Paroxysmal nocturnal hemoglobinuria and pregnancy before the eculizumab era: the French experience

Background

Pregnancy in women with paroxysmal nocturnal hemoglobinuria is rare, with few reports on maternal and fetal mortality rates.

Design and Methods

A specific questionnaire designed to solicit data on pregnancies in women with paroxysmal nocturnal hemoglobinuria was sent to all members of the French Society of Hematology in January 2008.

Results

We identified 27 pregnancies in 22 women at 10 French Society of Hematology centers between 1978 and 2008. The median age was 21.5 years at diagnosis of paroxysmal nocturnal hemoglobinuria and 27 years at pregnancy. None of these women had received eculizumab during their pregnancy. Maternal complications, consisting mostly of cytopenias requiring transfusions, occurred in 95% of cases. Two cases of severe aplastic anemia (de novo in one case and relapse in the other) were recorded. No thrombotic events occurred during pregnancy, whereas 4 postpartum thromboses (16%) were recorded, 2 of which were fatal (maternal mortality rate 8%). Most patients received antithrombotic prophylaxis during pregnancy and postpartum (n=16; 64%). Delivery was preterm in 29% of cases, and birth weight was less than 3 kg in 53% of cases. Fetal mortality rate was 4%.

Conclusions

Pregnancy during paroxysmal nocturnal hemoglobinuria is associated with increased maternal and fetal mortality rates (8% and 4%, respectively, in this series). Maternal mortality is related to postpartum thromboses. Prophylactic anticoagulation is recommended during pregnancy and for six weeks postpartum.     

Paroxysmal nocturnal hemoglobinuria clones in severe aplastic anemia patients treated with horse anti-thymocyte globulin plus cyclosporine

Background

Clones of glycosylphosphatidylinositol-anchor protein-deficient cells are characteristic in paroxysmal nocturnal hemoglobinuria and are present in about 40–50% of patients with severe aplastic anemia. Flow cytometry has allowed for sensitive and precise measurement of glycosylphosphatidylinositol-anchor protein-deficient red blood cells and neutrophils in severe aplastic anemia.

Design and Methods

We conducted a retrospective analysis of paroxysmal nocturnal hemoglobinuria clones measured by flow cytometry in 207 consecutive severe aplastic anemia patients who received immunosuppressive therapy with a horse anti-thymocyte globulin plus cyclosporine regimen from 2000 to 2008.

Results

The presence of a glycosylphosphatidylinositol-anchor protein-deficient clone was detected in 83 (40%) patients pre-treatment, and the median clone size was 9.7% (interquartile range 3.5–29). In patients without a detectable clone pre-treatment, the appearance of a clone after immunosuppressive therapy was infrequent, and in most with a clone pre-treatment, clone size often decreased after immunosuppressive therapy. However, in 30 patients, an increase in clone size was observed after immunosuppressive therapy. The majority of patients with a paroxysmal nocturnal hemoglobinuria clone detected after immunosuppressive therapy did not have an elevated lactate dehydrogenase, nor did they experience hemolysis or thrombosis, and they did not require specific interventions with anticoagulation and/or eculizumab. Of the 7 patients who did require therapy for clinical paroxysmal nocturnal hemoglobinuria symptoms and signs, all had an elevated lactate dehydrogenase and a clone size greater than 50%. In all, 18 (8.6%) patients had a clone greater than 50% at any given time of sampling.

Conclusions

The presence of a paroxysmal nocturnal hemoglobinuria clone in severe aplastic anemia is associated with low morbidity and mortality, and specific measures to address clinical paroxysmal nocturnal hemoglobinuria are seldom required.     

Loss of expression of neutrophil proteinase-3: a factor contributing to thrombotic risk in paroxysmal nocturnal hemoglobinuria

Background

A deficiency of specific glycosylphosphatidyl inositol-anchored proteins in paroxysmal nocturnal hemoglobinuria may be responsible for most of the clinical features of this disease, but some functional consequences may be indirect. For example, the absence of certain glycosylphosphatidyl inositol-anchored proteins in paroxysmal nocturnal hemoglobinuria cells may influence expression of other membrane proteins. Membrane-bound proteinase 3 co-localizes with glycosylphosphatidyl inositol-linked neutrophil antigen 2a, which is absent in patients with paroxysmal nocturnal hemoglobinuria.

Design and Methods

We compared expression of proteinase 3 and neutrophil antigen 2a by flow cytometry and western blotting in normal and paroxysmal nocturnal hemoglobinuria cells and measured cytoplasmic and soluble levels of proteinase 3 by enzyme-linked immunosorbent assays in controls and patients with paroxysmal nocturnal hemoglobinuria. Finally, we studied the effects of proteinase 3 on platelet activation using an in vitro aggregometry assay and flow cytometry.

