Cytometry. Part B, Clinical cytometry, Jan 8, 2015
Diagnosing the cause of thrombocytopenia often requires a bone marrow aspiration or biopsy, an in... more Diagnosing the cause of thrombocytopenia often requires a bone marrow aspiration or biopsy, an invasive procedure. Reticulated platelets (RP) are immature RNA containing platelets, accurate RP enumeration has yet to be achieved, partially due to the lack of a robust reference method. To refine previous work and gating strategies distinguishing RP from mature platelets while incorporating accurate platelet enumeration into the analysis. After reviewing previously published studies on Thiazole Orange (TO) staining of RP, we systematically evaluated CD41/CD61 in combination with a commercial source of TO (BDBiosciences). Previous RP methods have not taken advantage of platelet enumeration therefore our goal was to incorporate the ICSH platelet enumeration protocol into our method. TO concentration, incubation and fixation method were determined to be 10% of stock concentration, 30min, and 1% formaldehyde respectively. Gating strategy to determine RP fraction used an unstained control t...
The majority of cancer-related deaths are as a result of metastatic disease, which has been corre... more The majority of cancer-related deaths are as a result of metastatic disease, which has been correlated with the presence of circulating tumor cells (CTCs) in the bloodstream. Therefore the ability to reliably enumerate and characterize these cells could provide useful information about the biology of the metastatic cascade; facilitate patient prognosis; act as a marker of therapeutic response; and/or aid in novel anticancer drug development. Several different techniques have been utilized for the enrichment and detection of these rare CTCs, each having their own unique advantages and disadvantages. In this chapter we will briefly discuss each of these techniques as well as the pros and cons of each approach. In particular, we will provide a comprehensive examination of two image cytometry approaches for CTC analysis that are in routine use in our laboratory; the iCys Laser Scanning Cytometer (Compucyte, Cambridge, MA), and the CellSearch® system (Veridex, North Raritan, NJ). The ability to detect, enumerate, and characterize CTCs is an important tool for the study of the metastatic cascade and the improved clinical management of cancer patients. These rare cells could shed light on the basic biology behind this highly lethal process and ultimately change current patient treatment guidelines.
The challenge for modern hematology laboratories is to provide accurate and reproducible results,... more The challenge for modern hematology laboratories is to provide accurate and reproducible results, with seamless performance between facilities, in a cost-effective manner. Beckman Coulter recently developed the Coulter LH 500 to meet the needs of smaller laboratories or serve as a backup in larger laboratories. The principal goal of this study was to validate all parameters and performance specifications of the LH 500 compared to the Coulter LH 750 predicate analyzer. A total of 245 spent clinical samples from the London Health Sciences Centre (LHSC) and 251 from the University of Pittsburgh Medical Center Health System (UPMCHS) were analyzed during the study. The samples were selected to include 75% abnormal and 25% normal blood samples. According to the results of a rank sum test, there was no significant difference between the LH 500 and LH 750 for all complete blood count parameters (P > .05) except the red cell distribution width, which showed a slight negative bias on the LH 500. Differential parameters comparing the LH 500 to a 400-cell manual differential showed correlation coefficients (r2) from 0.75 to 0.99 for all parameters except basophils. Of the samples run on the LH 500 at LHSC, the false-positive differential flagging rate was 17.32% and the false-negative rate was 3.03%. Sensitivity was 82.93%, specificity 78.95%, and efficiency 79.65%. At UPMCHS, the false-positive differential flagging rate was 13.37% and false-negative rate 2.97%. Sensitivity was 91.89%, specificity 78.91%, and efficiency 83.66%. Overall, the LH 500 performed accurately and reproducibly compared to the LH 750 and the reference procedures. It would be an excellent second instrument for larger laboratories concerned with harmonization of instrumentation and reagents or as a primary instrument for smaller hematology laboratories with limited space.
