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Waldenstrom macroglobulinaemia (WM) is an indolent non-Hodgkin lymphoma which usually presents with symptoms related to infiltration of bone marrow or other tissues like lymph nodes, liver or spleen and has certain unusual clinical manifestations, e.g., renal and central nervous system (CNS) involvement. It also has an array of laboratory features including hypersecretion of IgM, cryoglobulinaemia, increased plasma viscosity and identification of mutated MYD88L265P in more than 90% of cases. In this review, we aim to provide a guide to the laboratory investigations recommended for WM at initial diagnosis and at follow-up. A discussion on the nuances of diagnosis and differential diagnoses is followed by bone marrow (BM) assessment, measurement of paraprotein and other ancillary investigations. Recommendations are provided on laboratory work-up at diagnosis, in the asymptomatic follow-up phase, and during and post-treatment. Finally, we briefly discuss the implications of laboratory diagnosis in regard to recruitment and monitoring on clinical trials.Copyright © 2019

Waldenstrom macroglobulinaemia (WM) is an indolent non-Hodgkin lymphoma which usually presents with symptoms related to infiltration of bone marrow or other tissues like lymph nodes, liver or spleen and has certain unusual clinical manifestations, e.g., renal and central nervous system (CNS) involvement. It also has an array of laboratory features including hypersecretion of IgM, cryoglobulinaemia, increased plasma viscosity and identification of mutated MYD88L265P in more than 90% of cases. In this review, we aim to provide a guide to the laboratory investigations recommended for WM at initial diagnosis and at follow-up. A discussion on the nuances of diagnosis and differential diagnoses is followed by bone marrow (BM) assessment, measurement of paraprotein and other ancillary investigations. Recommendations are provided on laboratory work-up at diagnosis, in the asymptomatic follow-up phase, and during and post-treatment. Finally, we briefly discuss the implications of laboratory diagnosis in regard to recruitment and monitoring on clinical trials.Copyright © 2019

Waldenstrom macroglobulinaemia (WM) is an indolent B-cell malignancy characterised by the presence of immunoglobulin M (IgM) paraprotein and bone marrow infiltration by clonal small B lymphocytes, plasmacytoid lymphocytes and plasma cells. The symptoms of WM are protean, often follow an asymptomatic phase and may include complications related to the paraneoplastic effects of IgM paraprotein. The revised 2016 World Health Organization classification includes the MYD88 L265P mutation, which is seen in >90% of cases, within the diagnostic criteria for WM. While treatment of WM has often been considered together with other indolent B cell lymphomas, there are unique aspects of WM management that require specific care. These include the unreliability of IgM and paraprotein measurements in monitoring patients prior to and after treatment, the lack of correlation between disease burden and symptoms and rituximab-induced IgM flare. Moreover, while bendamustine and rituximab has recently been approved for reimbursed frontline use in WM in Australia, other regimens, including ibrutinib- and bortezomib-based treatments, are not funded, requiring tailoring of treatment to the regional regulatory environment. The Medical and Scientific Advisory Group of the Myeloma Foundation Australia has therefore developed clinical practice guidelines with specific recommendations for the work-up and therapy of WM to assist Australian clinicians in the management of this disease.Copyright © 2017 Royal Australasian College of Physicians

Waldenstrom macroglobulinaemia (WM) is an indolent B-cell malignancy characterised by the presence of immunoglobulin M (IgM) paraprotein and bone marrow infiltration by clonal small B lymphocytes, plasmacytoid lymphocytes and plasma cells. The symptoms of WM are protean, often follow an asymptomatic phase and may include complications related to the paraneoplastic effects of IgM paraprotein. The revised 2016 World Health Organization classification includes the MYD88 L265P mutation, which is seen in >90% of cases, within the diagnostic criteria for WM. While treatment of WM has often been considered together with other indolent B cell lymphomas, there are unique aspects of WM management that require specific care. These include the unreliability of IgM and paraprotein measurements in monitoring patients prior to and after treatment, the lack of correlation between disease burden and symptoms and rituximab-induced IgM flare. Moreover, while bendamustine and rituximab has recently been approved for reimbursed frontline use in WM in Australia, other regimens, including ibrutinib- and bortezomib-based treatments, are not funded, requiring tailoring of treatment to the regional regulatory environment. The Medical and Scientific Advisory Group of the Myeloma Foundation Australia has therefore developed clinical practice guidelines with specific recommendations for the work-up and therapy of WM to assist Australian clinicians in the management of this disease.Copyright © 2017 Royal Australasian College of Physicians

