Haemophilia : the official journal of the World Federation of Hemophilia, 2017
Varying initial doses of activated eptacog beta (recombinant human FVIIa, rhFVIIa) may provide th... more Varying initial doses of activated eptacog beta (recombinant human FVIIa, rhFVIIa) may provide therapeutic options when treating bleeding in patients with congenital haemophilia who have developed inhibitory antibodies to factor VIII (FVIII) or factor IX (FIX). This study evaluated escalated doses of a new rhFVIIa product as a prelude to selecting the doses for clinical efficacy evaluation in haemophilia patients. To assess the safety, pharmacokinetics, and laboratory pharmacodynamics of 3 doses of rhFVIIa in non-bleeding patients with congenital haemophilia A or B with or without inhibitors. Adult male patients (18-75 years old) with congenital haemophilia A or B (with or without inhibitors) received infusions of rhFVIIa at doses of 25, 75 or 225 μg/kg body weight. Ten patients were treated at each dose level, and each patient received 2 different dose levels. Descriptive methods were used to analyse the data. Administration of rhFVIIa at all doses was well tolerated. Pharmacokinet...
Haemophilia : the official journal of the World Federation of Hemophilia, Jan 3, 2017
Haemophilia A or B patients with inhibitors have been treated with FVIIa-containing bypassing age... more Haemophilia A or B patients with inhibitors have been treated with FVIIa-containing bypassing agents for over 20 years. However, due to uncertainty regarding dose response and thrombotic risk, the use of a gradual, titrated, minimal dosing strategy remains prevalent, potentially hampering early haemostasis. Evaluate the dose-dependent efficacy, safety and immunogenicity of activated eptacog beta (rhFVIIa), a new recombinant inhibitor bypassing agent for the treatment of bleeding episodes (BEs). A Phase 3, randomized, cross-over study of initial dose regimens (IDRs) in 27 bleeding congenital haemophilia A or B subjects with inhibitors was conducted to evaluate on-demand treatment of mild/moderate BEs. Intravenous 75 μg/kg or 225 μg/kg initial doses with 75 μg/kg subsequent doses by schedule were administered until clinical response. The primary endpoint was sustained clinical response within 12 hours, determined by a composite of objective and pain measures. In the 75 μg/kg IDR, 84.9...
We describe two patients with a new clinical pathologic syndrome of diffuse osteosclerosis in ass... more We describe two patients with a new clinical pathologic syndrome of diffuse osteosclerosis in association with hairy cell leukemia. In both patients bone marrow biopsies could not be obtained due to extremely hard bones and inability to insert the biopsy needle; neither patient had a history of bony pain or fracture. The osteosclerotic process in one patient stabilized after successful treatment of her hairy cell leukemia with interferon alpha and deoxycoformycin suggesting that the osteosclerosis observed was related to the underlying malignant disease. Possible etiologic mechanisms are discussed.
Platelet adherence at high wall shear rates requires plasma von Willebrand factor (vWF). Clinical... more Platelet adherence at high wall shear rates requires plasma von Willebrand factor (vWF). Clinically, the ristocetin cofactor (RCof) activity is the only widely available assay for vWF function. When purified vWF is treated with neuraminidase to yield asialo-vWF (AS- vWF), its RCof activity is increased by 20% to 40%. AS-vWF binds to normal human platelets independently of ristocetin and induces platelet aggregation in the presence of fibrinogen. To determine whether AS-vWF also shows an enhanced capacity to support platelet adherence to subendothelium, we used the Baumgartner technique. Intact vWF, AS-vWF, or AS-vWF treated with beta-galactosidase (asialo, agalacto-vWF; AS,AG- vWF) was added to normal citrated whole blood before perfusion over human umbilical artery segments (wall shear rate, 2,600 sec-1). Four micrograms per milliliter AS-vWF caused a 69% reduction in total platelet adherence compared with citrated whole blood (P less than .001), and 4 micrograms/mL AS,AG-vWF led t...