Breast cancer often spreads from the primary tumor to regional lymph nodes. Lymph node status pro... more Breast cancer often spreads from the primary tumor to regional lymph nodes. Lymph node status provides clinically important information for making treatment decisions. Spread via lymphatics is also important for the biology of breast cancer, as tumor cells in lymph nodes may provide a reservoir of cells leading to distant, lethal metastases. Improved understanding of the biology of lymphatic spread thus is important for improved breast cancer survival. Advances towards understanding the interactions between tumors cells and lymphatic vessels have in part been limited by the lack of suitable cell lines and experimental models. We have addressed this need by developing a new model of lymphatic metastasis. Here we describe the establishment of 468LN cells, a variant of the MDA-MB-468 human breast adenocarcinoma cell line, which produces extensive lymph node metastasis following orthotopic injection of nude mice. 468LN cells are also more aggressive in vitro, produce more osteopontin and express different surface integrins compared to the parent line. The dramatic in vitro and in vivo phenotypic and molecular differences of 468LN and parental 468GFP cells make this pair of cell lines a unique model for the specific study of lymph node metastasis of breast cancer.
External quality assessment (EQA) of D-dimer assays has been limited by a lack of standardized hu... more External quality assessment (EQA) of D-dimer assays has been limited by a lack of standardized human-derived testing material. In 2006 and 2007, the Quality Management Program--Laboratory Services, Toronto, Canada, investigated the use of commercially prepared lyophilized human plasma spiked with human-derived D-dimer components manufactured by Affinity Biologicals, Hamilton, Canada. Four surveys were performed. Participants reported the level or presence of D-dimer using quantitative or qualitative methods. Participants performing quantitative testing provided their unit of measure and reference interval. Results were considered correct if they fell within the range appropriate for each sample (normal/negative or abnormal/positive). Overall, survey results were excellent, with 4.0% (95% confidence interval [CI], 1.3%-9.1%), 0.8% (CI, 0.0%-1.5%), 2.3% (CI, 0.5%-6.6%), and 2.3% (CI, 0.4%-6.6%) of participants reporting an incorrect result in the first, second, third, and fourth surveys, respectively. A commercially prepared D-dimer is a suitable material for EQA testing.
Paroxysmal nocturnal hemoglobinuria (PNH) is an uncommon disorder characterized by hemolysis, thr... more Paroxysmal nocturnal hemoglobinuria (PNH) is an uncommon disorder characterized by hemolysis, thrombosis and marrow failure. Whereas venous and arterial thrombosis is a very common symptom of the disease, the frequency of PNH clones in patients with unexplained venous thromboembolism, including deep vein thrombosis and pulmonary embolism, has not been studied. We conducted a cross sectional study evaluating the presence of PNH clones in patients with prevalent venous thromboembolism using a high sensitivity flow cytometry assay for erythrocytes and neutrophils. Among the 388 patients enrolled in the study one patient had a detectable PNH clone of 0.02% in the neutrophil population (0.26%; 95% CI 0.05 to 1.45) and no detectable erythrocyte clone. We conclude that the presence of PNH clones in patients with idiopathic venous thrombosis is rare. Screening for PNH clones among VTE patients might be better reserved for patients with signs of hemolysis.
Cytometry. Part B, Clinical cytometry, Jan 8, 2015
Diagnosing the cause of thrombocytopenia often requires a bone marrow aspiration or biopsy, an in... more Diagnosing the cause of thrombocytopenia often requires a bone marrow aspiration or biopsy, an invasive procedure. Reticulated platelets (RP) are immature RNA containing platelets, accurate RP enumeration has yet to be achieved, partially due to the lack of a robust reference method. To refine previous work and gating strategies distinguishing RP from mature platelets while incorporating accurate platelet enumeration into the analysis. After reviewing previously published studies on Thiazole Orange (TO) staining of RP, we systematically evaluated CD41/CD61 in combination with a commercial source of TO (BDBiosciences). Previous RP methods have not taken advantage of platelet enumeration therefore our goal was to incorporate the ICSH platelet enumeration protocol into our method. TO concentration, incubation and fixation method were determined to be 10% of stock concentration, 30min, and 1% formaldehyde respectively. Gating strategy to determine RP fraction used an unstained control t...
