Complete remission of a radiochemotherapy-resistant cutaneous T-cell lymphoma with allogeneic non-myeloablative stem cell transplantation.
Explore the source record for details and available documents.
Adult↗
Biomedical subjects
R Fijnheer
Publications and source records attributed to R Fijnheer.
Differential diagnosis of skin lesions after allogeneic haematopoietic stem cell transplantation.
Allogeneic haematopoietic stem cell transplantation (i.e. bone marrow or peripheral blood stem cell transplantation) is a common procedure in the treatment of various haematological disorders such as aplastic anaemia, (pre)leukaemias, some malignant lymphomas, multiple myeloma and immunodeficiency states. Many of these patients develop erythematous skin lesions following transplantation. Although graft- versus-host disease is the major differential diagnosis in these situations, many other causes of erythema are encountered. The large number of transplant patients means that more and more pathologists are confronted with the challenging problem of making a correct diagnosis in these situations. In this review article we therefore describe the different causes of erythema and their differential diagnoses. In most cases the clinical presentation is related to the microscopical features. Besides acute and chronic graft-versus-host disease, we discuss the (common) drug reactions and non-specific features such as Sweet's syndrome, erythema nodosum and eosinophilic folliculitis. In addition, we deal with the recurrence of original diseases and infections. With this knowledge every pathologist should feel comfortable when looking at skin biopsies of patients after haematological stem cell transplantation.
Diagnosis, Differential↗
Extremely high levels of von Willebrand factor antigen and of procoagulant factor VIII found in multiple myeloma patients are associated with activity status but not with thalidomide treatment.
Venous thromboembolism (VTE) is a major complication in patients with multiple myeloma (MM) during treatment with thalidomide combined with chemotherapy and/or dexamethasone. The pathophysiology is not clear. We performed a cross-sectional study in 20 MM patients who were treated with thalidomide for refractory/relapsed disease. Seven patients (35%) experienced an episode of VTE. Plasma samples were analyzed for known risk factors for VTE and compared with those from 30 MM patients without thalidomide treatment. The patients groups differed in their baseline characteristics in activity status only. Extremely high levels of factor VIII-coagulant activity (FVIII:C, mean 352%) and von Willebrand factor antigen (VWF-Ag, 374%) were found in all patients using thalidomide. All other prothrombotic risk factors were normal. In patients with VTE, VWF-Ag but not FVIII:C, levels were significantly higher as compared with patients without VTE. Patients without thalidomide treatment had significantly lower levels of both coagulation factors but the difference was only due to difference in activity status. High FVIII:C/VWF-Ag levels are found in patients with active MM and this is probably a reflection of increased bone marrow angiogenesis in MM. These prothrombogenic circumstances could contribute to the high incidence of VTE during treatment with thalidomide in combination with dexamethasone/chemotherapy.
Aged↗
No effect of acenocoumarol therapy on levels of endothelial activation markers in sickle cell disease.
Sickle cell patients are characterized by a chronic inflammatory and hypercoagulable state, depicted by elevated levels of pro-inflammatory cytokines, endothelial adhesion molecules, and elevated markers of thrombin generation. We set out to determine whether anticoagulation with a coumadin derivative reduces inflammation in sickle cell disease. Therefore, serum levels of NFkappaB-regulated endothelial adhesion molecule soluble vascular cell adhesion molecule-1 and serum levels of non-NFkappaB-dependent markers of endothelial activation (soluble cellular fibronectin and von Willebrand factor antigen) were compared during treatment with acenocoumarol (INR 1.6-2.0) and placebo. No effect on circulating levels of the measured parameters was observed during treatment with acenocoumarol as compared to placebo. In the targeted INR range, anticoagulation of sickle cell patients with acenocoumarol does not seem to reduce endothelial activation.
Acenocoumarol↗
Endothelial cell activation is associated with cerebral white matter lesions in patients with cerebrovascular disease.