Results

We showed that membrane-bound proteinase 3 is deficient in patients’ cells, but invariantly present in the cytoplasm regardless of disease phenotype. When we isolated lipid rafts from patients, both molecules were detected only in the rafts from normal cells, but not diseased ones. Membrane-bound proteinase 3 was associated with a decrease in plasma proteinase 3 levels, clone size and history of thrombosis. In addition, we found that treating platelets ex vivo with proteinase 3, but not other agonists, decreased the exposure of an epitope on protease activated receptor-1 needed for thrombin activation. Conversely, treatment of whole blood with serine protease inhibitor enhanced expression of this epitope on protease activated receptor-1 located C-terminal to the thrombin cleavage site on platelets.

Conclusions

We demonstrated that deficiency of glycosylphosphatidyl inositol-anchored proteins in paroxysmal nocturnal hemoglobinuria results in decreased membrane-bound and soluble proteinase 3 levels. This phenomenon may constitute another mechanism contributing to a prothrombotic propensity in patients with paroxysmal nocturnal hemoglobinuria.     

Allogeneic stem cell transplantation in paroxysmal nocturnal hemoglobinuria

Background

In the era of eculizumab, identifying patients with paroxysmal nocturnal hemoglobinuria who may benefit from allogeneic stem cell transplantation is challenging.

Design and Methods

We describe the characteristics and overall survival of 211 patients transplanted for paroxysmal nocturnal hemoglobinuria in 83 EBMT centers from 1978 to 2007. Next, we conducted a comparison with a cohort of 402 non-transplanted patients with paroxysmal nocturnal hemoglobinuria diagnosed between 1950 and 2005 in 92 French centers. We compared the occurrence of complications (i.e. thromboembolism and aplastic anemia) using either an individual or a stratum-matching procedure.

Results

After a median follow-up of 5 years, the 5-year overall survival rate ± standard error (%) was 68±3 in the transplanted group (54±7 in the case of thromboembolism, 69±5 in the case of aplastic anemia without thromboembolism and 86±6 in the case of recurrent hemolytic anemia without thromboembolism or aplastic anemia). Only thromboembolism as the indication for transplantation was associated with worse outcome (P=0.03). We identified 24 pairs of transplanted and non-transplanted patients with thromboembolism for the matched comparison, with worse overall survival for the transplanted patients (hazard ratio=10.0; 95% confidence interval, 1.3-78.1; P=0.007). This was confirmed by the global matching procedure (P=0.03). As regards aplastic anemia without thromboembolism, 30 pairs were identified for the matched comparison. It was not observed that transplanted patients had a significantly worse overall survival (hazard ratio=4.0; 95% confidence interval, 0.9-18.9; P=0.06). A global matching procedure was not feasible.

Conclusions

Allogeneic stem cell transplantation is probably not a suitable treatment option for life-threatening thromboembolism in paroxysmal nocturnal hemoglobinuria.Key words: paroxysmal nocturnal hemoglobinuria, hematopoietic stem cell transplantation     

Detection of paroxysmal nocturnal hemoglobinuria clones in patients with myelodysplastic syndromes and related bone marrow diseases, with emphasis on diagnostic pitfalls and caveats

Background

The presence of paroxysmal nocturnal hemoglobinuria clones in the setting of aplastic anemia or myelodysplastic syndrome has been shown to have prognostic and therapeutic implications. However, the status of paroxysmal nocturnal hemoglobinuria clones in various categories of myelodysplastic syndrome and in other bone marrow disorders is not well-studied.

Design and Methods

By using multiparameter flow cytometry immunophenotypic analysis with antibodies specific for four glycosylphosphatidylinositol-anchored proteins (CD55, CD59, CD16, CD66b) and performing an aerolysin lysis confirmatory test in representative cases, we assessed the paroxysmal nocturnal hemoglobinuria-phenotype granulocytes in 110 patients with myelodysplastic syndrome, 15 with myelodysplastic/myeloproliferative disease, 5 with idiopathic myelofibrosis and 6 with acute myeloid leukemia.