Objectives: Plasmaor serum hyperviscosity in plasma cell dyscrasias (PCD) has been described as a risk factor for circulatory disturbances. Whole blood viscosity (WBV) would theoretically be a better biomarker but has not been studied in PCD. Design and methods: Plasma viscosity (PV) and WBV were measured in 89 subjects with PCD and in 60 healthy blood donors by free oscillation rheometry. A complete blood count was obtained using an automated hematology analyzer. Plasma proteins were quantitated by immunoturbidimetry. Results: The reference intervals for men & women were 1.16-1.36 & 1.16-1.38 mPa for PV, and 4.9-6.3 & 4.4-6.2 mPa for WBV, respectively. Of the PCD patients, 71% had PV above the reference limit and 40% were above the WBV limit. Multivariate analysis showed that WBV was independently related to hematocrit, PV, concentration of the monoclonal protein (M-protein), plasma fibrinogen concentration and albumin concentration. This model accounted for 76% of the variance in WBV. When the same model was applied to PV, only the concentration of the M-protein was significantly related and the model accounted only for 20% of the variance in PV. Conclusion: PV cannot be used as a surrogate marker for WBV in PCD patients. Whole blood viscosity should replace plasma viscosity in patients with PCD.

The peripheral arterial disease (PAD) and the critical limb ischemia (CLI) are frequent and serious pathologies in dialysis, in both diabetic and non-diabetic patients, and represent serious clinical and social problems. Patients having serious trophic injuries often have to recur to amputation, despite the use of all the therapies that are currently available. In this article we attempt to underline the importance of the microcirculation and rheopheresis in affecting the prognosis of this pathology., La peripheral arterial disease (PAD) e la critical limb ischemia (CLI) sono una frequente e grave patologia dei pazienti in dialisi, diabetici e non diabetici, e rappresentano un grave problema clinico e sociale. I pazienti che si presentano con gravi lesioni trofiche arrivano frequentemente all'amputazione, nonostante l'utilizzo di tutti i presidi terapeutici oggi a nostra disposizione. In questo lavoro cerchiamo di sottolineare l'importanza del microcircolo e della Reoferesi nel condizionare la prognosi di questa patologia.

The peripheral arterial disease (PAD) and the critical limb ischemia (CLI) are frequent and serious pathologies in dialysis, in both diabetic and non-diabetic patients, and represent serious clinical and social problems. Patients having serious trophic injuries often have to recur to amputation, despite the use of all the therapies that are currently available. In this article we attempt to underline the importance of the microcirculation and rheopheresis in affecting the prognosis of this pathology., La peripheral arterial disease (PAD) e la critical limb ischemia (CLI) sono una frequente e grave patologia dei pazienti in dialisi, diabetici e non diabetici, e rappresentano un grave problema clinico e sociale. I pazienti che si presentano con gravi lesioni trofiche arrivano frequentemente all'amputazione, nonostante l'utilizzo di tutti i presidi terapeutici oggi a nostra disposizione. In questo lavoro cerchiamo di sottolineare l'importanza del microcircolo e della Reoferesi nel condizionare la prognosi di questa patologia.

The peripheral arterial disease (PAD) and the critical limb ischemia (CLI) are frequent and serious pathologies in dialysis, in both diabetic and non-diabetic patients, and represent serious clinical and social problems. Patients having serious trophic injuries often have to recur to amputation, despite the use of all the therapies that are currently available. In this article we attempt to underline the importance of the microcirculation and rheopheresis in affecting the prognosis of this pathology., La peripheral arterial disease (PAD) e la critical limb ischemia (CLI) sono una frequente e grave patologia dei pazienti in dialisi, diabetici e non diabetici, e rappresentano un grave problema clinico e sociale. I pazienti che si presentano con gravi lesioni trofiche arrivano frequentemente all'amputazione, nonostante l'utilizzo di tutti i presidi terapeutici oggi a nostra disposizione. In questo lavoro cerchiamo di sottolineare l'importanza del microcircolo e della Reoferesi nel condizionare la prognosi di questa patologia.