Cerebral MRI scanning frequently shows white matter lesions in elderly people. They are related to cognitive impairment and may result in dementia. Although vascular risk factors are associated with the presence of white matter lesions, the exact pathogenesis remains unclear. Animal studies have indicated involvement of endothelial cells in the pathogenesis of white matter lesions and possibly dementia. We investigated the relation between endothelial cell activation and white matter lesions in individuals with cerebrovascular disease. In 29 patients with an acute stroke (n = 11) or TIAs associated with a symptomatic internal carotid artery stenosis (n = 18), markers of endothelial cell activation such as intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), sE-selectin, and sP-selectin were measured by means of ELISA. All individuals underwent 1.5-T MRI scanning. White matter lesions were rated for the periventricular and the subcortical region separately. Individuals with severe periventricular white matter lesions had higher levels of sP-selectin (245.5 ng/mL vs. 172.7 ng/mL, p = 0.01) and sVCAM-1 (547.8 ng/mL vs. 454.0 ng/mL, p = 0.04) than those without. This association was only found in individuals with a symptomatic carotid artery stenosis. No such association was found for subcortical white matter lesions. We did not detect any relation between sICAM-1 and sE-selectin and white matter lesions. Endothelial cell activation may play a role in the pathogenesis of white matter lesions, especially in periventricular white matter. Possibly, this activation represents the influence of vascular factors on the cerebral endothelium as a prelude to increasingly severe small vessel disease.
Brain↗
Antibodies that stop the adrenals in their tracks.
Explore the source record for details and available documents.
Adrenal Glands↗
Cyclosporine is associated with endothelial dysfunction but not with platelet activation in renal transplantation.
BACKGROUND: Cyclosporine (CsA) is associated with thrombotic micro-angiopathy and endothelial dysfunction. Markers of endothelial dysfunction may serve to identify patients at risk for development of vascular injury. In this study we measured von Willebrand Factor (vWF) and sP-selectin as possible markers for endothelial dysfunction in renal transplant recipients at different concentrations of CsA. Because sP-selectin can also be derived from platelets an additional in vitro study was performed to study the potential effect of CsA on the expression of P-selectin on platelet surface, while the effects of CsA on the interaction of platelets with Endothelial Cell Matrix (ECM) were studied under flow conditions in a perfusion chamber model. METHODS: CsA was stepwisely replaced by mycophenolate mofetil (MMF) in 15 renal transplant recipients (more than 6 months after transplantation). VWF and sP-selectin were measured at normal CsA (median trough level 130 microg/l), low CsA (trough level 45 microg/l) and after stopping CsA. MMF 2 g daily was added while lowering and stopping CsA. Platelet activation was investigated by measurement of P-selectin on platelet surface by flow-cytometry (FACS), after incubation with CsA (0, 2, 20 and 200 mg/l) in vitro and after perfusion of whole blood over ECM with CsA (0 or 2 mg/l, peak levels). RESULTS: Stepwise withdrawal of CsA gave a dose-related decrease of both vWF and sP-selectin, suggesting reversible endothelial dysfunction. FACS showed no expression of P-selectin on platelets by CsA. Also perfusion studies over ECM demonstrated no platelet activation by CsA but even inhibition of platelet adhesion and aggregation. CONCLUSIONS: The use of CsA is not accompanied by platelet activation. However endothelial dysfunction induced by CsA does occur as reflected by increased vWF and sP-selectin. (See Editorial p. 1).
Adult↗
Relationship between graft-versus-host disease and graft-versus-leukaemia in partial T cell-depleted bone marrow transplantation.
The success of allogeneic bone marrow transplantation (BMT) is limited by the major complications, graft-versus-host disease (GVHD) and relapse. The very beneficial effect of maximal T-cell depletion of the graft for prevention of GVHD has been counterbalanced by an increase in graft failure and relapse of disease. Therefore, we started an approach of partial T-cell depletion of the graft. GVHD and graft-versus-leukaemia (GVL) are strongly correlated after non-T cell-depleted BMT. Here, we report whether the correlation between GVHD and GVL also exists in partial T cell-depleted BMT from sibling donors. We retrospectively studied 117 adult patients with early haematological malignancies. Our method of partial T-cell depletion gave a relapse rate in patients with acute leukaemias similar to that observed in non-T cell-depleted BMT. However, patients with chronic myeloid leukaemia had a relapse rate that was similar to that observed in maximal T cell-depleted BMT. We found a significant correlation between the presence of chronic GVHD and an improved disease-free survival. Nevertheless, overall survival was lower in patients with chronic GVHD. There was no correlation between the occurrence of acute GVHD and disease-free or overall survival.