Results

Paroxysmal nocturnal hemoglobinuria-phenotype granulocytes were detected in nine patients with low grade myelodysplastic syndrome who showed clinicopathological features of bone marrow failure, similar to aplastic anemia. All paroxysmal nocturnal hemoglobinuria-positive cases demonstrated loss of the four glycosylphosphatidylinositol-anchored proteins, with CD16⁻CD66b⁻ clones being larger than those of CD55⁻CD59⁻ (p<0.05). Altered glycosylphosphatidylinositol-anchored protein expression secondary to granulocytic hypogranulation, immaturity, and/or immunophenotypic abnormalities was present in a substantial number of cases and diagnostically challenging.

Conclusions

These results show that routine screening for paroxysmal nocturnal hemoglobinuria clones in patients with an intrinsic bone marrow disease who show no clinical evidence of hemolysis has an appreciable yield in patients with low grade myelodysplastic syndromes. The recognition of diagnostic caveats and pitfalls associated with the underlying intrinsic bone marrow disease is essential in interpreting paroxysmal nocturnal hemoglobinuria testing correctly. In our experience, the CD16/CD66b antibody combination is superior to CD55/CD59 in screening for subclinical paroxysmal nocturnal hemoglobinuria because it detects a large clone size and is less subject to analytical interference.     

Hematopoietic stem cell transplantation for paroxysmal nocturnal hemoglobinuria: long-term results of a retrospective study on behalf of the Gruppo Italiano Trapianto Midollo Osseo (GITMO)

Background

Paroxysmal nocturnal hemoglobinuria is an acquired clonal disorder of the hemopoietic stem cells for which the only curative treatment is allogeneic hematopoietic stem cell transplantation.

Design and Methods

The aim of this retrospective study was to assess the long-term clinical and hematologic results in 26 paroxysmal nocturnal hemoglobinuria patients who received hematopoietic stem cell transplantation in Italy between 1988 and 2006. The patients were aged 22 to 60 years (median 32 years). Twenty-three donors were HLA-identical (22 siblings and one unrelated) and 3 were HLA-mismatched (2 related and one unrelated).

Results

Fifteen patients received a myeloablative conditioning consisting of busulfan and cyclophosphamide (in all cases from identical donor) and 11 were given a reduced intensity conditioning (8 from identical donor and 3 from mismatched donor). The cumulative incidence of graft failure was 8% (4% primary and 4% secondary graft failure). Transplant-related mortality for all patients was 42% (26% and 63% for patients transplanted following myeloablative or reduced intensity conditioning, respectively). As of October 31, 2009, 15 patients (11 in the myeloablative conditioning group and 4 in the reduced intensity conditioning group) are alive with complete hematologic recovery and no evidence of paroxysmal nocturnal hemoglobinuria following a median follow-up of 131 months (range 30–240). The 10-year Kaplan-Meier probability of disease-free survival was 57% for all patients: 65% for 23 patients transplanted from identical donor and 73% for 15 patients transplanted with myeloablative conditioning. No thromboembolic event nor recurrence of the disease were reported following transplant.

Conclusions

The findings of this study confirm that most patients with paroxysmal nocturnal hemoglobinuria may be definitively cured with hematopoietic stem cell transplantation.     

The small population of PIG-A mutant cells in myelodysplastic syndromes do not arise from multipotent hematopoietic stem cells

Background

Patients with paroxysmal nocturnal hemoglobinuria harbor clonal glycosylphosphatidylinositol-anchor deficient cells arising from a multipotent hematopoietic stem cell acquiring a PIG-A mutation. Many patients with aplastic anemia and myelodysplastic syndromes also harbor small populations of glycosylphosphatidylinositol-anchor deficient cells. Patients with aplastic anemia often evolve into paroxysmal nocturnal hemoglobinuria; however, myelodysplastic syndromes seldom evolve into paroxysmal nocturnal hemoglobinuria. Here, we investigate the origin and clonality of small glycosylphosphatidylinositol-anchor deficient cell populations in aplastic anemia and myelodysplastic syndromes.

Design and Methods

We used peripheral blood flow cytometry to identify glycosylphosphatidylinositol-anchor deficient blood cells, a proaerolysin-resistant colony forming cell assay to select glycosylphosphatidylinositol-anchor deficient progenitor cells, a novel T-lymphocyte enrichment culture assay with proaerolysin selection to expand glycosylphosphatidylinositol-anchor deficient T lymphocytes, and PIG-A gene sequencing assays to identify and analyze PIG-A mutations in patients with aplastic anemia and myelodysplastic syndromes.