The Journal of laboratory and clinical medicine, 1987
Platelet adherence to subendothelium depends on binding of plasma von Willebrand factor (VWF) to ... more Platelet adherence to subendothelium depends on binding of plasma von Willebrand factor (VWF) to the subendothelial surface and its subsequent interaction with platelet membrane glycoprotein Ib (GPIb) in the Baumgartner perfusion technique. To examine the role of the platelet glycoprotein IIb-IIIa (GPIIb-IIIa) complex in these processes, we performed studies in patients with platelets deficient in GPIIb-IIIa (thrombasthenia) or GPIb (Bernard-Soulier syndrome) in the Baumgartner system with human umbilical artery segments at a wall shear rate of 2600 sec-1. Morphometry specified the percentage of the subendothelial surface covered with contact (C) or spread (S) platelets or platelet thrombi. Total platelet adherence was defined as C + S. In thrombasthenia, C showed a small but significant increase compared with controls, whereas C + S was reduced by approximately 40%; thrombi were totally absent. With Bernard-Soulier platelets, each parameter was reduced by 72% to 93%. To verify that...
Fifteen patients with hairy cell leukemia (HCL) were treated with deoxycoformycin (pentostatin; d... more Fifteen patients with hairy cell leukemia (HCL) were treated with deoxycoformycin (pentostatin; dCF) (4 mg/m2 intravenous [IV] every week x 3) and recombinant interferon-alpha 2a (rIFN-alpha 2a) (3 x 10(6) units subcutaneously [SC] daily x 4 weeks) in alternating months for a total of 14 months. Eleven patients had undergone splenectomy; four had received prior systemic therapy with chlorambucil and/or steroids. All 15 are evaluable for toxicity and peripheral blood response, while 14 are assessable for bone marrow response. Toxicity was tolerable with grade 3 or 4 nausea and vomiting in three patients, neutropenic fevers in five, transient but significant depression in eight, and localized cutaneous herpes zoster in four. Circulating hairy cells were undetectable by the end of the first month in 10 of 13 patients, and by the end of the second month in the other three. Fourteen patients had bilateral bone marrow biopsies performed at baseline after 6 months of treatment, at the end ...
Arteriosclerosis, Thrombosis, and Vascular Biology, 1995
Increased platelet aggregation is associated with higher coronary artery disease mortality. Enhan... more Increased platelet aggregation is associated with higher coronary artery disease mortality. Enhanced platelet aggregation in platelet-rich plasma has also been described in the elderly. To define age-related changes in primary hemostasis, we studied 37 elderly and 31 young blood donors. There were no significant age-related differences in whole-blood platelet aggregation, platelet adherence and thrombus formation on human umbilical artery segments, or bleeding time. Plasma fibrinogen was significantly higher in elderly men and women, whereas activated factor VII was elevated only in elderly women. Collagen-induced platelet aggregation was significantly correlated with platelet adherence to the subendothelium in elderly ( r =.488, P =.002) but not in young donors. Accordingly, collagen-induced platelet aggregation showed a significant inverse correlation with bleeding time only in the elderly ( r =−.401, P =.014). Arachidonic acid–induced platelet aggregation was significantly associ...
