or bleeding events were recorded during treatment (RVT group) and 1 year after VKA withdrawal (both groups). Among 409 patients evaluated for unprovoked DVT, 33.2% (136 of 409 patients) did not have RVT and VKA was stopped. The remaining 273 (66.8%) patients with RVT received anticoagulants for an additional 21 months; during this period of treatment, recurrent venous thromboembolism and major bleeding occurred in 4.7% and 1.1% of patients, respectively. After VKA suspension, the rates of recurrent thrombotic events were 1.4% and 10.4% in the no‐RVT and RVT groups, respectively (relative risk = 7.4; 95% confidence interval = 4.9–9.9). These results indicate that in patients without RVT, a short period of treatment with a VKA is sufficient; in those with persistent RVT, treatment extended to 2 years substantially reduces, but does not eliminate, the risk of recurrent thrombosis. Am. J. Hematol. 2011.

Rituximab for managing relapsing or refractory patients with idiopathic thrombotic thrombocytopenic purpura--haemolytic uraemic syndrome.

Thrombotic thrombocytopenic purpura (TTP) is a rare disorder characterized by thrombocytopenia, microangiopathic haemolytic anaemia, neurological and renal abnormalities and fever1, with a mortality rate, in the absence of treatment, of almost 90%. Since such criteria do not distinguish TTP from haemolytic uraemic syndrome (HUS), the comprehensive term TTP-HUS is more approriate2. The standard therapy is urgent plasma exchange (PE)1, which reduces mortality to 10% or less3–9. Because of its dramatic effect on short and long-term outcome, it is now accepted that PE can be begun, in the absence of an alternative diagnosis, even when not all of the above criteria are fulfilled3,4,6,9,10. The evident advantage of early initiation of therapy along with the decreased diagnostic threshold has resulted in a 7-fold increase of patients treated with PE for TTP-HUS from 1981 to 199711. The symptoms of TTP are related to the presence of von Willebrand factor (VWF)-rich platelet thrombi in arterioles and capillaries. VWF is a multimeric plasma glycoprotein crucial for both platelet adhesion and aggregation, especially at the high shear rates present in the microvasculature. The size of VWF multimers is physiologically regulated in vivo by a specific metalloprotease, ADAMTS-13 (a disintegrin-like and metalloprotease with thrombospondin type 1 repeats)12. A severe deficiency of ADAMTS-13 (< 5% of normal activity) may be specific for TTP13 and it has been proposed that severe ADAMTS-13 deficiency now defines TTP14,15. Because ADAMTS-13 deficiency, whether idiopathic or caused by an autoantibody, provides a possible explanation for the effectiveness of PE (removal of the autoantibody by apheresis; supply of ADAMTS-13 by plasma replacement), it has been suggested that the levels of this metalloprotease can be used to guide treatment decisions14,16–19. At present it is not possible to establish the sensitivity of ADAMTS-13 deficiency for identifying patients who may respond to PE. In seven reports, 45% to 100% of patients with TTP were reported to have severe deficiency of ADAMTS-13 activity19–25 while such a high rate has not been described in those with HUS19,20,23. However, the interpretation of these studies is limited by the absence of explicit criteria for distinguishing patients with TTP from patients with HUS. PE has been proven effective even in patients without deficiency of ADAMTS-13 activity, which makes it difficult to understand how PE is benificial2. In conclusion, the role of ADAMTS-13 activity in the diagnosis and treatment decisions in patients with TTP or HUS remains unknown. Therapy with PE should be implemented in all patients with TTP-HUS and continued until the resolution of signs and/or symptoms and normalisation of laboratory tests; this can require long-term therapy. PE has some other disadvantages: first of all, it is not a risk-free procedure since a substantial number of major complications have been reported26,27. Furthermore, about 10% to 20% of TTP-HUS patients do not respond or have only an incomplete response2. Various different types of immunosuppressive treatment have been proposed for refractory patients14,29,30,32, including steroids and immunosuppressive or immune-modulating agents; however, the lack of robust data does not allow proper suggestion of such agents in the setting of acute refractory or chronic relapsing TTP28,32. Splenectomy has been proposed for patients with refractory or relapsing TTP, with reported remission rates of 50–100%29, but relapses have occurred in a considerable proportion of patients, most of them with severe ADAMTS-13 deficiency2,29,33,35. It has recently been shown that splenectomy can cause the disappearance of antibodies, normalisation of ADAMTS-13 activity and clinical remission in cases of refractory/relapsing TTP associated with anti-ADAMTS-13 autoantibodies. Other authors reported a low frequency of relapses in a large cohort of patients who underwent splenectomy30. Rituximab, a chimaeric monoclonal antibody directed against the CD20 antigen present on B lymphocytes, is used in lymphoma patients and those with rheumatoid arthritis33. Its action relies on clearance of the B lymphocytes responsible for antibody production by complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity or directly by inducing apoptosis31,33. The understanding that ADAMTS-13 deficiency could be antibody-mediated first provided the rationale for the use of rituximab in TTP-HUS12, but its reported effectiveness even in TTP-HUS patients without antibody-mediated ADAMTS-13 deficiency as well as in cases of refractory/relapsing cases makes this monoclonal antibody a very attractive therapeutic agent33–35. The data suggest that the drug may not simply decrease ADAMTS-13 autoantibody production by depleting B cells, but that it may have additional mechanisms of action. Kameda et al.34 suggested that B-cell depletion by rituximab reduces excessive cytokine production in patients with secondary TTP, thus containing the level of VWF multimers within the normal range. At present, only data from case series have been published and many questions remain open regarding the target population, timing of initiation, duration of treatment and concomitant PE34–49. Here we describe four patients with refractory/relapsing idiopathic TTP-HUS who were successfully treated with rituximab (Table I). Table I Patients’ characteristics