Hintergrund: Das akute Nierenversagen ist eine häufige Komplikation nach einer Herzoperation bei Neugeborenen, Säuglingen und Kleinkindern. Die Bedeutung der postoperativen Hämodynamik für eine Nierenschädigung ist gut bekannt, jedoch ist der Einfluß des kardiopulmonalen Bypasses und des tiefen hypothermen Kreislaufstillstandes weniger klar. Überdies gibt es Veränderungen der Blutviskosität während und nach der Herzoperation am kardiopulmonalen Bypass, welche die Nierenfunktion beeinflussen können. Aus diesem Grunde wurde der Einfluß der Blutviskosität am kardiopulmonalen Bypass und des tiefen hypothermen Kreislaufstillstandes auf die Nierenfunktion in dieser Patientengruppe untersucht. Methode: Untersucht wurden 44 Patienten mit einem Körpergewicht unter 10 kg, die am kardiopulmonalen Bypass operiert wurden. Von diesen erfolgte die Herzoperation bei 7 Patienten unter zusätzlicher Anwendung des tiefen hypothermen Kreislaufstillstandes. Bei allen Patienten wurden zu verschiedenen Zeitperioden Messungen zur Beschreibung der Nierenfunktion (Diurese, Kreatinin-Clearance und Gesamtprotein, Albumin, alpha-1-Mikroglobulin, Transferrin, IgG, N-Acetyl-beta-D-Glucosaminidase im Urin) und Bestimmungen der Blut- und Plasmaviskosität, der Erythrozytenaggregation und des kolloidosmotischen Druckes durchgeführt. Beide Gruppen wurden hinsichtlich des Einflusses des Kreislaufstillstandes auf die Nierenfunktion miteinander verglichen. Ergebnisse: Die während des kardiopulmonalen Bypasses im Zusammenhang mit einem erhöhten transglomerulären Filtrationsgradienten entstandene Polyurie und Proteinurie normalisierte sich innerhalb von 24 Stunden postoperativ. Die renale Ausscheidung von N-Acetyl-beta-D-Glucosaminidase und die erhöhte Natriumausscheidung zeigten zusätzlich eine tubuläre Schädigung an. Bei Hypothermie hatte die Plasmaviskosität einen deutlichen Einfluß auf die Blutviskosität, die während hypothermer Perfusion mit den im Urin gemessenen Werten von Albumin und N-Acetyl-beta-D, Background: Acute renal failure is a common complication after cardiopulmonary bypass in infants. Whereas it is well known that postoperative hemodynamics inflict acute renal failure, the influence of extracoporeal circulation on the kidney is less clear. Moreover, changes in blood viscosity occur during and after surgery, which may influence renal dysfunction. For this reason, the impact of blood viscosity during cardiopulmonary bypass and circulatory arrest on renal function was investigated. Methods: 44 patients weighting less than 10 kg operated on cardiopulmonary bypass were investigated, inclusive of 7 patients who additionally underwent circulatory arrest. In all patients analyses of renal function (diuresis, creatinine clearance, urinary total protein, albumin, alpha-1-microglobulin, transferrin, IgG, and N-acetyl-beta-D-glucosaminidase), blood, and plasma viscosity measurements, erythrocyte aggregation and colloid osmotic pressure were performed. Both groups were compared with regard to the impact of circulatory arrest on renal function. Results: Polyuria and proteinuria that appeared during cardiopulmonary bypass indicated an elevated transglomerular filtration gradient, which recovered within 24 hours. The appearance of N-acetyl-beta-D-glucosaminidase in the urine and elevated sodium excretion were additionally indicative of mild tubular damage. With hypothermia, plasma viscosity could had a major impact on the blood viscosity, which, during hypothermic perfusion, seemed to be related to proteinuria and N-acetyl-beta-D-glucosaminidase values. The patients of the circulatory arrest group had a longer bypass time and a lower body temperature in compare to the patients without circulatory arrest (p < 0.05). Diuresis and creatinine clearance revealed no differences between both groups. During reperfusion in the circulatory arrest group significantly more albumin were excreted as in the comparison group, likewise albumin and N-acetyl-beta-D-glucosaminidase aft