Interferons are not curative in hairy cell leukemia (HCL), and retreatment is necessary in most p... more Interferons are not curative in hairy cell leukemia (HCL), and retreatment is necessary in most patients whose therapy is stopped. In an attempt to maintain or improve responses, we administered recombinant interferon-da (rlFN-da) continuously to patients with HCL who initially responded to this therapy. Of 53 evaluable patients enrolled in this study, 32 have received rlFN-da continuously for a median of 5 years. Patients received 3 million units of rlFN-da subcutaneously (SC) daily for 6 months, followed, in responding patients, by the same dose three times weekly. Twenty-one patients (40%) discontinued IFN after a median of 29 months, seven of whom developed resistant disease in association with antiIFN antibodies. Treatment produced high response rates: complete response plus partial response (CR + PR) = 40 of 53 (76%). CR + PR + minor response (MR) = 43 of 53 (82%), with no differences in response rates between patients with
Though cardiovascular disease remains the most common cause of death in Western countries, signif... more Though cardiovascular disease remains the most common cause of death in Western countries, significant progress has been made in the management of it during the past 2 decades. Increased use of anticoagulant therapy has played an important role in the improved outlook for patients with occlusive arterial or venous thromboembolic disease. However, while anticoagulant drugs reduce a patient’s risk of heart attack and stroke by making the blood less clottable, this same effect increases the patient’s risk of hemorrhage. This necessitates laboratory monitoring of the patient’s response to these drugs on an ongoing basis. For instance, of the approximately 300 million coagulation tests performed annually in the United States, more than 40 million are prothrombin times (PT) performed for monitoring of warfarin therapy. While monitoring of anticoagulant therapy may have the most immediate impact on patient management and outcome, clinicians also rely heavily on the accuracy of screening and diagnostic PT and activated partial thromboplastin time (APTT) tests; platelet function studies; work-ups to identify inherited thrombotic predisposition; and measurement of coagulation factors and inhibitors, D-dimer, and other coagulation analytes. Because of the significantly improved instrumentation and highly sensitive reagents available in modern coagulation laboratories, preanalytical variability now represents the most important source of errors that can lead to inaccurate patient results, patient mismanagement, and preventable hemorrhagic or thrombotic complications. This article will review the importance of the quality and integrity of the coagulation sample for the accuracy and precision of patient test results, and discuss approaches to improve coagulation laboratory performance by controlling preanalytical variability.
We describe a patient with the so-called "prolymphocytic variant" form of hairy cell le... more We describe a patient with the so-called "prolymphocytic variant" form of hairy cell leukemia (HCL) resistant to treatment with interferon-alpha (IFN-alpha). Analysis of immunoglobulin (Ig) and T-cell receptor-beta (TCR beta) gene rearrangements from serial peripheral blood mononuclear cell specimens (MNCs) confirmed not only the B-cell nature of the disease, but also the subsequent emergence of a morphologically indistinguishable population of cells with a clonal TCR beta rearrangement in addition to the original Ig gene rearrangement. With the exception of a transient increase in peripheral blood T cells during treatment with deoxycoformycin (DCF), the MNCs remained essentially constant throughout therapy with no evidence of a co-existing T-cell clone to account for the TCR beta rearrangement. Although MNCs from this patient bound significantly less IFN-alpha than did MNCs from other HCL patients, the binding was of high affinity with a kd similar to that of control cell...
Histologic, histochemical, and ultrastructural features of eight adenoid cystic carcinomas arisin... more Histologic, histochemical, and ultrastructural features of eight adenoid cystic carcinomas arising at diverse sites were compared in order to determine diagnostic values and to investigate histogenetic mechanisms. These tumors originated in the salivary glands, breast, uterine cervix, and tracheobronchial tree. By light microscopy each tumor was seen to have morphologic features of adenoid cystic carcinoma, yet only five of the eight cases showed differential staining for the two mucin types, stromal and epithelial, which are reportedly present in these tumors. In contrast, every case showed a set of fine structural features which, in aggregate, are specific for adenoid cystic carcinoma. These features include pseudocysts, intercellular spaces, basal lamina, and true glandular lumens. The most prominent feature is the pseudocyst, which mimics a glandular lumen by light microscopy but is actually a rounded extracellular space containing basal lamina. Ultrastructurally, the variation in composition of the extracellular compartments, including pseudocysts and true lumens, appears to explain the lack of uniformity in the histochemical staining. The tumors also contained cytoplasmic microfilaments in parallel bundles, consistent with myofilaments. The presence of these filaments combined with basal lamina suggests myoepithelial differentiation, yet it is not known whether these tumors truly originate from myoepithelium or show differentiation toward myoepithelium as a part of the neoplastic process. Regardless of their histogenesis, this study shows that true adenoid cystic carcinomas do arise in different organs. Knowledge of the specific ultrastructural features of adenoid cystic carcinomas can be useful in classifying these tumors in some cases.
