Safety and efficacy of pharmacological thromboprophylaxis for hospitalized patients with cirrhosis: a single-center retrospective cohort study.

BACKGROUND: Hospitalized patients with cirrhosis are at increased risk for venous thromboembolism (VTE). The benefits and risks of pharmacological thromboprohylaxis in these patients have not been well studied. OBJECTIVES: To examine the safety and efficacy of pharmacological VTE prophylaxis in hospitalized cirrhotic patients. PATIENTS/METHODS: Retrospective cohort study of patients with cirrhosis hospitalized at an academic tertiary care referral center over a 5-year period. RESULTS: Six hundred hospital admissions accounting for 402 patients were included. VTE prophylaxis was administered during 296 (49%) admissions. Patients receiving VTE prophylaxis were older (59 years vs. 55 years, P < 0.001), had longer lengths of stay (9.6 days vs. 6.8 days, P = 0.002), and lower Model for End-Stage Liver Disease scores (13.2 vs. 16.1, P < 0.001). In-hospital bleeding events (8.1% vs. 5.5%, P = 0.258), gastrointestinal bleeding events (3.0% vs. 3.2% P = 0.52), new VTE events (2.37% vs. 1.65%, P = 0.537), and mortality (8.4% vs. 7.3%, P = 0.599) were similar in the two groups. VTE prophylaxis did not reduce the risk of VTE (odds ratio 0.94, 95% confidence interval 0.23-3.71), and patients receiving unfractionated heparin, but not low molecular weight heparin, were at increased risk for in-hospital bleeding events (odds ratio 2.38, 95% confidence interval 1.15-4.94 vs. 0.87, 0.37-2.05, respectively). CONCLUSION: The rate of VTE in this cohort of hospitalized cirrhotic patients was low and was unaffected by pharmacological thromboprophylaxis. Unfractionated heparin was associated with an increased risk for in-hospital bleeding, suggesting that if thromboprophylaxis is indicated, low molecular weight heparin may be favored.

Remission of paroxysmal atrial fibrillation with iron reduction in haemophilia A.

SUMMARY: Two male first cousins with mild haemophilia A had baseline factor VIII levels of 12-15% and experienced bleeding requiring coagulation factor infusion therapy with trauma and surgical procedures. Both the patients with haemophilia A also had electrocardiographically documented symptomatic paroxysmal atrial fibrillation (PAF) for several years that had become resistant to pharmacological suppression. Radiofrequency ablation was considered in both the cases but deferred considering refusal of consent by the patients to undergo the procedure. Remission of arrhythmias has been reported in patients with iron-overload syndromes. Body iron stores assessed by serum ferritin levels were elevated in both men but neither had the C282Y or H63D genes for haemochromatosis. Calibrated reduction of iron stores by serial phlebotomy, avoiding iron deficiency, was followed by remission of symptomatic PAF in both cases. Iron reduction may be an effective treatment for arrhythmias apart from the classic iron-overload syndromes and deserves further study particularly in patients with bleeding disorders who might be at risk for arrhythmias and other diseases of ageing.

Activated platelets enhance ovarian cancer cell invasion in a cellular model of metastasis.

Increased platelet counts and systemic coagulation activation are associated with ovarian cancer progression. Platelet activation occurs in the tumor microenvironment and may influence local invasion and metastasis. We used a cellular model of tumor invasion to investigate the effect of activated platelets on the human ovarian cancer cell line, SKOV3. SKOV3 cells were exposed to washed, thrombin receptor activating peptide (TRAP)-activated or TRAP-naïve platelets under various experimental conditions, and tumor cell invasion was assayed in Matrigel chambers. The effect of platelets on the content of urokinase plasminogen activator (uPA) and VEGF in SKOV3 cell conditioned medium was measured using an ELISA assay. TRAP-activated platelets stimulated a dose-dependent increase in SKOV3 cell invasion. Exposure to activated platelet membranes and to soluble proteins contained in activated platelet releasate both contributed to the observed increase in invasion. The inhibition of platelet activation with prostaglandin E1 (PGE(1)) attenuated the invasive capacity of SKOV3 cells. Exposure to platelets resulted in significantly increased uPA and VEGF content of SKOV3 cell conditioned medium. Activated platelets enhance SKOV3 human ovarian cancer cell invasion through Matrigel and increase the amount of uPA and VEGF secreted into SKOV3 cell conditioned medium. If generalizable to additional cell lines and human disease, this observation may partially explain the adverse prognosis associated with thrombocytosis in ovarian cancer. Platelets, therefore, may represent a potential target for therapeutic intervention in human ovarian cancer.