Results

Twelve of 15 aplastic anemia patients were found to harbor a small population of glycosylphosphatidylinositol-anchor deficient granulocytes; 11 of them were found to harbor a small population of glycosylphosphatidylinositol-anchor deficient erythrocytes, 10 patients were detected to harbor glycosylphosphatidylinositol-anchor deficient T lymphocytes, and 3 of them were detected only after T-lymphocyte enrichment in proaerolysin selection. PIG-A mutation analyses on 3 patients showed that all of them harbored a matching PIG-A mutation between CFU-GM and enriched T lymphocytes. Two of 26 myelodysplastic syndromes were found to harbor small populations of glycosylphosphatidylinositol-anchor deficient granulocytes and erythrocytes transiently. Bone marrow derived CD34⁺ cells from 4 patients grew proaerolysin-resistant colony forming cells bearing PIG-A mutations. No glycosylphosphatidylinositol-anchor deficient T lymphocytes were detected in myelodysplastic syndrome patients.

Conclusions

In contrast to aplastic anemia and paroxysmal nocturnal hemoglobinuria, where PIG-A mutations arise from multipotent hematopoietic stem cells, glycosylphosphatidylinositol-anchor deficient cells in myelodysplastic syndromes appear to arise from more committed progenitors.     

Thrombectomy reduces the systemic complications in device-related right atrial septic thrombosis

BACKGROUND:

Septic thrombosis of the right atrium is an unusual complication associated with the use of indwelling devices. The optimal management of this condition is unclear. Our experience with a patient with hemodialysis catheter-related septic thrombosis of the right atrium illustrates the difficulties associated with this condition.

OBJECTIVES:

To determine the effects of surgical thrombectomy compared with nonsurgical treatment with antibiotics (with or without anticoagulation) on mortality rates and complications in patients with device-related septic thrombosis of the right atrium.

METHODS:

A retrospective analysis of all reported cases of device-related right heart septic thrombosis in which therapy and outcome were reported was conducted using a PubMed search in the English-language literature (1985 to 2006).

RESULTS:

Forty cases of device-related right atrial septic thromboses were reported in the literature during the chosen time period. The treatments administered were none (12.5%), antibiotics (12.5%), antibiotics and anticoagulation (20%), and thrombectomy (55%). The mean clot size was significantly larger in patients who underwent thrombectomy. All untreated patients died. Excluding the untreated patients from the analysis, systemic complications were significantly lower in the thrombectomy group than in the groups receiving nonsurgical therapies. Using multivariate modelling with survival as the primary outcome, age, sex, clot size, clot location, microbial organism or type of treatment were not predictive of the outcome.

CONCLUSION:

Device-related right atrial septic thrombosis is associated with significant mortality and is uniformly fatal if untreated. Surgical thrombectomy is associated with less frequent systemic complications. A well-designed prospective, randomized trial is needed to determine the optimal treatment of this condition.     

Thrombolytic therapy for inferior vena cava thrombosis in paroxysmal nocturnal hemoglobinuria

Two patients with paroxysmal nocturnal hemoglobinuria had increasing abdominal girth and ascites. The Budd-Chiari syndrome or inferior vena cava thrombosis was shown by angiography. After thrombolytic therapy, both patients improved, and thrombolysis was shown by radiography. Neither patient had induction of hemolysis secondary to these agents. These studies suggest that both streptokinase and urokinase are safe and effective in the treatment of intra-abdominal venous thromboses associated with paroxysmal nocturnal hemoglobinuria.     

Phenotypic and functional characterization of a mouse model of targeted Pig-a deletion in hematopoietic cells

Background

Somatic mutation in the X-linked phosphatidylinositol glycan class A gene (PIG-A) causes glycosyl phosphatidylinositol anchor deficiency in human patients with paroxysmal nocturnal hemoglobinuria.

Design and Methods

We produced an animal model of paroxysmal nocturnal hemoglobinuria by conditional Pig-a gene inactivation (Pig-a^−/−) in hematopoietic cells; mice carrying two lox sites flanking exon 6 of the Pig-a gene were bred with mice carrying the transgene Cre-recombinase under the human c-fes promoter. We characterized the phenotypic and functional properties of glycosyl phosphatidylinositol-deficient and glycosyl phosphatidylinositol-normal hematopoietic cells from these Pig-a^−/− mice using gene expression microarray, flow cytometry, bone marrow transplantation, spectratyping, and immunoblotting.