Haemophilia : the official journal of the World Federation of Hemophilia, 2017
Varying initial doses of activated eptacog beta (recombinant human FVIIa, rhFVIIa) may provide th... more Varying initial doses of activated eptacog beta (recombinant human FVIIa, rhFVIIa) may provide therapeutic options when treating bleeding in patients with congenital haemophilia who have developed inhibitory antibodies to factor VIII (FVIII) or factor IX (FIX). This study evaluated escalated doses of a new rhFVIIa product as a prelude to selecting the doses for clinical efficacy evaluation in haemophilia patients. To assess the safety, pharmacokinetics, and laboratory pharmacodynamics of 3 doses of rhFVIIa in non-bleeding patients with congenital haemophilia A or B with or without inhibitors. Adult male patients (18-75 years old) with congenital haemophilia A or B (with or without inhibitors) received infusions of rhFVIIa at doses of 25, 75 or 225 μg/kg body weight. Ten patients were treated at each dose level, and each patient received 2 different dose levels. Descriptive methods were used to analyse the data. Administration of rhFVIIa at all doses was well tolerated. Pharmacokinet...
Haemophilia : the official journal of the World Federation of Hemophilia, Jan 3, 2017
Haemophilia A or B patients with inhibitors have been treated with FVIIa-containing bypassing age... more Haemophilia A or B patients with inhibitors have been treated with FVIIa-containing bypassing agents for over 20 years. However, due to uncertainty regarding dose response and thrombotic risk, the use of a gradual, titrated, minimal dosing strategy remains prevalent, potentially hampering early haemostasis. Evaluate the dose-dependent efficacy, safety and immunogenicity of activated eptacog beta (rhFVIIa), a new recombinant inhibitor bypassing agent for the treatment of bleeding episodes (BEs). A Phase 3, randomized, cross-over study of initial dose regimens (IDRs) in 27 bleeding congenital haemophilia A or B subjects with inhibitors was conducted to evaluate on-demand treatment of mild/moderate BEs. Intravenous 75 μg/kg or 225 μg/kg initial doses with 75 μg/kg subsequent doses by schedule were administered until clinical response. The primary endpoint was sustained clinical response within 12 hours, determined by a composite of objective and pain measures. In the 75 μg/kg IDR, 84.9...
We describe two patients with a new clinical pathologic syndrome of diffuse osteosclerosis in ass... more We describe two patients with a new clinical pathologic syndrome of diffuse osteosclerosis in association with hairy cell leukemia. In both patients bone marrow biopsies could not be obtained due to extremely hard bones and inability to insert the biopsy needle; neither patient had a history of bony pain or fracture. The osteosclerotic process in one patient stabilized after successful treatment of her hairy cell leukemia with interferon alpha and deoxycoformycin suggesting that the osteosclerosis observed was related to the underlying malignant disease. Possible etiologic mechanisms are discussed.
Platelet adherence at high wall shear rates requires plasma von Willebrand factor (vWF). Clinical... more Platelet adherence at high wall shear rates requires plasma von Willebrand factor (vWF). Clinically, the ristocetin cofactor (RCof) activity is the only widely available assay for vWF function. When purified vWF is treated with neuraminidase to yield asialo-vWF (AS- vWF), its RCof activity is increased by 20% to 40%. AS-vWF binds to normal human platelets independently of ristocetin and induces platelet aggregation in the presence of fibrinogen. To determine whether AS-vWF also shows an enhanced capacity to support platelet adherence to subendothelium, we used the Baumgartner technique. Intact vWF, AS-vWF, or AS-vWF treated with beta-galactosidase (asialo, agalacto-vWF; AS,AG- vWF) was added to normal citrated whole blood before perfusion over human umbilical artery segments (wall shear rate, 2,600 sec-1). Four micrograms per milliliter AS-vWF caused a 69% reduction in total platelet adherence compared with citrated whole blood (P less than .001), and 4 micrograms/mL AS,AG-vWF led t...