The isotype control has long been considered a useful part of both microscopic and flow cytometri... more The isotype control has long been considered a useful part of both microscopic and flow cytometric immuno- logic assays, and, consequently, is still routinely used in clinical laboratories. In flow cytometry, the isotype control has traditionally been used to distinguish between fluores- cent positive and fluorescent negative cell populations. Additionally, it has been used to estimate the number of cells
The majority of cancer-related deaths occur subsequent to the development of metastatic disease. ... more The majority of cancer-related deaths occur subsequent to the development of metastatic disease. This highly lethal disease stage is associated with the presence of circulating tumor cells (CTCs). These rare cells have been demonstrated to be of clinical significance in metastatic breast, prostate, and colorectal cancers. The current gold standard in clinical CTC detection and enumeration is the FDA-cleared CellSearch system (CSS). This manuscript outlines the standard protocol utilized by this platform as well as two additional adapted protocols that describe the detailed process of user-defined marker optimization for protein characterization of patient CTCs and a comparable protocol for CTC capture in very low volumes of blood, using standard CSS reagents, for studying in vivo preclinical mouse models of metastasis. In addition, differences in CTC quality between healthy donor blood spiked with cells from tissue culture versus patient blood samples are highlighted. Finally, several commonly discrepant items that can lead to CTC misclassification errors are outlined. Taken together, these protocols will provide a useful resource for users of this platform interested in preclinical and clinical research pertaining to metastasis and CTCs.
The need for a rapid and reliable marker for the engraftment potential of hematopoietic stem and ... more The need for a rapid and reliable marker for the engraftment potential of hematopoietic stem and progenitor cell (HPC) transplants has led to the development of flow cytometric assays to quantitate such cells on the basis of their expression of CD34. The variability associated with enumeration of low-frequency cells (i.e., as low as 0.1% or 5 cells/microl) is exceedingly large, but recent developments have improved the accuracy and precision of the assay. Here, we review and compare the major techniques. Based on the current state of the art, we recommend 1) bright fluorochrome conjugates of class II or III monoclonal antibodies (mAbs) that detect all glycoforms of CD34, 2) use of a vital nucleic acid dye to exclude platelets, unlysed red cells, and debris or use of 7-amino actinomycin D to exclude dead cells during data acquisition, 3) counterstaining with CD45 mAb to be included in the definition of HPC, 4) during list mode data analysis, Boolean gating to resolve the CD34+ HPCs from irrelevant cell populations on the basis of the low levels of CD45 expression and low sideward light-scatter signals of HPCs, 5) inclusion of CD34dim and CD34bright populations in the CD34+ cell count, 6) omission of the negative control staining, and 7) for apheresis products, enumeration of at least 100 CD34+ cells to ensure a 10% precision. Unresolved technical questions are 1) the replacement of conventional dual-platform by single-platform assay formats, i.e., derivation of absolute CD34+ cell counts from a single flow cytometric assessment instead of from combined flow cytometer (percent CD34+) and hematology analyzer (absolute leukocyte count) data, 2) the cross-calibration of the available single-platform assays, and 3) the optimal method for sample preparation. An important clinical question to be addressed is the definition of the precise phenotypes and required numbers of HPCs responsible for short- and long-term recovery to optimize HPC transplant strategies.
SummaryOver the last few years, the number of clinical applications for autologous and allogeneic... more SummaryOver the last few years, the number of clinical applications for autologous and allogeneic stem cell transplantation has expanded considerably. Concurrently, stem cell collections have been obtained from increasingly diverse sources, including bone marrow, peripheral blood and umbilical cord blood. Various ex vivo manipulations have been developed to process stem cell transplants for specific clinical requirements (e.g. positive selection techniques
Many patients with venous thromboembolism are being treated with low molecular weight heparin for... more Many patients with venous thromboembolism are being treated with low molecular weight heparin for extended periods of time. It is not certain if it is necessary to assess anti-Xa levels for extended treatment periods. This study is a prospective assessment of anti-Xa levels in patients on long-term therapy for acute venous thromboembolism who have active cancer. Consecutive consenting patients from one center in a multicenter trial that compared 6 months of low molecular weight heparin with oral anticoagulant therapy were treated with therapeutic doses of dalteparin (200 IU per kilogram) subcutaneously daily. Anti-Xa levels were assessed at the end of weeks 1 and 4,4-6 hours after injection of dalteparin. Patients were followed for bleeding and recurrent venous thromboembolism. There were 24 patients who had anti-Xa levels measured at weeks 1 and 4. Two other patients had week 1 measurements performed but died before the week 4 sample was collected due to their underlying cancer. The mean anti-Xa levels at weeks 1 and 4 were 1.11 and 1.03 anti-Xa units/ml respectively (P=0.13). These results suggest that for patients with active cancer receiving extended duration therapy with low molecular weight heparin (dalteparin) there is no accumulation of anti-Xa effect over the first month of therapy. Monitoring of anti-Xa levels in this situation is usually not required.