Results

In comparison to glycosyl phosphatidylinositol-normal bone marrow cells, glycosyl phosphatidylinositol-deficient bone marrow cells from the same Pig-a^−/− animals showed up-regulation of the expression of immune function genes and contained a significantly higher proportion of CD8 T cells. Both characteristics were maintained when glycosyl phosphatidylinositol-deficient cells were transplanted into lethally-irradiated recipients. Glycosyl phosphatidylinositol-deficient T cells were inactive, showed pronounced Vβ5.1/5.2 skewing, had fewer γ-interferon-producing cells after lectin stimulation, and contained fewer CD4⁺CD25⁺FoxP3⁺ regulatory T cells. However, the levels of T-cell receptor signaling proteins from glycosyl phosphatidylinositol-deficient cells were normal relative to glycosyl phosphatidylinositol-normal cells from wild type animals, and cells were capable of inducing target cell apoptosis in vitro.

Conclusions

Deletion of the Pig-a gene in hematopoietic cells does not cause frank marrow failure but leads to the appearance of clonally-restricted, inactive yet functionally competent CD8 T cells.     

CMS Reimbursement Reform and the Incidence of Hospital-Acquired Pulmonary Embolism or Deep Vein Thrombosis

BACKGROUND

In October 2008, the Centers for Medicare & Medicaid Services (CMS) stopped reimbursing hospitals for the marginal cost of treating certain preventable hospital-acquired conditions.

OBJECTIVE

This study evaluates whether CMS’s refusal to pay for hospital-acquired pulmonary embolism (PE) or deep vein thrombosis (DVT) resulted in a lower incidence of these conditions.

DESIGN

We employ difference-in-differences modeling using 2007–2009 data from the Nationwide Inpatient Sample, an all-payer database of inpatient discharges in the U.S. Discharges between 1 January 2007 and 30 September 2008 were considered “before payment reform;” discharges between 1 October 2008 and 31 December 2009 were considered “after payment reform.” Hierarchical regression models were fit to account for clustering of observations within hospitals.

PARTICIPANTS

The “before payment reform” and “after payment reform” incidences of PE or DVT among 65–69-year-old Medicare recipients were compared with three different control groups of: a) 60–64-year-old non-Medicare patients; b) 65–69-year-old non-Medicare patients; and c) 65–69-year-old privately insured patients. Hospital reimbursements for the control groups were not affected by payment reform.

INTERVENTION

CMS payment reform for hospital-based reimbursement of patients with hip and knee replacement surgeries.

MAIN MEASURES

The outcome was the incidence proportion of hip and knee replacement surgery admissions that developed pulmonary embolism or deep vein thrombosis.

KEY RESULTS

At baseline, pulmonary embolism or deep vein thrombosis were present in 0.81 % of all hip or knee replacement surgeries for Medicare patients aged 65–69 years old. CMS payment reform resulted in a 35 % lower incidence of hospital-acquired pulmonary embolism or deep vein thrombosis in these patients (p = 0.015). Results were robust to sensitivity analyses.

CONCLUSION

CMS’s refusal to pay for hospital-acquired conditions resulted in a lower incidence of hospital-acquired pulmonary embolism or deep vein thrombosis after hip or knee replacement surgery. Payment reform had the desired direction of effect.KEY WORDS: payment reform, pay-for-performance, hospital-acquired conditions, pulmonary embolism, deep vein thrombosis     

Should symptomatic,isolated distal deep vein thrombosis be treated with anticoagulation?

BACKGROUND:

During the past two decades, the diagnosis of deep venous thrombosis (DVT) has made considerable progress. The term distal or calf vein thrombosis includes thrombosis in infrapopliteal veins, including the posterior tibial, peroneal, anterior tibial and muscular calf veins. The necessity of treating of distal DVT is debatable.

OBJECTIVE:

To determine whether treatment of isolated, distal DVT with anticoagulation versus no treatment affects patient outcome.

METHODS:

All patients discharged with a diagnosis of distal DVT from Tan Tock Seng Hospital, Singapore, between January 1, 2006, and December 31, 2007, were identified by the medical records office of the hospital. Compression of the intraluminal thrombus by duplex scan was used to diagnose distal DVT. Excluded were patients who either had both distal and proximal DVT, or had distal DVT along with pulmonary embolism (PE) at presentation.Complete resolution of distal DVT on repeat duplex scan was used to measure the primary outcome. Repeat follow-up scans were performed at two weeks, one month, three months and six months, or on subsequent follow-up until the distal DVT had resolved completely.Secondary outcome measures were complete improvement of symptoms, progression of thrombosis, or PE or death during the follow-up period.The study included 68 patients with distal DVT; however, 17 patients with PE, two of whom had proximal DVT (in the iliac and common femoral veins) at the first presentation along with distal DVT, were excluded from the study. In total, 51 patients were included for analysis. The follow-up scan was available in 35 patients; therefore, the primary analysis was performed in 35 patients (47 incidences of distal DVT). However, the secondary analysis was available in all 51 patients.Of the 35 patients available for follow-up scans, 17 patients (25 incidences of distal DVT) received anticoagulation and 18 patients (22 incidences of distal DVT) received no anticoagulation.Of the 17 patients who were treated with anticoagulation, nine patients (13 incidences of distal DVT) received enoxaparin at a dose of 1 mg/kg twice a day for two weeks and eight patients (12 incidences of distal DVT) received warfarin for a period of three months with initial overlap of enoxaparin 1 mg/kg twice a day for three to five days. Once the prothrombin time international normalized ratio of a patient on warfarin was between 2 and 3, enoxaparin was discontinued. The 18 patients who did not receive anticoagulation received follow-up with regular duplex scan.