Hintergrund: Das akute Nierenversagen ist eine häufige Komplikation nach einer Herzoperation bei Neugeborenen, Säuglingen und Kleinkindern. Die Bedeutung der postoperativen Hämodynamik für eine Nierenschädigung ist gut bekannt, jedoch ist der Einfluß des kardiopulmonalen Bypasses und des tiefen hypothermen Kreislaufstillstandes weniger klar. Überdies gibt es Veränderungen der Blutviskosität während und nach der Herzoperation am kardiopulmonalen Bypass, welche die Nierenfunktion beeinflussen können. Aus diesem Grunde wurde der Einfluß der Blutviskosität am kardiopulmonalen Bypass und des tiefen hypothermen Kreislaufstillstandes auf die Nierenfunktion in dieser Patientengruppe untersucht. Methode: Untersucht wurden 44 Patienten mit einem Körpergewicht unter 10 kg, die am kardiopulmonalen Bypass operiert wurden. Von diesen erfolgte die Herzoperation bei 7 Patienten unter zusätzlicher Anwendung des tiefen hypothermen Kreislaufstillstandes. Bei allen Patienten wurden zu verschiedenen Zeitperioden Messungen zur Beschreibung der Nierenfunktion (Diurese, Kreatinin-Clearance und Gesamtprotein, Albumin, alpha-1-Mikroglobulin, Transferrin, IgG, N-Acetyl-beta-D-Glucosaminidase im Urin) und Bestimmungen der Blut- und Plasmaviskosität, der Erythrozytenaggregation und des kolloidosmotischen Druckes durchgeführt. Beide Gruppen wurden hinsichtlich des Einflusses des Kreislaufstillstandes auf die Nierenfunktion miteinander verglichen. Ergebnisse: Die während des kardiopulmonalen Bypasses im Zusammenhang mit einem erhöhten transglomerulären Filtrationsgradienten entstandene Polyurie und Proteinurie normalisierte sich innerhalb von 24 Stunden postoperativ. Die renale Ausscheidung von N-Acetyl-beta-D-Glucosaminidase und die erhöhte Natriumausscheidung zeigten zusätzlich eine tubuläre Schädigung an. Bei Hypothermie hatte die Plasmaviskosität einen deutlichen Einfluß auf die Blutviskosität, die während hypothermer Perfusion mit den im Urin gemessenen Werten von Albumin und N-Acetyl-beta-D, Background: Acute renal failure is a common complication after cardiopulmonary bypass in infants. Whereas it is well known that postoperative hemodynamics inflict acute renal failure, the influence of extracoporeal circulation on the kidney is less clear. Moreover, changes in blood viscosity occur during and after surgery, which may influence renal dysfunction. For this reason, the impact of blood viscosity during cardiopulmonary bypass and circulatory arrest on renal function was investigated. Methods: 44 patients weighting less than 10 kg operated on cardiopulmonary bypass were investigated, inclusive of 7 patients who additionally underwent circulatory arrest. In all patients analyses of renal function (diuresis, creatinine clearance, urinary total protein, albumin, alpha-1-microglobulin, transferrin, IgG, and N-acetyl-beta-D-glucosaminidase), blood, and plasma viscosity measurements, erythrocyte aggregation and colloid osmotic pressure were performed. Both groups were compared with regard to the impact of circulatory arrest on renal function. Results: Polyuria and proteinuria that appeared during cardiopulmonary bypass indicated an elevated transglomerular filtration gradient, which recovered within 24 hours. The appearance of N-acetyl-beta-D-glucosaminidase in the urine and elevated sodium excretion were additionally indicative of mild tubular damage. With hypothermia, plasma viscosity could had a major impact on the blood viscosity, which, during hypothermic perfusion, seemed to be related to proteinuria and N-acetyl-beta-D-glucosaminidase values. The patients of the circulatory arrest group had a longer bypass time and a lower body temperature in compare to the patients without circulatory arrest (p < 0.05). Diuresis and creatinine clearance revealed no differences between both groups. During reperfusion in the circulatory arrest group significantly more albumin were excreted as in the comparison group, likewise albumin and N-acetyl-beta-D-glucosaminidase aft