Acute Disease↗
Lupus anticoagulant and history of thrombosis are not associated with persistent endothelial cell activation in systemic lupus erythematosus.
Antiphospholipid antibodies (aPL), especially lupus anticoagulant (LAC), characterize systemic lupus erythematosus (SLE) patients at increased risk for arterial and venous thromboembolic complications. It has been reported that purified human anti-phospholipid antibodies cause endothelial cell activation in in vitro experiments. In order to investigate whether increased endothelial cell activation is associated with thromboembolic events in SLE patients with LAC, we measured plasma levels of thrombomodulin (TM), von Willebrand factor (vWf), sP-selectin, vascular cell adhesion molecule-1 (sVCAM-1) and ED1-fibronectin in a study of 76 patients with SLE. Patients were subdivided on the basis of: no history of thrombosis and LAC-negative (n = 22) or LAC-positive (n = 17); positive history of thrombosis and LAC-negative (n = 16) or LAC-positive (n = 21). The median SLE disease activity index (SLEDAI) was 4. Although concentrations of sTM, vWf, sP-selectin and sVCAM-1 were significantly elevated in SLE compared with values in healthy controls, they did not differ between the four groups, between patients with or without history of thrombosis, and between patients with or without LAC. Presence of anticardiolipin antibodies could not explain these negative findings. Adjustment of the concentrations for significantly associated variables, such as age, hypertension, smoking, immunosuppressive treatment and concentrations of creatinine, cholesterol and homocysteine, did not change the main results of the study. Only sTM was significantly lower in patients with both LAC and thrombosis than in patients without both these features after adjustment for serum creatinine concentrations. In conclusion, we did not find an association between endothelial cell activation and presence of LAC or history of thrombosis in SLE.
Adult↗
Plasma levels of cellular fibronectin in diabetes.
OBJECTIVE: Cellular fibronectin is an endothelium-derived protein involved in subendothelial matrix assembly. Elevated plasma levels of cellular fibronectin therefore reflect loss of endothelial cell polarization or injury to blood vessels. Consequently, elevated plasma levels of circulating cellular fibronectin have been described in clinical syndromes with vascular damage, although not in diabetes or atherosclerosis. RESEARCH DESIGN AND METHODS: We determined fibronectin levels in 52 patients with type 1 diabetes, 50 patients with type 2 diabetes, 54 patients with a history of ischemic stroke, 23 patients with renal artery stenosis, and 64 healthy subjects. RESULTS: Circulating cellular fibronectin was significantly elevated in patients with diabetes (4.3 +/- 2.8 microg/ml) compared with patients with ischemic stroke (2.0 +/- 0.9 microg/ml), patients with renovascular hypertension (1.7 +/- 1.1 microg/ml), and healthy subjects (1.4 +/- 0.6 microg/ml). Patients with diabetes and at least one cardiovascular risk factor had an almost 2.5-fold increase in cellular fibronectin compared with diabetic subjects without such a risk factor. In multivariate regression analysis, higher triglycerides, current or past cigarette smoking, and higher urinary albumin excretion were independently associated with an increase in circulating cellular fibronectin in diabetes. CONCLUSIONS: These results suggest that circulating cellular fibronectin may be a marker protein for endothelial cell activation, especially in diabetes. Prospective studies are needed to explore this possibility
Adult↗
Persistent increase in plasma thrombomodulin in patients with a history of lupus nephritis: endothelial cell activation markers.