RESULTS:

There were no statistically significant differences among the groups in the resolution of distal DVT or symptom improvement with or without treatment. In the group that received no treatment, one death occurred. Proximal extension and PE were not recorded in any of the patients.

CONCLUSION:

Distal DVT may not require treatment with anticoagulation. If leg symptoms worsen, or if there is an extension of distal DVT on the follow-up scan, treatment with anticoagulation is recommended.     

Percutaneous management of prosthetic valve thrombosis

Background

Thrombosis of a prosthetic valve is a serious complication in patients with prosthetic heart valves. Thrombolysis is the initial choice of treatment. Patients who do not respond to thrombolysis are subjected to surgery which carries a high risk. We report a case series of 5 patients with prosthetic mitral valve thrombosis who did not respond to thrombolysis and were subjected to percutaneous manipulation of the prosthetic valves successfully and improved.

Methods

Five patients who were diagnosed to have prosthetic mitral valve thrombosis and failed to respond to a minimum of 36 h of thrombolysis (persistent symptoms with increased gradients, abnormal findings on fluoroscopy),were subjected to percutaneous treatment after receiving proper consent. None of them had a visible thrombus on transthoracic echocardiogram. All patients underwent transseptal puncture following which a 6F JR4 guiding catheter was passed into the left atrium. The valve leaflets were repeatedly hit gently under fluoroscopic guidance till they regained their normal mobility.

Results

Mean age was 38.8 years. Average peak and mean gradients prior to the procedure were 38 and 25 and after the procedure were 12 and 6 mm of Hg respectively. All patients had successful recovery of valve motion on fluoroscopy with normalization of gradients and complete resolution of symptoms. None of the patients had any focal neurological deficits, embolic manifestations or bleeding complications.

Conclusions

Percutaneous manipulation of prosthetic valves in selected patients with prosthetic valve thrombosis who do not respond to thrombolytic therapy is feasible and can be used as an alternative to surgery.     

Post-thrombotic syndrome in children: a systematic review of frequency of occurrence, validity of outcome measures, and prognostic factors

Background

Post-thrombotic syndrome is a manifestation of chronic venous insufficiency following deep venous thrombosis. This systematic review was conducted to critically evaluate pediatric evidence on frequency of occurrence, validity of outcome measures, and prognostic indicators of post-thrombotic syndrome.

Design and Methods

A comprehensive literature search of original reports revealed 19 eligible studies, totaling 977 patients with upper/lower extremity deep venous thrombosis. Calculated weighted mean frequency of post-thrombotic syndrome was 26% (95% confidence interval: 23–28%) overall, and differed significantly by prospective/non-prospective analysis and use/non-use of a standardized outcome measure.

Results

Standardized post-thrombotic syndrome outcome measures included an adaptation of the Villalta scale, the Clinical-Etiologic-Anatomic-Pathologic classification, and the Manco-Johnson instrument. Data on validity were reported only for the Manco-Johnson instrument. No publications on post-thrombotic syndrome-related quality of life outcomes were identified. Candidate prognostic factors for post-thrombotic syndrome in prospective studies included use/non-use of thrombolysis and plasma levels of factor VIII activity and D-dimer.

Conclusions

Given that affected children must endure chronic sequelae for many decades, it is imperative that future collaborative pediatric prospective cohort studies and trials assess as key objectives and outcomes the incidence, severity, prognostic indicators, and health impact of post-thrombotic syndrome, using validated measures.     

Initial thrombolysis treatment compared with anticoagulation for acute intermediate-risk pulmonary embolism: a meta-analysis

Background

The use of thrombolysis in patients with acute, intermediate-risk pulmonary embolism (PE) remains controversial. This meta-analysis compared the efficacy and safety of thrombolysis and anticoagulation treatments for intermediate-risk PE patients.