Nonmyeloablative allogeneic peripheral blood stem cell transplantation for multifocal extramedullary plasmacytomas progressing after autologous transplantation.

Multifocal extramedullary plasmacytomas (EMP) are an uncommon manifestation of plasma cell malignancies. We report two patients with multiple EMP who developed rapidly progressive and ultimately fatal disease shortly after undergoing nonmyeloablative, matched-related donor allogeneic peripheral blood stem cell transplantation (PBSCT). We have not observed a similar course in patients transplanted for multiple myeloma without extramedullary manifestations and hypothesize that the intense immunosuppression associated with the fludarabine, busulfan and anti-thymocyte globulin conditioning regimen may have contributed to rapid disease progression in the two EMP patients. Our observations support the assertion that extramedullary disease is a marker for an aggressive, refractory plasma cell malignancy and suggest that patients should be treated intensively from the time of diagnosis. The utility of a graft-versus-tumor effect and the role of nonmyeloablative allogeneic PBSCT is yet to be defined in patients with extramedullary plasma cell malignancies, but it is logical to consider using it at the time of minimal residual disease rather than at disease relapse or progression. Nevertheless, we recommend circumspection in the administration of highly immunosuppressive conditioning regimens to patients with refractory EMP and encourage further clinical research in this area.

Low-molecular-weight heparins for the prevention and treatment of venous thromboembolism.

Low-molecular-weight heparins (LMWHs) are rapidly becoming the anticoagulants of choice for the prevention and treatment of venous thromboembolism. LMWHs are at least as safe and effective as unfractionated heparin, and they have the added advantage of improved pharmacokinetic and safety profiles. The result is that LMWHs are easier to use, provide a more predictable anticoagulant effect, and do not require routine laboratory monitoring in most circumstances. Currently, the LMWHs ardeparin, dalteparin, danaparoid, enoxaparin, and tinzaparin have Food and Drug Administration-approved indications in the United States. This paper reviews the clinical use and cost-effectiveness of the LMWHs for the prevention and treatment of venous thromboembolism.

Treatment of cancer with anticoagulants: rationale in the treatment of melanoma.

The blood coagulation mechanism regulates the growth and dissemination of malignancy by multiple mechanisms, and anticoagulant drugs have been shown to inhibit the progression of certain cancers. Although progress has been slow, there is ample information on the effects of anticoagulants in various tumors that suggests that the use of anticoagulants has considerable potential in the treatment of some cancers. For example, melanoma is one of a small number of human tumor types in which the tumor is associated with an intact coagulation pathway leading to thrombin generation and conversion of fibrinogen to fibrin in situ immediately adjacent to viable tumor cells. Observations in experimental models combined with the limited clinical trial data on this subject suggest that inhibition of tumor cell thrombin generation may improve outcomes in melanoma cases. Thus, we postulate that pharmacological interruption of the tumor cell-associated coagulation pathway at any one step or even at multiple levels might constitute effective therapy for this disease. Drugs that block the activity of tissue factor, factor Xa, or thrombin are available for clinical testing and, if effective, offer the prospect of a relatively nontoxic, novel treatment for this aggressive tumor.

Graft failure in a patient with systemic lupus erythematosus (SLE) treated with high-dose immunosuppression and autologous stem cell rescue.