The Journal of laboratory and clinical medicine, 1987
Platelet adherence to subendothelium depends on binding of plasma von Willebrand factor (VWF) to ... more Platelet adherence to subendothelium depends on binding of plasma von Willebrand factor (VWF) to the subendothelial surface and its subsequent interaction with platelet membrane glycoprotein Ib (GPIb) in the Baumgartner perfusion technique. To examine the role of the platelet glycoprotein IIb-IIIa (GPIIb-IIIa) complex in these processes, we performed studies in patients with platelets deficient in GPIIb-IIIa (thrombasthenia) or GPIb (Bernard-Soulier syndrome) in the Baumgartner system with human umbilical artery segments at a wall shear rate of 2600 sec-1. Morphometry specified the percentage of the subendothelial surface covered with contact (C) or spread (S) platelets or platelet thrombi. Total platelet adherence was defined as C + S. In thrombasthenia, C showed a small but significant increase compared with controls, whereas C + S was reduced by approximately 40%; thrombi were totally absent. With Bernard-Soulier platelets, each parameter was reduced by 72% to 93%. To verify that...
Fifteen patients with hairy cell leukemia (HCL) were treated with deoxycoformycin (pentostatin; d... more Fifteen patients with hairy cell leukemia (HCL) were treated with deoxycoformycin (pentostatin; dCF) (4 mg/m2 intravenous [IV] every week x 3) and recombinant interferon-alpha 2a (rIFN-alpha 2a) (3 x 10(6) units subcutaneously [SC] daily x 4 weeks) in alternating months for a total of 14 months. Eleven patients had undergone splenectomy; four had received prior systemic therapy with chlorambucil and/or steroids. All 15 are evaluable for toxicity and peripheral blood response, while 14 are assessable for bone marrow response. Toxicity was tolerable with grade 3 or 4 nausea and vomiting in three patients, neutropenic fevers in five, transient but significant depression in eight, and localized cutaneous herpes zoster in four. Circulating hairy cells were undetectable by the end of the first month in 10 of 13 patients, and by the end of the second month in the other three. Fourteen patients had bilateral bone marrow biopsies performed at baseline after 6 months of treatment, at the end ...
Arteriosclerosis, Thrombosis, and Vascular Biology, 1995
Increased platelet aggregation is associated with higher coronary artery disease mortality. Enhan... more Increased platelet aggregation is associated with higher coronary artery disease mortality. Enhanced platelet aggregation in platelet-rich plasma has also been described in the elderly. To define age-related changes in primary hemostasis, we studied 37 elderly and 31 young blood donors. There were no significant age-related differences in whole-blood platelet aggregation, platelet adherence and thrombus formation on human umbilical artery segments, or bleeding time. Plasma fibrinogen was significantly higher in elderly men and women, whereas activated factor VII was elevated only in elderly women. Collagen-induced platelet aggregation was significantly correlated with platelet adherence to the subendothelium in elderly ( r =.488, P =.002) but not in young donors. Accordingly, collagen-induced platelet aggregation showed a significant inverse correlation with bleeding time only in the elderly ( r =−.401, P =.014). Arachidonic acid–induced platelet aggregation was significantly associ...