Cytometry. Part B, Clinical cytometry, Jan 8, 2015
Diagnosing the cause of thrombocytopenia often requires a bone marrow aspiration or biopsy, an in... more Diagnosing the cause of thrombocytopenia often requires a bone marrow aspiration or biopsy, an invasive procedure. Reticulated platelets (RP) are immature RNA containing platelets, accurate RP enumeration has yet to be achieved, partially due to the lack of a robust reference method. To refine previous work and gating strategies distinguishing RP from mature platelets while incorporating accurate platelet enumeration into the analysis. After reviewing previously published studies on Thiazole Orange (TO) staining of RP, we systematically evaluated CD41/CD61 in combination with a commercial source of TO (BDBiosciences). Previous RP methods have not taken advantage of platelet enumeration therefore our goal was to incorporate the ICSH platelet enumeration protocol into our method. TO concentration, incubation and fixation method were determined to be 10% of stock concentration, 30min, and 1% formaldehyde respectively. Gating strategy to determine RP fraction used an unstained control t...
The majority of cancer-related deaths are as a result of metastatic disease, which has been corre... more The majority of cancer-related deaths are as a result of metastatic disease, which has been correlated with the presence of circulating tumor cells (CTCs) in the bloodstream. Therefore the ability to reliably enumerate and characterize these cells could provide useful information about the biology of the metastatic cascade; facilitate patient prognosis; act as a marker of therapeutic response; and/or aid in novel anticancer drug development. Several different techniques have been utilized for the enrichment and detection of these rare CTCs, each having their own unique advantages and disadvantages. In this chapter we will briefly discuss each of these techniques as well as the pros and cons of each approach. In particular, we will provide a comprehensive examination of two image cytometry approaches for CTC analysis that are in routine use in our laboratory; the iCys Laser Scanning Cytometer (Compucyte, Cambridge, MA), and the CellSearch® system (Veridex, North Raritan, NJ). The ability to detect, enumerate, and characterize CTCs is an important tool for the study of the metastatic cascade and the improved clinical management of cancer patients. These rare cells could shed light on the basic biology behind this highly lethal process and ultimately change current patient treatment guidelines.
The challenge for modern hematology laboratories is to provide accurate and reproducible results,... more The challenge for modern hematology laboratories is to provide accurate and reproducible results, with seamless performance between facilities, in a cost-effective manner. Beckman Coulter recently developed the Coulter LH 500 to meet the needs of smaller laboratories or serve as a backup in larger laboratories. The principal goal of this study was to validate all parameters and performance specifications of the LH 500 compared to the Coulter LH 750 predicate analyzer. A total of 245 spent clinical samples from the London Health Sciences Centre (LHSC) and 251 from the University of Pittsburgh Medical Center Health System (UPMCHS) were analyzed during the study. The samples were selected to include 75% abnormal and 25% normal blood samples. According to the results of a rank sum test, there was no significant difference between the LH 500 and LH 750 for all complete blood count parameters (P > .05) except the red cell distribution width, which showed a slight negative bias on the LH 500. Differential parameters comparing the LH 500 to a 400-cell manual differential showed correlation coefficients (r2) from 0.75 to 0.99 for all parameters except basophils. Of the samples run on the LH 500 at LHSC, the false-positive differential flagging rate was 17.32% and the false-negative rate was 3.03%. Sensitivity was 82.93%, specificity 78.95%, and efficiency 79.65%. At UPMCHS, the false-positive differential flagging rate was 13.37% and false-negative rate 2.97%. Sensitivity was 91.89%, specificity 78.91%, and efficiency 83.66%. Overall, the LH 500 performed accurately and reproducibly compared to the LH 750 and the reference procedures. It would be an excellent second instrument for larger laboratories concerned with harmonization of instrumentation and reagents or as a primary instrument for smaller hematology laboratories with limited space.