Methods

Two investigators independently reviewed the literature and collected data from randomized controlled trials (RCTs) of thrombolysis for intermediate-risk PE in the PubMed, MEDLINE, EMBASE, the Cochrane Library, and Chinese Biomedical Literature Databases (CBM).

Results

A total of 1,631 intermediate-risk PE patients from seven studies were included. Significant differences were not found regarding the 30-day, all-cause mortality rates between the thrombolytic and anticoagulant groups [odds ratio (OR), 0.60; 95% confident interval (CI), 0.34-1.06; P=0.08]. The rate of clinical deterioration in the thrombolytic group was lower than that in the anticoagulant group (OR, 0.27; 95% CI, 0.18-0.41; P<0.01). Recurrent PE in the thrombolytic group was also significantly lower than that in the anticoagulant group (OR, 0.34; 95% CI, 0.15-0.77; P=0.01). Comparing the thrombolytic and anticoagulation groups, the incidence of minor bleeding was significantly higher in the thrombolytic group (OR, 5.33; 95% CI, 2.85-9.97; P<0.00001), but there were no difference in the incidences of major bleeding events (OR, 2.07; 95% CI, 0.60-7.16; P=0.25).

Conclusions

Thrombolytic treatment for intermediate-risk PE patients, if not contraindicated, could reduce clinical deterioration and recurrence of PE, and trends towards a decrease in all-cause, 30-day mortality. Despite thrombolytic treatment having an increased total bleeding risk, there was no difference in the incidence of major bleeding events, compared with patients receiving anticoagulation treatment.     

Risk factors and complications following percutaneous endoscopic gastrostomy: a case series of 1041 patients

BACKGROUND:

Most studies exclude patients with severe coagulation disorders or those taking anticoagulants when evaluating the outcomes of percutaneous endoscopic gastrostomy (PEG).

OBJECTIVE:

To investigate complications and risk factors of PEG in a large clinical series including patients undergoing antiplatelet and anticoagulant therapy.

METHODS:

During a six-year period, 1057 patients referred for PEG placement were prospectively audited for clinical outcome. Exclusion criteria and follow-up care were defined. Complications were defined as minor or severe. Uni- and multivariate analyses were used to evaluate 14 risk factors. No standardized antibiotic prophylaxis was given.

RESULTS:

A total of 1041 patients (66% male, 34% female) with the following conditions underwent PEG: neurogenic dysphagia (n=450), cancer (n=385) and others (n=206). No anticoagulants were administered to 351 patients, thrombosis prophylaxis was given to 348 while full therapeutic anticoagulation was received by 313. No increased bleeding risk was associated with patients who had above-normal international normalized ratio values (OR 0.79 [95% CI 0.08 to 7.64]; P=1.00). The total infection rate was 20.5% in patients with malignant disease, and 5.5% in those with nonmalignant disease. Severe complications occurred in 19 patients (bleeding 0.5%, peritonitis 1.3%). Cirrhosis (OR 2.91 [95% CI 1.31 to 6.54]; P=0.008), cancer (OR 2.34 [95% CI 1.33 to 4.12]; P=0.003) and radiation therapy (OR 2.34 [95% CI 1.35 to 4.05]; P=0.002) were significant predictors of post-PEG infection. The 30-day mortality rate was 5.8%. There were no procedure-related deaths.

CONCLUSIONS:

Cancer, cirrhosis and radiation therapy were predictors of infection. Post-PEG bleeding and other complications were rare events. Collectively, the data suggested that patients taking concurrent anticoagulants had no elevated risk of post-PEG bleeding.     

Thrombolysis for Acute Stroke in Hemodialysis: International Survey of Expert Opinion

Summary

Background and objectives

Although data are absent, it has been stated that thrombolysis is probably not safe in the treatment of acute stroke in patients undergoing hemodialysis. The objective of this study was for stroke experts to define the range of management concerning thrombolytic treatment of acute stroke in hemodialysis.

Design, setting, participants, & measurements

Sixty-five stroke experts in thrombolytic therapy of acute ischemic stroke were queried regarding their personal experience in the use of thrombolysis in hemodialysis patients. Hypothetical case scenarios were presented.

Results

Of the 65 stroke experts who were queried, 40 (62%) responded. One-third of the responders had previously treated hemodialysis patients with recombinant tissue-type plasminogen activator (rt-PA). Most favored use of intravenous rt-PA for hemodialysis patients with acute ischemic stroke. When presented with a case of a patient who had recently undergone dialysis with a mildly prolonged activated partial thromboplastin time (aPTT), 50% favored immediate intravenous thrombolysis. Seventy-eight percent of the experts would have considered an intra-arterial approach and would have preferred mechanical clot retrieval to thrombolysis.