Thrombotic complications in paroxysmal nocturnal haemoglobinuria: a literature review

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, clonal haematopoietic stem cell disease caused by mutations in an X-linked gene called phosphatidylinositol glycan class A (PIG-A). The disease can present with bone marrow failure, haemolytic anaemia, smooth muscle dystonia and thrombosis. The PIG-A gene product is necessary for the first step in the biosynthesis of glycosylphosphatidyinositol (GPI) anchors - the transfer of GlcNAc from UDP-GlcNAc to form N-acetylglucosaminyl phosphatidylinositol (GlcNAc-PI) - where expansion and differentiation of the PIG-A mutant stem cell leads to clinical manifestations of the disease1. PNH may occur de novo (classical PNH) or in the setting of aplastic anaemia (hypoplastic PNH); the absence of GPI-linked complement regulatory proteins on PNH erythrocytes renders these cells susceptible to terminal complement-mediated haemolysis2. The natural history of PNH is highly variable, ranging from indolent to life-threatening. The median survival is 10 to 15 years, but the range is wide. Thrombosis is the leading cause of death, and an initial thrombotic event increases the relative risk of death by 5- to 10-fold in PNH3. Haemolysis most likely contributes to thromboembolism, as patients with larger PNH clones have a higher incidence of thromboembolism and events have been temporally associated with increased haemolysis. Although the mechanism is not fully understood, haemolysis has been implicated in the initiation of platelet activation and aggregation4. This review discusses the underlying mechanisms that lead to thrombosis in PNH and therapeutic approaches.

Gastrointestinal bleeding due to angiodysplasia in patients with type 1 von Willebrand disease: report on association and management