A 32-year-old female with WHO grade IV, dialysis dependent, lupus nephritis was treated with high-dose immunosuppression and autologous stem cell rescue. Stem cells were mobilized with cyclophosphamide (CY) and G-CSF, and 4.07 x 10(6) CD34+ cells/kg were obtained after CD34+ cell selection using the CellPro column. The preparative regimen consisted of CY, and antithymocyte globulin (ATG), with methylprednisolone. After apparent primary engraftment of neutrophils on day 9, the patient developed recurrent neutropenia on day 19. She showed no evidence of engraftment by day 35, and back-up unmanipulated stem cells were given without effect. Subsequently, she received unmanipulated peripheral stem cells (2 x 10(6) CD34+ cells/kg) from an HLA-identical sibling. The patient remained pancytopenic and expired on day 62 from disseminated fungal infection. An autopsy revealed no evidence of hematopoietic recovery. Progenitor cell assays were performed with the patient's stem cells, which were collected prior to transplantation, and serum collected day 27. Morphologic examination of the patient's cell colonies grown in the presence of her serum revealed abnormal shapes and non-adherent cells. There were significantly fewer BFU-e colonies and a trend toward fewer CFU-GM colonies with the patient's cells and serum compared to normal donor cells. We concluded that a substance present in her serum mediated graft failure and prevented engraftment after additional stem cell infusions.

Treatment of severe thrombocytopenia in alloimmunized, transfusion-refractory patients.

A significant proportion of patients with hematologic malignancies who are exposed to multiple transfusions will develop alloantibodies to platelet human leukocyte antigens (HLA), resulting in poor responses to subsequent platelet transfusions. Transfusion of HLA-identical platelets is an effective method of platelet support in these patients, but perfectly HLA-matched platelets are often not available. In this paper, we review the recent literature on platelet transfusion support in alloimmunized individuals and illustrate alternative management strategies with cases from our own practice.

Cancer treatment with inhibitors of urokinase-type plasminogen activator and plasmin.

The urokinase-type plasminogen activator-plasmin system plays an important role in many normal physiological processes including clot lysis, wound healing, embryogenesis and tissue remodelling. It is also involved in the pathogenesis of human malignancy through its ability to mediate tumour cell growth, invasion and metastatic dissemination. Interfering with this system is an appealing approach for experimental therapy of malignancy for several reasons. This concept is supported by a wealth of preclinical data. Evidence exists suggesting a role for this system in several major human tumour types. Preliminary evidence suggests that agents which block this pathway are effective in therapeutic doses that are already defined and relatively non-toxic. This form of treatment is not likely to carry cross-resistance with other types of cancer therapy and should be applicable to both localised and advanced tumours. Since heterogeneity in responsiveness among various tumour types is expected, clinical effects in given tumours would provide a basis for interpreting mechanisms of tumour progression in vivo and for future development of drugs with improved efficacy. Inhibition of the urokinase-type plasminogen activator-plasmin system remains a promising, but largely untested, area of experimental cancer therapeutics.

Low-molecular-weight heparin and cancer.

Heparin is a familiar anticoagulant drug with properties that may impede tumor growth; it modifies properties of cells that contribute to malignant dissemination such as angiogenesis, growth factor and protease activity, immune function, proliferation, and gene expression. Heparin has antitumor effects in animal models of malignancy, and studies in human malignancy show improved cancer outcome with heparin treatment. Meta-analyses comparing unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) for treatment of deep-vein thrombosis have shown apparent substantial improvement in cancer outcome in the subset of patients with malignancy who were randomly assigned to receive LMWH. This experience, together with the favorable pharmacokinetic properties of LMWH, provides a rationale for prospective clinical trials of LMWH in patients with cancer. Such trials should provide (a) definitive data on possible antitumor effects of this treatment, (b) insight into possible heterogeneous responses to heparin treatment among different histological types and stages of malignancy, and (c) a setting for exploring mechanisms of antineoplastic effect in human malignancy.

Cancer, thrombosis, and anticoagulants.