Interferons are not curative in hairy cell leukemia (HCL), and retreatment is necessary in most p... more Interferons are not curative in hairy cell leukemia (HCL), and retreatment is necessary in most patients whose therapy is stopped. In an attempt to maintain or improve responses, we administered recombinant interferon-da (rlFN-da) continuously to patients with HCL who initially responded to this therapy. Of 53 evaluable patients enrolled in this study, 32 have received rlFN-da continuously for a median of 5 years. Patients received 3 million units of rlFN-da subcutaneously (SC) daily for 6 months, followed, in responding patients, by the same dose three times weekly. Twenty-one patients (40%) discontinued IFN after a median of 29 months, seven of whom developed resistant disease in association with antiIFN antibodies. Treatment produced high response rates: complete response plus partial response (CR + PR) = 40 of 53 (76%). CR + PR + minor response (MR) = 43 of 53 (82%), with no differences in response rates between patients with
Though cardiovascular disease remains the most common cause of death in Western countries, signif... more Though cardiovascular disease remains the most common cause of death in Western countries, significant progress has been made in the management of it during the past 2 decades. Increased use of anticoagulant therapy has played an important role in the improved outlook for patients with occlusive arterial or venous thromboembolic disease. However, while anticoagulant drugs reduce a patient’s risk of heart attack and stroke by making the blood less clottable, this same effect increases the patient’s risk of hemorrhage. This necessitates laboratory monitoring of the patient’s response to these drugs on an ongoing basis. For instance, of the approximately 300 million coagulation tests performed annually in the United States, more than 40 million are prothrombin times (PT) performed for monitoring of warfarin therapy. While monitoring of anticoagulant therapy may have the most immediate impact on patient management and outcome, clinicians also rely heavily on the accuracy of screening and diagnostic PT and activated partial thromboplastin time (APTT) tests; platelet function studies; work-ups to identify inherited thrombotic predisposition; and measurement of coagulation factors and inhibitors, D-dimer, and other coagulation analytes. Because of the significantly improved instrumentation and highly sensitive reagents available in modern coagulation laboratories, preanalytical variability now represents the most important source of errors that can lead to inaccurate patient results, patient mismanagement, and preventable hemorrhagic or thrombotic complications. This article will review the importance of the quality and integrity of the coagulation sample for the accuracy and precision of patient test results, and discuss approaches to improve coagulation laboratory performance by controlling preanalytical variability.
We describe a patient with the so-called "prolymphocytic variant" form of hairy cell le... more We describe a patient with the so-called "prolymphocytic variant" form of hairy cell leukemia (HCL) resistant to treatment with interferon-alpha (IFN-alpha). Analysis of immunoglobulin (Ig) and T-cell receptor-beta (TCR beta) gene rearrangements from serial peripheral blood mononuclear cell specimens (MNCs) confirmed not only the B-cell nature of the disease, but also the subsequent emergence of a morphologically indistinguishable population of cells with a clonal TCR beta rearrangement in addition to the original Ig gene rearrangement. With the exception of a transient increase in peripheral blood T cells during treatment with deoxycoformycin (DCF), the MNCs remained essentially constant throughout therapy with no evidence of a co-existing T-cell clone to account for the TCR beta rearrangement. Although MNCs from this patient bound significantly less IFN-alpha than did MNCs from other HCL patients, the binding was of high affinity with a kd similar to that of control cell...
Histologic, histochemical, and ultrastructural features of eight adenoid cystic carcinomas arisin... more Histologic, histochemical, and ultrastructural features of eight adenoid cystic carcinomas arising at diverse sites were compared in order to determine diagnostic values and to investigate histogenetic mechanisms. These tumors originated in the salivary glands, breast, uterine cervix, and tracheobronchial tree. By light microscopy each tumor was seen to have morphologic features of adenoid cystic carcinoma, yet only five of the eight cases showed differential staining for the two mucin types, stromal and epithelial, which are reportedly present in these tumors. In contrast, every case showed a set of fine structural features which, in aggregate, are specific for adenoid cystic carcinoma. These features include pseudocysts, intercellular spaces, basal lamina, and true glandular lumens. The most prominent feature is the pseudocyst, which mimics a glandular lumen by light microscopy but is actually a rounded extracellular space containing basal lamina. Ultrastructurally, the variation in composition of the extracellular compartments, including pseudocysts and true lumens, appears to explain the lack of uniformity in the histochemical staining. The tumors also contained cytoplasmic microfilaments in parallel bundles, consistent with myofilaments. The presence of these filaments combined with basal lamina suggests myoepithelial differentiation, yet it is not known whether these tumors truly originate from myoepithelium or show differentiation toward myoepithelium as a part of the neoplastic process. Regardless of their histogenesis, this study shows that true adenoid cystic carcinomas do arise in different organs. Knowledge of the specific ultrastructural features of adenoid cystic carcinomas can be useful in classifying these tumors in some cases.
Uploads