OBJECTIVE: To investigate the presence of continuing endothelial cell activation in patients with systemic lupus erythematosus (SLE) and its relationship with lupus nephritis. METHODS: We measured plasma concentrations of soluble thrombomodulin (sTM), vascular cellular adhesion molecule-1 (sVCAM-1), von Willebrand factor (vWf), sP-selectin, and ED1-fibronectin in 75 SLE patients with a median SLE disease activity index (SLEDAI) of 4. Forty patients with a history of lupus nephritis, confirmed by renal biopsy in 33, were compared with 35 patients without lupus nephritis and 25 controls. For subgroup analysis in patients with clinically stable remission we excluded patients with a SLEDAI > 6 or with evidence of renal disease activity. RESULTS: In the total SLE patient group sTM, sVCAM-1, vWf, and sP-selectin were significantly elevated compared with controls. In patients with a history of lupus nephritis plasma levels of sTM and vWf were significantly increased compared with SLE patients without nephritis. After adjustment for significantly associated variables, especially creatinine clearance and age, in a multivariate linear regression analysis, sTM remained significantly elevated in patients with a history of lupus nephritis (difference 28.9 ng/ml, 95% CI 11.5-46.4). In the subgroup analysis of 57 patients, the results remained unchanged. CONCLUSION: The increase of sVCAM-1, sP-selectin, sTM, and vWf reflects a state of persistent endothelial cell activation. Multivariate regression analysis shows that the elevated sTM levels are strongly associated with a history of lupus nephritis, independent of creatinine clearance or disease activity, suggesting endothelial cell activation specifically localized in the kidneys.
Adolescent↗
Fcgamma receptor polymorphisms in systemic lupus erythematosus: association with disease and in vivo clearance of immune complexes.
OBJECTIVE: Fc receptors for IgG (FcgammaR) play a prominent role in the clearance of immune complexes in systemic lupus erythematosus (SLE). Polymorphisms of FcgammaR have been proposed as genetic factors that influence susceptibility to SLE. We analyzed 3 functional FcgammaR polymorphisms in a strictly Caucasian population of SLE patients, and determined the influence of these polymorphisms on the clearance of immune complexes in vivo. METHODS: Genomic DNA was isolated from 230 Caucasian patients with SLE and 154 controls. Amplification of FcgammaR-genomic regions in allotype-specific polymerase chain reactions was used to distinguish the genotypes. In addition, we analyzed the FcgammaR genotypes of 13 patients with SLE who participated in a study determining the half-life of IgG-coated erythrocytes in the blood. RESULTS: We found a strong trend toward skewing of FcgammaRIIa, with an enrichment of the homozygous FcgammaRIIa-R/R131 genotype in patients compared with controls. We did not find a correlation between this genotype and the development of lupus nephritis. However, we established that the half-life of IgG-coated erythrocytes in the blood was prolonged in patients expressing the FcgammaRIIa-R/R131 genotype. The homozygous FcgammaRIIIa-F/F158 genotype was found more frequently in patients with arthritis and/or serositis. CONCLUSION: In Caucasian populations, the R/H polymorphism of FcgammaRIIa is a minor determinant in susceptibility to SLE, whereas the V/F polymorphism of FcgammaRIIIa is associated with a set of disease manifestations. Notably, the R/H polymorphism of FcgammaRIIa affects the clearance of immune complexes in vivo, which may influence the course of a disease such as SLE.
Adolescent↗
Reduced activity of TAFI (thrombin-activatable fibrinolysis inhibitor) in acute promyelocytic leukaemia.
Acute promyelocytic leukaemia (APL) is a disease that is distinguished from other leukaemias by the high potential for early haemorrhagic death. Several processes are involved, such as disseminated intravascular coagulation and hyperfibrinolysis. Recently, TAFI (thrombin-activatable fibrinolysis inhibitor) was identified as a link between coagulation and fibrinolysis. TAFI can be activated by thrombin, and in its activated form potently attenuates fibrinolysis by removing C-terminal lysine and arginine residues that are important for the binding and activation of plasminogen. Activation of TAFI by the coagulation system results in a down-regulation of fibrinolytic activity and, thereby, prevents a rapid dissolution of the fibrin clot. To establish whether TAFI was involved in the severity of the bleeding complications in APL, the TAFI antigen and activity levels were determined in a group of 15 patients. The TAFI antigen concentration was normal, but the activity of TAFI was severely reduced in APL by approximately 60%. The reduction of TAFI activity was most probably caused by the action of plasmin on TAFI because in vitro experiments revealed that plasmin slightly reduced antigen levels but severely reduced TAFI activity. The acquired functional TAFI deficiency in APL may contribute to the severity of the haemorrhagic diathesis because of the impaired capacity of the coagulation system to protect the fibrin clot from fibrinolysis.