In der Literatur finden sich zahlreiche Hinweise dafür, daß die hämorheologischen Meßgrößen wie Hämatokrit, Erythrozytenaggregation und Erythrozytenrigidität, sowie Vollblut- und Plasmaviskosität bei Patienten mit Atherosklerose bzw. bereits bei Personen mit kardiovaskulären Risikofaktoren pathologisch verändert sind. Offen ist dagegen derzeit die Frage, ob derartige Veränderungen reversibel sind. Die vorliegende Arbeit sollte deshalb der Frage nachgehen, ob sich im Verlauf einer stationären Anschlußheilbehandlung (AHB) neben einer Normalisierung klassisch kardiovaskulärer Risikofaktoren auch positive Veränderungen rheologischer Parameter beobachten lassen. Dazu wurden 64 männliche und weibliche Patienten zu Beginn und am Ende ihrer vierwöchigen kardiologischen AHB untersucht. Es wurden der Blutdruck, Gewicht und Gesamtcholesterin, sowie die hämorheologischen Parameter Plasmaviskosität, Hämatokrit und Fibrinogen bestimmt. Bis auf geschlechtsspezifische Hämatokritwertunterschiede wurden keine statistisch signifikanten Differenzen der rheologischen Werte im Gruppenvergleich der verschiedenen Patientengruppen gefunden. Im Verlauf der AHB kam es neben einer statistisch signifikanten Reduktion klassisch kardiovaskulärer Risikofaktoren zu einer statistisch signifikanten, von koronarer Herzkrankheit und Risikofaktoren unabhängigen Verminderung der Plasmaviskosität und des Hämatokrits. Keine statistisch signifikanten Änderungen zeigten sich diesbezüglich des Fibrinogenspiegels. Desweiteren wurden einige schwach positive Korrelationen zwischen der Änderung klassischer Risikofaktoren und der Änderung hämorheologischer Faktoren aufgezeigt. Diese Ergebnisse bestätigen Zusammenhänge zwischen kardiovaskulären Risikofaktoren und hämorheologischen Meßgrößen. Sie implizieren weiterhin, daß es im Verlauf einer kardiovaskulären Rehabilitation nicht nur zu der erhofften Reduktion diverser Risikofaktoren kommt, sondern daß auch hämorheologische Kenngrößen günstig beeinflußt werden., The fact that hemorheological variables such as hematocrit, red cell flexibility and aggregability, plasma and blood viscosity are pathologically altered in the presence of cardiovascular risk factors and diseases is evidenced by a large and growing amount of data. The question whether and how such abnormalities might be reversible is still largely unanswered. This investigation was therefore aimed at determining the hemorheological effects of a 4-week cardiovascular rehabilitation programme in 64 male and female patients with cardiovascular disease and/or risk factors. Blood pressure, body weight and total cholesterol were measured together with hemorheological parameters such as plasma viscosity, hematocrit and fibrinogen. With the exception of gender-specific hematocrit differences, no significant differences were found regarding rheological values between various groups. In the course of the rehabilitation programme, a reduction of conventional cardiovascular risk factors was noted and a statistically significant reductions of plasma viscosity and hematocrit were found which were independent of coronary heart disease. No significant changes were seen in fibrinogen levels. Moreover, a weak positive correlation was observed between conventional risk factors and changes in hemorheological variables. These results confirm the links between conventional risk factors and hemorheological measurements. They also imply that, during a rehabilitation programme, a reduction of various risk factors may be associated with positive changes in hemorheological variables. In conclusion, this study has demonstrated a change in some hemorheological variables in the course of a complex rehabilitation programme for cardiac patients.

