Systemic bevacizumab for refractory bleeding and transfusion-dependent anemia in Heyde syndrome.

Heyde syndrome, the co-occurrence of aortic stenosis and bleeding gastrointestinal (GI) angiodysplasia, is managed with aortic valve replacement. However, severe bleeding and anemia can preclude safe use of the antiplatelet or anticoagulant therapy required for this intervention. We present a case of the novel and successful treatment of severe, refractory bleeding and transfusion dependence with antiangiogenic therapy in a patient with Heyde syndrome. After systemic bevacizumab was initiated, the patient achieved durable hemostasis with normalization of hemoglobin and liberation from red cell transfusion and dependence on iron infusion; aspirin therapy was successfully initiated where it had previously failed. This durable hemostasis facilitated her subsequent successful transcatheter aortic valve replacement. Plasma vascular endothelial growth factor levels, which were monitored during therapy, paradoxically rose after bevacizumab was initiated but normalized after it was discontinued. Given the angiogenic dysregulation of Heyde syndrome, systemic bevacizumab may be an effective and safe targeted therapy for managing refractory GI bleeding, which thereby facilitates antiplatelet therapy and aortic valve replacement in these challenging cases. Additional investigation into the therapeutic role of inhibiting angiogenesis as a hemostatic modality in Heyde syndrome is warranted.

Cancer Therapy-Associated Thrombosis.

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Effect of chemotherapy and longitudinal analysis of circulating extracellular vesicle tissue factor activity in patients with pancreatic and colorectal cancer.

INTRODUCTION: We conducted a longitudinal study in patients with pancreatic and colorectal cancer. We determined the effect of chemotherapy on extracellular vesicle tissue factor (EVTF) activity and the association of plasma EVTF activity with venous thromboembolism (VTE) and survival. MATERIAL AND METHODS: We enrolled 13 patients with pancreatic and 22 patients with colorectal cancer. Plasma samples were collected during the 85-day study period. Patients were followed for 3 months after the study period. We recorded symptomatic VTE during the study period (3 months) or asymptomatic deep vein thrombosis detected by ultrasound at day 85. We measured EVTF activity before and after chemotherapy. RESULTS AND CONCLUSIONS: In the pancreatic cancer group, 2 patients had elevated levels of EVTF activity. One of these patients developed symptomatic VTE and died, and the second patient did not have a VTE but died. Chemotherapy decreased EVTF activity in 2 pancreatic patients with high levels. In the colorectal cancer group, 4 patients developed VTE, but EVTF activity was not elevated in any patient and no patient died. We observed a borderline significant correlation between EVTF activity and D-dimer in the patients with pancreatic but not colorectal cancer. In this small descriptive study, 2 patients with pancreatic cancer had an elevated level of EVTF activity. Both patients died during the study period, and one had a VTE. Chemotherapy decreased EVTF activity in these patients. In contrast, elevated levels of EVTF activity were not observed in patients with colorectal cancer with or without VTE.

Secondary Immune Thrombocytopenia in Metastatic Renal Cell Carcinoma: A Case Report and Discussion of the Literature.

Immune thrombocytopenia (ITP) is a rare paraneoplastic syndrome of solid tumor malignancies. In previously described cases of renal cell carcinoma (RCC) associated with secondary ITP, treatment has consisted of nephrectomy, splenectomy, and corticosteroids. Here, we describe a case of metastatic RCC presenting with a right ventricular mass and subsequent development of secondary ITP. The clinical course was complicated by recurrent severe thrombocytopenia despite treatment with corticosteroids, rituximab, and thrombopoietin receptor agonists, precluding cancer-directed therapy and anticoagulation. Further study is needed to determine the optimal management strategy for malignancy-associated ITP.

Initiating and Managing Patients with Venous Thromboembolism on Anticoagulant Drugs: A Practical Overview.

Several new oral anticoagulants have recently been approved for the treatment of venous thromboembolism (VTE). In this review, we discuss the currently approved drugs and the factors that influence the choice of anticoagulant in a given patient. Once anticoagulation is initiated, periodic monitoring of adequacy of anticoagulation may be necessary depending on the choice of anticoagulant and patient-related factors, such as renal function. Situations that may warrant need for monitoring and the tests available for this purpose are discussed. We review reversal of anticoagulation in urgent/emergent situations as well as perioperative anticoagulation interruption in the elective setting. The data on use of direct oral anticoagulants in patients with compromised renal function, obesity and bariatric surgery, and in the treatment of cancer-associated thrombosis are discussed. The review aims to provide the clinician with the essential information to allow effective and safe use of anticoagulants for the treatment of VTE.

Host iron status and iron supplementation mediate susceptibility to erythrocytic stage Plasmodium falciparum.

Iron deficiency and malaria have similar global distributions, and frequently co-exist in pregnant women and young children. Where both conditions are prevalent, iron supplementation is complicated by observations that iron deficiency anaemia protects against falciparum malaria, and that iron supplements increase susceptibility to clinically significant malaria, but the mechanisms remain obscure. Here, using an in vitro parasite culture system with erythrocytes from iron-deficient and replete human donors, we demonstrate that Plasmodium falciparum infects iron-deficient erythrocytes less efficiently. In addition, owing to merozoite preference for young erythrocytes, iron supplementation of iron-deficient individuals reverses the protective effects of iron deficiency. Our results provide experimental validation of field observations reporting protective effects of iron deficiency and harmful effects of iron administration on human malaria susceptibility. Because recovery from anaemia requires transient reticulocytosis, our findings imply that in malarious regions iron supplementation should be accompanied by effective measures to prevent falciparum malaria.