Breast cancer often spreads from the primary tumor to regional lymph nodes. Lymph node status pro... more Breast cancer often spreads from the primary tumor to regional lymph nodes. Lymph node status provides clinically important information for making treatment decisions. Spread via lymphatics is also important for the biology of breast cancer, as tumor cells in lymph nodes may provide a reservoir of cells leading to distant, lethal metastases. Improved understanding of the biology of lymphatic spread thus is important for improved breast cancer survival. Advances towards understanding the interactions between tumors cells and lymphatic vessels have in part been limited by the lack of suitable cell lines and experimental models. We have addressed this need by developing a new model of lymphatic metastasis. Here we describe the establishment of 468LN cells, a variant of the MDA-MB-468 human breast adenocarcinoma cell line, which produces extensive lymph node metastasis following orthotopic injection of nude mice. 468LN cells are also more aggressive in vitro, produce more osteopontin and express different surface integrins compared to the parent line. The dramatic in vitro and in vivo phenotypic and molecular differences of 468LN and parental 468GFP cells make this pair of cell lines a unique model for the specific study of lymph node metastasis of breast cancer.
External quality assessment (EQA) of D-dimer assays has been limited by a lack of standardized hu... more External quality assessment (EQA) of D-dimer assays has been limited by a lack of standardized human-derived testing material. In 2006 and 2007, the Quality Management Program--Laboratory Services, Toronto, Canada, investigated the use of commercially prepared lyophilized human plasma spiked with human-derived D-dimer components manufactured by Affinity Biologicals, Hamilton, Canada. Four surveys were performed. Participants reported the level or presence of D-dimer using quantitative or qualitative methods. Participants performing quantitative testing provided their unit of measure and reference interval. Results were considered correct if they fell within the range appropriate for each sample (normal/negative or abnormal/positive). Overall, survey results were excellent, with 4.0% (95% confidence interval [CI], 1.3%-9.1%), 0.8% (CI, 0.0%-1.5%), 2.3% (CI, 0.5%-6.6%), and 2.3% (CI, 0.4%-6.6%) of participants reporting an incorrect result in the first, second, third, and fourth surveys, respectively. A commercially prepared D-dimer is a suitable material for EQA testing.
Paroxysmal nocturnal hemoglobinuria (PNH) is an uncommon disorder characterized by hemolysis, thr... more Paroxysmal nocturnal hemoglobinuria (PNH) is an uncommon disorder characterized by hemolysis, thrombosis and marrow failure. Whereas venous and arterial thrombosis is a very common symptom of the disease, the frequency of PNH clones in patients with unexplained venous thromboembolism, including deep vein thrombosis and pulmonary embolism, has not been studied. We conducted a cross sectional study evaluating the presence of PNH clones in patients with prevalent venous thromboembolism using a high sensitivity flow cytometry assay for erythrocytes and neutrophils. Among the 388 patients enrolled in the study one patient had a detectable PNH clone of 0.02% in the neutrophil population (0.26%; 95% CI 0.05 to 1.45) and no detectable erythrocyte clone. We conclude that the presence of PNH clones in patients with idiopathic venous thrombosis is rare. Screening for PNH clones among VTE patients might be better reserved for patients with signs of hemolysis.
Cytometry. Part B, Clinical cytometry, Jan 8, 2015
Diagnosing the cause of thrombocytopenia often requires a bone marrow aspiration or biopsy, an in... more Diagnosing the cause of thrombocytopenia often requires a bone marrow aspiration or biopsy, an invasive procedure. Reticulated platelets (RP) are immature RNA containing platelets, accurate RP enumeration has yet to be achieved, partially due to the lack of a robust reference method. To refine previous work and gating strategies distinguishing RP from mature platelets while incorporating accurate platelet enumeration into the analysis. After reviewing previously published studies on Thiazole Orange (TO) staining of RP, we systematically evaluated CD41/CD61 in combination with a commercial source of TO (BDBiosciences). Previous RP methods have not taken advantage of platelet enumeration therefore our goal was to incorporate the ICSH platelet enumeration protocol into our method. TO concentration, incubation and fixation method were determined to be 10% of stock concentration, 30min, and 1% formaldehyde respectively. Gating strategy to determine RP fraction used an unstained control t...