Adult↗
Homocysteine in inflammatory bowel disease: a risk factor for thromboembolic complications?
OBJECTIVE: Patients with inflammatory bowel disease (IBD) are at increased risk for thromboembolic events. Hyperhomocysteinemia, which is an established risk factor for arterial as well as venous thrombosis, may be more prevalent in IBD because of vitamin deficiencies. METHODS: In this retrospective study, we studied the concentrations of total homocysteine (tHcy), cobalamin, folate, and pyridoxine in 231 consecutive patients with IBD, of whom 16 patients had a history of venous thrombosis, and nine a history of arterial thrombosis. Age- and gender-matched healthy volunteers served as controls (n = 102). RESULTS: Homocysteine concentrations in patients were higher (12.3 micromol/L [range 4.6-51.3] vs 11.1 micromol/L [range 3.9-27.6], p = 0.001) and hyperhomocysteinemia tended to be more prevalent in patients than in the controls (11.1% vs 5%, p = 0.07). Folate, cobalamin, creatinine, and pyridoxine concentrations were correlated with tHcy. Folate deficiency was infrequently encountered in IBD patients (4.3%). The tHcy concentration in patients with a history of venous or arterial thrombosis was not higher than in patients without a history of thrombosis (12.7 micromol/L [range 4.6-40.1] and 15.2 micromol/L (range 10.5-26.8) vs 12.3 micromol/L [range 10.5-26.8], not significant). Hyperhomocysteinemia was found in 18.8% of the patients with venous thrombosis, 11.1% of the patients with arterial thrombosis, and 10.5% of the patients without thrombosis (not significant). CONCLUSIONS: Hyperhomocysteinemia is a common phenomenon in IBD and correlates with serum folate, cobalamin, creatinine, and pyridoxine concentrations. No correlation between tHcy and a history of venous or arterial thromboembolic complications is found. Hyperhomocysteinemia does not seem to be a major contributory factor in the development of venous or arterial thrombosis in IBD patients.
Adolescent↗
Elastase mediated fibrinolysis in acute promyelocytic leukemia.
The bleeding syndrome of acute promyelocytic leukemia (APL) is complex and consists of disseminated intravascular coagulation (DIC) and hyperfibrinolysis. Elastase, derived from malignant promyelocytes, is believed to mediate the fibrinogeno- and fibrinolysis by aspecific proteolysis. In this study we measured the role of elastase in fifteen patients with APL by using an assay for elastase degraded fibrin(ogen) and the results were compared with those obtained in patients with sepsis induced DIC. High levels of elastase were observed in sepsis and APL. The levels of fibrinogen and fibrin degradation products were significantly higher in APL patients compared to patients with sepsis induced DIC. Nevertheless, the level of elastase degraded fibrin(ogen) was higher in the sepsis group (635.3 ng/ml, compared to 144.3 ng/ml in APL; p <0.0001). So, the enormous increase in fibrin and fibrinogen degradation products in APL cannot be explained by elastase activity. This study suggests a minor role for elastase mediated proteolysis in the hemorrhagic diathesis in APL patients.
Adult↗
Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules.