The presence of gastrointestinal angiodysplasia (GI-A) can represent an urgent haematological problem as it produces serious bleeding, which is usually untreatable. It has been recognized that G-IA frequently occurs in patients with type 2–3 and acquired von Willebrand disease (VWD) but the strength of this association is unclear. One hypothesis relays on the lack of high molecular weight (HMW) molecules of von Willebrand factor (VWF) in the plasma [1]. Other findings suggest a potential role being played by the 3916T mutation of the esone 28 coding factor vW (domain A1) [2]. Angiodysplastic lesions can be found along the entire length of the GI tract, from the tongue to the colon. Although there are several diagnostic methods such as endoscopy, push enteroscopy, helical computed tomography (CT), mesenteric angiography and, more recently, video capsule endoscopy [3] available, the identification of angiodysplasia remains extremely difficult to document and most of the patients remain undiagnosed. Thereby, most patients are treated solely medically with several and mainly ineffective approaches [3]. Most previous publications on VWD and angiodysplasia have been reports of the association itself and there is little published data on the management and follow-up of affected patients. In addition, no such association has yet been documented in patients with type 1 VWD. We report our experiences in the management and follow-up of three patients suffering from angiodysplasia and type 1 VWD, according to the current classification [4]. Their baseline phenotypic characteristics are outlined in Table 1; investigation and management of individual patients are summarized in Table 2. The first patient was a 49-year-old female with inherited type 1 VWD but no serious bleeding tendency. She presented with melena and irondeficiency anaemia. Activity of both von Willebrand factor antigen (VWF:Ag) and von Willebrand factor Ristocetin co-factor activity (VWF:RCo) was reduced to <20%. GI endoscopy and colonoscopy proved normal at the time of her first hospital admission. The patient was treated with blood replacement, tranexamic acid and desmopressin (DDAVP) infusion, but these latter two approaches did not effectively reduce the bleeding. We therefore initiated VWF/factor VIII (FVIII) concentrate (Haemate P , CSL Behring) at the therapeutic dosage, 40–50 IU kg every day and then every two days for 4 weeks following hospital discharge. She did not display any bleeding symptoms for the next 5 months, when she then experienced a new incident of melena and serious anaemia (haemoglobin <7.0 g dL). Mesenteric angiography and capsular endoscopy were thus performed: the latter procedure revealed two small angiodysplastic lesions in the ileum, clinically insignificant. We therefore initiated medical therapy with oestrogen and Haemate P 30 IU kg every alternate day for 8 weeks. However, the patient experienced an adverse event to oestrogen therapy and serious bleeding when the VWF concentrate was withdrawn. Symptoms of anaemia continued for the next 22 months; GI bleeding was always reduced during prophylaxis with Haemate P but commenced again whenever this was suspended. At that time, we repeated GI Correspondence: Sergio Siragusa, MD, Haematology and Thrombosis/Haemostasis Unit, Department of Oncology, University Hospital of Palermo, Via del Vespro 127, I-90127 Palermo, Italy. Tel./fax: + 39 091 6554574; e-mail: sergio.siragusa@unipa.it

Safety of plasma-derived protein C for treating disseminated intravascular coagulation in adult patients with active cancer†

Cancer-related disseminated intravascular coagulation (DIC) is a life-threatening condition for which no effective treatment is currently available. Protein C (PC), a modulator of coagulation as well as the inflammatory system, has been successfully tested (in its activated recombinant form [a-rPC]) in sepsis-related coagulopathy, but with an increased risk for major bleeding. Plasma-derived PC (pd-PC) is more suitable than a-rPC in patients at high risk from bleeding due to its self-limiting process. We carried out a single-arm study evaluating the role of pd-PC in adult cancer patients with overt DIC. Over a period of 3 years, we treated 19 patients with overt DIC and a PC plasma concentration <50%; all received PC concentrate (Ceprotin(®), Baxter) for 72 hr in adjusted doses to restore normal PC values (70-120%). Blood coagulation, haematological tests, and the DIC score were recorded after 12, 24, 48 hr, 7 and 10 days, while clinical outcomes (bleeding, thrombosis and mortality) were recorded up to 28 days. Within 48 hr of starting pd-PC therapy, laboratory tests as well as the DIC score improved in all patients. At 28-days follow-up, no bleeding or thrombosis was observed. This is the first study to investigate the use of pd- PC for treatment of cancer-related overt DIC.

Buffy coat-derived platelets cryopreserved using a new method: Results from in vitro studies

Cryopreservation for the long-term storage of platelets (PLTs) is a useful method to overcome the limits of platelet shortage. This is an in vitro prospective study to evaluate the count, viability, and function of buffy coat-derived pooled platelet concentrates (BC-PLTs), treated with dimethyl sulphoxide (DMSO) and cryopreserved (CRY BC-PLTs) at -80 °C with a modified Valeri method. PLTs were stored in 6% DMSO with a patented kit. Overall, 49 BC-PLTs from 245 healthy volunteer donors were prepared, cryopreserved, and analysed before and after 3, 6, and 9 months of storage. In flow cytometry, a statistically significant reduction in CD 42b (92.7 ± 4.29% at T0 vs. 23.6 ± 27.5% at T3, 16.38 ± 12.54% at T6, and 17.3 ± 9.6% at T9) and PAC-1 (1.9 ± 1.34% at T0 vs. 0.62 ± 0.4% at T3, 0.63 ± 0.83% at T6, and 0.49 ± 0.48% at T9) was observed after storage. CRY BC-PLTs showed a good and stable endogenous thrombin generation potential (nM min): 529.25 ± 98.64 at T0 vs. 533.04 ± 103.15 at T9 months. CRY BC-PLTs showed a good viability in vitro, according to currently accepted criteria for cryopreserved PLTs.