The isotype control has long been considered a useful part of both microscopic and flow cytometri... more The isotype control has long been considered a useful part of both microscopic and flow cytometric immuno- logic assays, and, consequently, is still routinely used in clinical laboratories. In flow cytometry, the isotype control has traditionally been used to distinguish between fluores- cent positive and fluorescent negative cell populations. Additionally, it has been used to estimate the number of cells
The majority of cancer-related deaths occur subsequent to the development of metastatic disease. ... more The majority of cancer-related deaths occur subsequent to the development of metastatic disease. This highly lethal disease stage is associated with the presence of circulating tumor cells (CTCs). These rare cells have been demonstrated to be of clinical significance in metastatic breast, prostate, and colorectal cancers. The current gold standard in clinical CTC detection and enumeration is the FDA-cleared CellSearch system (CSS). This manuscript outlines the standard protocol utilized by this platform as well as two additional adapted protocols that describe the detailed process of user-defined marker optimization for protein characterization of patient CTCs and a comparable protocol for CTC capture in very low volumes of blood, using standard CSS reagents, for studying in vivo preclinical mouse models of metastasis. In addition, differences in CTC quality between healthy donor blood spiked with cells from tissue culture versus patient blood samples are highlighted. Finally, several commonly discrepant items that can lead to CTC misclassification errors are outlined. Taken together, these protocols will provide a useful resource for users of this platform interested in preclinical and clinical research pertaining to metastasis and CTCs.
The need for a rapid and reliable marker for the engraftment potential of hematopoietic stem and ... more The need for a rapid and reliable marker for the engraftment potential of hematopoietic stem and progenitor cell (HPC) transplants has led to the development of flow cytometric assays to quantitate such cells on the basis of their expression of CD34. The variability associated with enumeration of low-frequency cells (i.e., as low as 0.1% or 5 cells/microl) is exceedingly large, but recent developments have improved the accuracy and precision of the assay. Here, we review and compare the major techniques. Based on the current state of the art, we recommend 1) bright fluorochrome conjugates of class II or III monoclonal antibodies (mAbs) that detect all glycoforms of CD34, 2) use of a vital nucleic acid dye to exclude platelets, unlysed red cells, and debris or use of 7-amino actinomycin D to exclude dead cells during data acquisition, 3) counterstaining with CD45 mAb to be included in the definition of HPC, 4) during list mode data analysis, Boolean gating to resolve the CD34+ HPCs from irrelevant cell populations on the basis of the low levels of CD45 expression and low sideward light-scatter signals of HPCs, 5) inclusion of CD34dim and CD34bright populations in the CD34+ cell count, 6) omission of the negative control staining, and 7) for apheresis products, enumeration of at least 100 CD34+ cells to ensure a 10% precision. Unresolved technical questions are 1) the replacement of conventional dual-platform by single-platform assay formats, i.e., derivation of absolute CD34+ cell counts from a single flow cytometric assessment instead of from combined flow cytometer (percent CD34+) and hematology analyzer (absolute leukocyte count) data, 2) the cross-calibration of the available single-platform assays, and 3) the optimal method for sample preparation. An important clinical question to be addressed is the definition of the precise phenotypes and required numbers of HPCs responsible for short- and long-term recovery to optimize HPC transplant strategies.
SummaryOver the last few years, the number of clinical applications for autologous and allogeneic... more SummaryOver the last few years, the number of clinical applications for autologous and allogeneic stem cell transplantation has expanded considerably. Concurrently, stem cell collections have been obtained from increasingly diverse sources, including bone marrow, peripheral blood and umbilical cord blood. Various ex vivo manipulations have been developed to process stem cell transplants for specific clinical requirements (e.g. positive selection techniques
Many patients with venous thromboembolism are being treated with low molecular weight heparin for... more Many patients with venous thromboembolism are being treated with low molecular weight heparin for extended periods of time. It is not certain if it is necessary to assess anti-Xa levels for extended treatment periods. This study is a prospective assessment of anti-Xa levels in patients on long-term therapy for acute venous thromboembolism who have active cancer. Consecutive consenting patients from one center in a multicenter trial that compared 6 months of low molecular weight heparin with oral anticoagulant therapy were treated with therapeutic doses of dalteparin (200 IU per kilogram) subcutaneously daily. Anti-Xa levels were assessed at the end of weeks 1 and 4,4-6 hours after injection of dalteparin. Patients were followed for bleeding and recurrent venous thromboembolism. There were 24 patients who had anti-Xa levels measured at weeks 1 and 4. Two other patients had week 1 measurements performed but died before the week 4 sample was collected due to their underlying cancer. The mean anti-Xa levels at weeks 1 and 4 were 1.11 and 1.03 anti-Xa units/ml respectively (P=0.13). These results suggest that for patients with active cancer receiving extended duration therapy with low molecular weight heparin (dalteparin) there is no accumulation of anti-Xa effect over the first month of therapy. Monitoring of anti-Xa levels in this situation is usually not required.
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