Platelet activation leads to secretion of granule contents and to the formation of microvesicles by shedding of membranes from the cell surface. Recently, we have described small internal vesicles in multivesicular bodies (MVBs) and alpha-granules, and suggested that these vesicles are secreted during platelet activation, analogous to the secretion of vesicles termed exosomes by other cell types. In the present study we report that two different types of membrane vesicles are released after stimulation of platelets with thrombin receptor agonist peptide SFLLRN (TRAP) or alpha-thrombin: microvesicles of 100 nm to 1 microm, and exosomes measuring 40 to 100 nm in diameter, similar in size as the internal vesicles in MVBs and alpha-granules. Microvesicles could be detected by flow cytometry but not the exosomes, probably because of the small size of the latter. Western blot analysis showed that isolated exosomes were selectively enriched in the tetraspan protein CD63. Whole-mount immuno-electron microscopy (IEM) confirmed this observation. Membrane proteins such as the integrin chains alpha(IIb)-beta(3) and beta(1), GPIbalpha, and P-selectin were predominantly present on the microvesicles. IEM of platelet aggregates showed CD63(+) internal vesicles in fusion profiles of MVBs, and in the extracellular space between platelet extensions. Annexin-V binding was mainly restricted to the microvesicles and to a low extent to exosomes. Binding of factor X and prothrombin was observed to the microvesicles but not to exosomes. These observations and the selective presence of CD63 suggest that released platelet exosomes may have an extracellular function other than the procoagulant activity, attributed to platelet microvesicles.
Blood Platelets↗
von Willebrand factor propeptide in vascular disorders: A tool to distinguish between acute and chronic endothelial cell perturbation.
Before de novo synthesized von Willebrand factor (vWF) leaves the endothelial cell, it undergoes endoproteolytic cleavage of its propeptide (vW antigen II). The processed vWF and propeptide are either released constitutively or, following activation of the endothelium, released through the regulated pathway. In a recent study (Borchiellini et al, Blood 88:2951, 1996), we showed that the half-life of mature vWF and of its propeptide differ fourfold to fivefold. We postulated that the molar ratio of the propeptide to mature vWF could serve as a tool to assess the extent of endothelial cell activation under physiologic and clinical conditions. To test this hypothesis, we measured mature vWF and propeptide in patients with documented acute and chronic vascular disease, including patients with thrombotic thrombocytopenic purpura (TTP), acute septicemia, and diabetes mellitus. These data were compared with experimental conditions in healthy subjects in which perturbation of the endothelium was simulated by physical exercise or by administration of 1-deamino-8-D-arginine vasopressin (DDAVP) or endotoxin. In all individuals of the latter study group, both vWF and propeptide levels were elevated during the acute phase of the experimentally induced vascular perturbation; at later time points after stimulation, only vWF levels remained elevated. In patients with sepsis and TTP, both vWF and propeptide were elevated several-fold. Thus, this pattern can readily be explained in terms of acute perturbation of the endothelium. In contrast, in patients with diabetes mellitus propeptide levels were only slightly elevated, whereas vWF levels were elevated twofold to threefold. This pattern is a typical feature of chronic, low-grade activation of the endothelium. These observations support our hypothesis that measurement of both propeptide and vWF levels allows to discriminate between chronic and acute phases of endothelial cell activation in vivo. Measurement of only vWF is less indicative in this respect.
Acute Disease↗
von Willebrand factor proteolysis is deficient in classic, but not in bone marrow transplantation-associated, thrombotic thrombocytopenic purpura.
Thrombotic thrombocytopenic purpura (TTP) after bone marrow transplantation (BMT) differs from classic TTP in its clinical course and therapy. A characteristic of classic TTP is the inhibition of a plasma protease that specifically cleaves von Willebrand factor (vWF), thus reducing its multimeric size. We investigated whether this protease was also inhibited in BMT-associated TTP. Plasma from patients with classic or BMT-associated TTP was incubated with recombinant vWF R834Q, a vWF mutant with enhanced sensitivity to the protease. The proteolysis of vWF multimers was analyzed and quantified on Western blot. Metalloprotease activity was strongly inhibited in the classic TTP patient group. However, metalloprotease activity was normal in the BMT-associated TTP patient group. The difference in activity between the two patient groups was highly significant (P =.0016). The results indicate that the etiologies of classic and BMT-associated TTP are indeed different and provide an explanation for the lack of success of plasma exchange in BMT-associated TTP.
Adolescent↗