Anthracycline treatment of the human monocytic leukemia cell line THP-1 increases phosphatidylserine exposure and tissue factor activity.

INTRODUCTION: Cancer associated thrombosis is a well-recognized phenomenon that results in considerable patient morbidity and mortality. Malignancy conveys an increased risk for thrombosis and chemotherapy further elevates this risk. The pathophysiological mechanisms underlying this process remain poorly defined. MATERIALS AND METHODS: A human acute monocytic leukemia cell line (THP-1) was treated with commonly used anthracycline chemotherapeutics at concentrations similar to those found in the plasma of cancer patients. Cells were analyzed for tissue factor (TF) mRNA, protein, and activity. Microparticle (MP) TF activity was also measured. Phosphatidylserine (PS) exposure on cells and MPs was analyzed by flow cytometry. PS levels on MPs was also evaluated in an annexin V capture assay. RESULTS: Anthracycline treatment of THP-1 cells resulted in a concentration-dependent increase in cellular TF activity without a change in TF protein, which was associated with increased PS exposure on the cell surface and apoptosis. The increase in TF activity was abolished by annexin V or lactadherin indicating that PS exposure was required. Anthracycline treatment of THP-1 cells also increased the number of TF-positive MPs. CONCLUSION: Treatment of THP-1 cells with anthracyclines induces apoptosis and increases cellular TF activity. The increased activity required an increase in exposure of PS. Additionally, anthracyclines increase the release of TF-positive MPs from THP-1 cells. We propose that the increase in cellular TF activity in circulating leukemic cells, combined with increased numbers of TF-positive MPs, may contribute to thrombosis in cancer patients receiving chemotherapy.

Role of tissue factor in cancer.

Tissue factor (TF) is a transmembrane glycoprotein that localizes the coagulation serine protease factor VII/VIIa (FVII/VIIa) to the cell surface. The primary function of TF is to activate the clotting cascade. The TF:FVIIa complex also activates cells by cleavage of a G-protein coupled receptor called protease-activated receptor 2 (PAR2). TF is expressed by tumor cells and contributes to a variety of pathologic processes, such as thrombosis, metastasis, tumor growth, and tumor angiogenesis. For instance, tumor cells release TF-positive procoagulant microparticles into the circulation and these may trigger venous thromboembolism in patients with cancer. TF on circulating tumor cells also leads to the coating of the cells with fibrin that traps them within the microvasculature and facilitates hematogenous metastasis. In addition, TF:FVIIa-dependent activation of PAR2 on tumor cells increases tumor growth via an undefined mechanism. One possibility is that PAR2-dependent signaling increases the expression of proangiogenic proteins. Other studies have reported that endothelial cells in the tumor vasculature express TF and this may enhance angiogenesis. These results suggest that inhibition of TF should reduce several pathologic pathways that increase tumor growth and metastasis. This would represent a novel approach to anticancer therapy. Initial studies using inhibitors of the TF:FVIIa complex in mouse tumor models have produced encouraging results. Nevertheless, additional studies are needed to determine if this strategy can be successfully translated to the treatment of cancer patients.

O-glycoside biomarker of apolipoprotein C3: responsiveness to obesity, bariatric surgery, and therapy with metformin, to chronic or severe liver disease and to mortality in severe sepsis and graft vs host disease.

The glyco-isoforms of intact apolipoprotein C3 (ApoC3) were used to probe glycomic changes associated with obesity and recovery following bariatric surgery, liver diseases such as chronic hepatitis C (CHC) and alcoholic liver cirrhosis, as well as severe, multiorgan diseases such as sepsis and graft vs host disease (GVHD). ApoC3 glyco-isoform ratios responded to unique stimuli that did not correlate with serum lipids or with other blood components measured in either a control population or a group of extremely obese individuals. However, glyco-isoform ratios correlated with obesity with a 1.8-fold change among subjects eligible for bariatric surgery relative to a nonobese control population. Bariatric surgery resulted in rapid change of isoform distribution to that of nonobese individuals, after which the distribution was stable in each individual. Although multiple simultaneous factors complicated effector attribution, the isoform ratios of very obese individuals were nearly normal for diabetic individuals on metformin therapy. Glyco-isoform ratios were sensitive to liver diseases such as chronic hepatitis C and alcoholic liver cirrhosis. The correlation coefficient with fibrosis was superior to that of current assays of serum enzyme levels. Diseases of pregnancy that can result in liver damage, HELLP syndrome and pre-eclampsia, did not alter ApoC3 glyco-isoform ratios. Early after umbilical cord blood transplantation the isoform ratios changed and returned to normal in long-term survivors. Larger changes were observed in persons who died. GVHD had little effect. Persons with severe sepsis showed altered ratios. Similar cut-points for mortality (3.5-fold difference from controls) were found for UCBT and sepsis. Similar values characterized liver cirrhosis. Overall, while changes of glyco-isoform ratios occurred in many situations, individual stability of isoform distribution was evident and large changes were limited to high-level disease. If ratio changes associated with obesity are found to document a risk factor for long-term outcomes, the information provided by glyco-isoform ratio changes may provide important, novel information for diagnostic, prognostic and therapy response to metabolic conditions.