In der Literatur finden sich zahlreiche Hinweise dafür, daß die hämorheologischen Meßgrößen wie Hämatokrit, Erythrozytenaggregation und Erythrozytenrigidität, sowie Vollblut- und Plasmaviskosität bei Patienten mit Atherosklerose bzw. bereits bei Personen mit kardiovaskulären Risikofaktoren pathologisch verändert sind. Offen ist dagegen derzeit die Frage, ob derartige Veränderungen reversibel sind. Die vorliegende Arbeit sollte deshalb der Frage nachgehen, ob sich im Verlauf einer stationären Anschlußheilbehandlung (AHB) neben einer Normalisierung klassisch kardiovaskulärer Risikofaktoren auch positive Veränderungen rheologischer Parameter beobachten lassen. Dazu wurden 64 männliche und weibliche Patienten zu Beginn und am Ende ihrer vierwöchigen kardiologischen AHB untersucht. Es wurden der Blutdruck, Gewicht und Gesamtcholesterin, sowie die hämorheologischen Parameter Plasmaviskosität, Hämatokrit und Fibrinogen bestimmt. Bis auf geschlechtsspezifische Hämatokritwertunterschiede wurden keine statistisch signifikanten Differenzen der rheologischen Werte im Gruppenvergleich der verschiedenen Patientengruppen gefunden. Im Verlauf der AHB kam es neben einer statistisch signifikanten Reduktion klassisch kardiovaskulärer Risikofaktoren zu einer statistisch signifikanten, von koronarer Herzkrankheit und Risikofaktoren unabhängigen Verminderung der Plasmaviskosität und des Hämatokrits. Keine statistisch signifikanten Änderungen zeigten sich diesbezüglich des Fibrinogenspiegels. Desweiteren wurden einige schwach positive Korrelationen zwischen der Änderung klassischer Risikofaktoren und der Änderung hämorheologischer Faktoren aufgezeigt. Diese Ergebnisse bestätigen Zusammenhänge zwischen kardiovaskulären Risikofaktoren und hämorheologischen Meßgrößen. Sie implizieren weiterhin, daß es im Verlauf einer kardiovaskulären Rehabilitation nicht nur zu der erhofften Reduktion diverser Risikofaktoren kommt, sondern daß auch hämorheologische Kenngrößen günstig beeinflußt werden., The fact that hemorheological variables such as hematocrit, red cell flexibility and aggregability, plasma and blood viscosity are pathologically altered in the presence of cardiovascular risk factors and diseases is evidenced by a large and growing amount of data. The question whether and how such abnormalities might be reversible is still largely unanswered. This investigation was therefore aimed at determining the hemorheological effects of a 4-week cardiovascular rehabilitation programme in 64 male and female patients with cardiovascular disease and/or risk factors. Blood pressure, body weight and total cholesterol were measured together with hemorheological parameters such as plasma viscosity, hematocrit and fibrinogen. With the exception of gender-specific hematocrit differences, no significant differences were found regarding rheological values between various groups. In the course of the rehabilitation programme, a reduction of conventional cardiovascular risk factors was noted and a statistically significant reductions of plasma viscosity and hematocrit were found which were independent of coronary heart disease. No significant changes were seen in fibrinogen levels. Moreover, a weak positive correlation was observed between conventional risk factors and changes in hemorheological variables. These results confirm the links between conventional risk factors and hemorheological measurements. They also imply that, during a rehabilitation programme, a reduction of various risk factors may be associated with positive changes in hemorheological variables. In conclusion, this study has demonstrated a change in some hemorheological variables in the course of a complex rehabilitation programme for cardiac patients.

The blood flow property is one of the factors determining blood perfusion and oxygen supply. The viscosity of the blood is primarily related to the hematocrit, but also to the amount of fibrinogen and other macromolecules present in the blood. Patients with ischemic heart disease have shown a rapid and safe improvement in their hemorheological state when treated with heparin-induced extracorporeal low-density lipoprotein (LDL) precipitation (HELP). In this study we used two extracorporeal hemapheresis methods, plasmapheresis (PP) and immunoadsorption (IA), in 15 patients (eight patients treated with PP and seven patients with IA) with various diseases. Hemorheological variables and plasma fibrinogen were measured before and after the first and before the third treatment performed at 3 consecutive days. The aim of our study was to investigate the immediate effects of these two treatment modalities on the flow properties of blood. Immediately after the first PP and IA session statistically significant declines in plasma fibrinogen concentration, plasma viscosity, whole blood viscosity, and erythrocyte aggregation tendency were found. These changes persisted before the third treatment session. The erythrocyte fluidity and hematocrit remained unchanged. We conclude that extracorporeal hemapheresis therapy, with plasmapheresis or immunoadsorption, affects the blood rheology by decreasing the plasma viscosity and erythrocyte aggregation tendency. The decrease in plasma fibrinogen is probably the main factor underlying that, but other factors such as a decrease in immunoglobulins may also be of importance.