Giorgia Saccullo

Prognostic significance of residual venous obstruction in patients with treated unprovoked deep vein thrombosis: a patient-level meta-analysis.

Residual venous obstruction (RVO) could improve the stratification of the risk of recurrence after unprovoked deep vein thrombosis (DVT), but results from clinical studies and study-level meta-analyses are conflicting. It was the objective of this analysis to determine if RVO is a valid predictor of recurrent venous thromboembolism (VTE) in patients with a first unprovoked DVT who had received at least three months of anticoagulant therapy. Individual patient data were obtained from the datasets of original studies, after a systematic search of electronic databases (Medline, Embase, Cochrane Library), supplemented by manual reviewing of the reference lists and contacting content experts. A multivariate, shared-frailty Cox model was used to calculate hazard ratios (HRs) for recurrent VTE, including, as covariates: RVO; age; sex; anticoagulation duration before RVO assessment; and anticoagulation continuation after RVO assessment. A total of 2,527 patients from 10 prospective studies were included. RVO was found in 1,380 patients (55.1%) after a median of six months from a first unprovoked DVT. Recurrent VTE occurred in 399 patients (15.8%) during a median follow-up of 23.3 months. After multivariate Cox analysis, RVO was independently associated with recurrent VTE (HR = 1.32, 95% confidence interval [CI]: 1.06-1.65). The association was stronger if RVO was detected early, i.e. at three months after DVT (HR = 2.17; 95% CI: 1.11-4.25), but non-significant if detected later, i.e. >6 months (HR = 1.19; 95% CI: 0.87-1.61). In conclusion, after a first unprovoked DVT, RVO is a weak overall predictor of recurrent VTE. The association is stronger if RVO is detected at an earlier time (3 months) after thrombosis.

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.

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

Incidence of thromboembolic complications in patients with mechanical heart valves with a subtherapeutic international normalized ratio

OBJECTIVE Subtherapeutic international normalized ratios are frequently encountered in clinical practice, and patients with mechanical heart valves with inadequate anticoagulation may be exposed to an increased risk of thromboembolic events. There are no data on thromboembolic event risk for these patients. METHODS We assessed the current practice patterns in the management of patients with mechanical heart valves with subtherapeutic international normalized ratios and assessed the risk of thromboembolic complications in this setting. The charts of patients with mechanical heart valves followed up in two anticoagulation clinics were reviewed. Patients with a history of stable, therapeutic anticoagulation but with a subtherapeutic international normalized ratio were included. Patients who underwent invasive procedures requiring temporary suspension of antithrombotic therapy were excluded. Data on use and dose of low-molecular weight heparin bridging therapy were collected. RESULTS The incidence of objectively confirmed thromboembolic events within 90 days after obtaining the index international normalized ratio was assessed. Two hundred ninety-four patients with mechanical heart valves were included (mean age 63.3 years, 47.3% male). Low-molecular weight heparin was prescribed in 14 cases (4.8%). At 90 days, 1 patient had a thromboembolic complication (0.3%, 95% confidence interval 0%-1.9%). CONCLUSION Patients with previously stable, therapeutic anticoagulation with a subtherapeutic international normalized ratio have a low risk of thromboembolic events. Withholding low-molecular weight heparin bridging therapy is a reasonable therapeutic option in these cases.

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.

Ultrasonography-guided central venous catheterisation in haematological patients with severe thrombocytopenia

BACKGROUND Cannulation of the internal jugular vein (CVC) is a blind surface landmark-guided technique that could be potentially dangerous in patients with very low platelet counts. In such patients, ultrasonography (US)-guided CVC may be a valid approach. There is a lack of published data on the efficacy and safety of urgent US-guided CVC performed in haematological patients with severe thrombocytopenia. MATERIALS AND METHODS We retrospectively studied the safety of urgent CVC procedures in haematological patients including those with severe thrombocytopenia (platelet count <30×10(9)/L). From January 1999 to June 2009, 431 CVC insertional procedures in 431 consecutive patients were evaluated. Patients were included in the study if they had a haematological disorder and required urgent CVC insertion. Patients were placed in Trendelenburgs position, an 18-gauge needle and guide-wire were advanced under real-time US guidance into the last part of the internal jugular vein; central venous cannulation of the internal jugular vein was performed using the Seldinger technique in all the procedures. Major and minor procedure-related complications were recorded. RESULTS All 431 patients studied had haematological disorders: 39 had severe thrombocytopenia, refractory to platelet transfusion (group 1), while 392 did not have severe thrombocytopenia (group 2). The general characteristics of the patients in the two groups differed only for platelet count. The average time taken to perform the procedure was 4 minutes. Success rates were 97.4% and 97.9% in group 1 and group 2, respectively. No major complications occurred in either group. DISCUSSION US-guided CVC is a safe and effective approach in haematological patients with severe thrombocytopenia requiring urgent cannulation for life support, plasma-exchange, chemotherapy and transfusion.

Cancer patients requiring interruption of long-term warfarin because of surgery or chemotherapy induced thrombocytopenia: The use of fixed sub-therapeutic doses of low-molecular weight heparin

No data are available regarding the management of cancer patients requiring interruption of long‐term vitamin‐K antagonist (VKA) therapy. For this purpose, we tested the efficacy and safety of fixed doses of low‐molecular weight heparin (LMWH) in substitution of VKA because of invasive procedures or chemotherapy‐induced thrombocytopenia. In cancer patients on VKA, therapy was discontinued 5 ± 1 days before surgery or chemotherapy. Heparin was given at prophylactic dosage in patients at low risk and at fixed subtherapeutic doses (3,800 or 4,000 UI anti‐FXa, b.i.d.) in those at high‐risk for thrombosis. LMWH was reinitiated 12 hr after surgery and VKA the day after. In patients receiving chemotherapy, LMWH was reinitiated 12/24 hr after obtaining a stable platelet count ≥ 30,000 mmc3 and VKA after a stable platelet count ≥ 50,000 mmc3. Thromboembolism and major bleeding events were recorded from the time of VKA suspension to 30 ± 2 days postprocedure or until the next chemotherapy. Overall, 156 patients (56.4% at low risk and 43.5% at high risk for thrombosis) were enrolled; 34.6% underwent major surgery, 40.4% nonmajor surgery, and 25% chemotherapy. Thrombotic events occurred in five patients [3.2%, 95% confidence interval (CI): 1.41–7.27], four belonging to the high‐risk and one to the low‐risk group. Major bleeding occurred in five patients (3.2%, 95 CI: 1.41–7.27), all belonging to the high‐risk group (three during major surgery and two during chemotherapy). In conclusion, LMWH given at fixed subtherapeutic is a feasible and relatively safe approach for bridging therapy in cancer patients on long‐term VKA. Am. J. Hematol., 2012.