Rapid progress has been made recently in our understanding of the pathogenesis of coagulation activation in malignancy and mechanisms by which the coagulation mechanism may control malignant growth. Idiopathic thromboembolic disease may be the sentinel presentation in patients subsequently diagnosed with malignancy. Thrombosis complicating the course of malignancy may be notoriously difficult to treat, but the introduction of the low-molecular-weight heparins has greatly improved management and may obviate the need for invasive approaches, such as the use of inferior vena cava filters, in many cases. Tantalizing clues from clinical trials of anticoagulant therapy in cancer have suggested that components of coagulation pathways may support tumor growth. Many of these can be intercepted using drugs that are well known and non-toxic. The importance of performing high-quality controlled clinical trials that build on past studies and on data from basic research cannot be overemphasized.

Association of age, sex, and race with body iron stores in adults: analysis of NHANES III data.

BACKGROUND: This study examined age-, sex-, and race- related increases in body iron stores that have been implicated in disease and the relative utility of the serum ferritin versus the percentage of transferrin saturation for population-based estimation of iron status. METHODS AND RESULTS: Serum ferritin levels were examined by age, sex, and race, and values were compared with the percent transferrin saturation in 20,040 individuals >17 years of age from the third National Health and Nutrition Examination Survey (NHANES III) database. Body iron stores reflected by serum ferritin levels rose in the late teens in men and after menopause in women. This rise was more rapid and maximum ferritin levels were greater for blacks than whites and Hispanics of comparable age and sex. The distribution of values for the serum ferritin differed from the percent transferrin saturation. CONCLUSIONS: Different patterns of iron accumulation exist according to age, sex, and race. Serum ferritin levels reflect graded, population-based differences in body iron stores, but the percentage of transferrin saturation does not. The hypothesis that iron accumulation may contribute to higher morbidity and mortality rates can be tested in clinical trials of calibrated reduction of body iron stores in defined disease settings.

Correlation of CD34+ cell counts with volume of bone marrow collected for allogeneic bone marrow harvests.

The quantity of bone marrow collected for allogeneic bone marrow transplantation is based on collecting 10 to 15 cc of bone marrow/kg of recipient weight. We hypothesized that the percentage of CD34+ cells collected during a bone marrow harvest decreased at the end of the harvest because of increasing amounts of peripheral blood contamination. We performed a prospective, blinded study in which we measured CD34+ percentages and cell counts at 200-cc intervals during bone marrow harvests from 11 consecutive human leukocyte antigen (HLA)-matched sibling bone marrow donors. We observed that the percentage of CD34+ cells in aspirated bone marrow did not vary significantly from the start to the end of the bone marrow harvest, and the total number of CD34+ cells/kg increased in a linear fashion, thus disproving our original hypothesis. In conclusion, the percentage of CD34+ cells in aspirated bone marrow will remain constant throughout a bone marrow harvest.

Docetaxel (Taxotere) in combination chemotherapy and in association with thoracic radiotherapy for the treatment of non-small-cell lung cancer. Thoracic Oncology Program.

Docetaxel is one of the most active single agents for the treatment of non-small-cell lung cancer. Given the preclinical indications for synergy and the lack of cross-resistance with other active agents in this disease, clinical trials of docetaxel combinations have been undertaken. Phase I and II clinical trials of docetaxel in combination with cisplatin, carboplatin, gemcitabine, vinorelbine, or thoracic radiation for patients with non-small-cell lung cancer were reviewed. The endpoint for phase I trials was to define the phase II doses for the docetaxel combinations where overall response rates, median and one year survival were the endpoints. Five phase I-II studies of docetaxel and cisplatin have reported response rates ranging from 21% to 48%. Median survival times ranged from 8 to 13 months, and one-year survivals from 32% to 58%. Combining docetaxel with vinorelbine resulted in a 37% response rate and a median survival of 9.4 months. Docetaxel in combination with gemcitabine produced a response rate of 53%. The adverse events of these combinations were manageable. Responses have also been reported in studies of docetaxel administered with carboplatin or thoracic radiation therapy. Combinations of docetaxel with platinum, vinorelbine, gemcitabine, and radiation were active in non-small-cell lung cancer with acceptable adverse effects. Phase III trials are currently in progress to further define the role of docetaxel combinations in the first-line treatment of this disease.