Conclusions

Despite the acknowledged absence of data and prevalent concerns about bleeding risk, most surveyed experts favored its use. One-third reported treating hemodialysis patients with this therapy. Although these results do not substitute for data, they usefully define the range of current practice of stroke experts.     

Behavioral Cardiology: Cardiology’s New Frontier of Action

Introduction

Atrial fibrillation and atrial flutter account for one third of hospitalizations due to arrhythmias, determining great social and economic impacts. In Brazil, data on hospital care of these patients is scarce.

Objective

To investigate the arrhythmia subtype of atrial fibrillation and flutter patients in the emergency setting and compare the clinical profile, thromboembolic risk and anticoagulants use.

Methods

Cross-sectional retrospective study, with data collection from medical records of every patient treated for atrial fibrillation and flutter in the emergency department of Instituto de Cardiologia do Rio Grande do Sul during the first trimester of 2012.

Results

We included 407 patients (356 had atrial fibrillation and 51 had flutter). Patients with paroxysmal atrial fibrillation were in average 5 years younger than those with persistent atrial fibrillation. Compared to paroxysmal atrial fibrillation patients, those with persistent atrial fibrillation and flutter had larger atrial diameter (48.6 ± 7.2 vs. 47.2 ± 6.2 vs. 42.3 ± 6.4; p < 0.01) and lower left ventricular ejection fraction (66.8 ± 11 vs. 53.9 ± 17 vs. 57.4 ± 16; p < 0.01). The prevalence of stroke and heart failure was higher in persistent atrial fibrillation and flutter patients. Those with paroxysmal atrial fibrillation and flutter had higher prevalence of CHADS2 score of zero when compared to those with persistent atrial fibrillation (27.8% vs. 18% vs. 4.9%; p < 0.01). The prevalence of anticoagulation in patients with CHA2DS2-Vasc ≤ 2 was 40%.

Conclusions

The population in our registry was similar in its comorbidities and demographic profile to those of North American and European registries. Despite the high thromboembolic risk, the use of anticoagulants was low, revealing difficulties for incorporating guideline recommendations. Public health strategies should be adopted in order to improve these rates.     

Pharmaco – Mechanical management of acute massive pulmonary embolism in a postpartum female

Background

The optimal use of pharmaco-mechanical therapy is not clear in the management of the acute massive pulmonary thromboembolism.

Methods

A 30-year-old postpartum female presented with acute massive pulmonary embolism and was managed with catheter mediated thrombus aspiration and fragmentation after the standard intravenous thrombolysis had failed. Thrombus was aspirated by 7F Mullins sheath with 50cc aspiration syringe and was fragmented by TYSHAK II PTV balloon. This was followed by catheter directed thrombolysis.

Results

Intravenous thrombolysis was only partially successful whereas catheter mediated thrombus aspiration and fragmentation followed by catheter directed thrombolysis resulted in hemodynamic stabilization and early discharge from the hospital.

Conclusion

Pharmaco-mechanical therapy is an effective therapy of acute massive pulmonary embolism and may be beneficial over the standard systemic thrombolysis.     

Detection of paroxysmal atrial fibrillation or flutter in patients with acute ischemic stroke or transient ischemic attack by Holter monitoring

Background and purpose

Paroxysmal atrial fibrillation and flutter are strong risk factors for stroke. Due to high recurrence rate of ischemic events and given the benefit of oral anticoagulation over antiplatelet drugs, it is important to identify this arrhythmia. Unfortunately, paroxysmal AF or flutter is asymptomatic in majority and therefore, difficult to detect.

Methods

Consecutive patients presenting with symptoms of acute ischemic stroke or transient ischemic attack were included. All patients free of AF or flutter on presentation underwent 24 h Holter monitoring within 7 days of admission.

Results

Overall, fifty two (52) patients (mean age 59.51 ± 13.45 years) with acute stroke (80.8%) and TIA (19.8%) underwent 24 h Holter monitoring. Paroxysmal AF was detected in 3 cases (5.8%), all 3 patients had acute stroke and were older than age 60 years. Type of stroke was the only factor which was associated with greater risk of having paroxysmal AF or flutter, AF accounted for 50% cases (2 out of 4) of clinically suspected cardio embolic stroke.

Conclusion

Screening consecutive patients with ischemic stroke with routine Holter monitoring will identify new atrial fibrillation/flutter in approximately one in 17 patients. Older age and type of stroke are strongly associated with increased risk. By carefully selecting the patients, the detection rates could be further increased.