NSAID treatment with meloxicam enhances peripheral stem cell mobilization in myeloma.

Chemotherapy with G-CSF is used to mobilize peripheral stem cells in multiple myeloma (MM) patients, with plerixafor as a rescue strategy for poorly mobilizing patients. Preclinical studies suggested that the nonsteroidal anti-inflammatory drug meloxicam enhances the mobilization of CD34+ cells. In this single-center study, we evaluated whether adding meloxicam to chemotherapy/G-CSF mobilization increases peripheral hematopoietic CD34+ cell levels and reduces the need of using plerixafor. We prospectively compared two consecutive cohorts of MM patients in first remission mobilized with G-CSF and non-myelosuppressive chemotherapy with vinorelbine or gemcitabine. The second cohort additionally received oral meloxicam. The cohorts comprised 84 patients without meloxicam (-M) and 66 patients with meloxicam (+M). Meloxicam was well tolerated and associated with similar hematologic engraftment after transplantation and equal survival rates. However, the meloxicam group had higher CD34+ cell levels on day 8 of the mobilization procedure (53 200 versus 35 600 CD34+ cells/mL; P=0.007), and fewer patients needed >1 collection day (+M: 6 (9%) patients versus -M: 16 (19%) patients; P=0.04). This resulted in reduced plerixafor administrations (+M: 7 (11%) patients versus -M: 18 (21%) patients; P=0.03) and less costs. Our data suggest that meloxicam enhances the mobilization of hematopoietic CD34+ blood cells in MM patients.

Treatment of thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP), characterized by thrombocytopenia and microangiopathic haemolytic anaemia, was almost universally fatal until the introduction of plasma exchange (PE) therapy in the 1970s. Based on clinical studies, daily PE has become the first-choice therapy since 1991. Recent findings may explain its effectiveness, which may include, in particular, the removal of anti-ADAMTS13 autoantibodies and unusually large von Willebrand factor multimers and/or supply of ADAMTS13 in acquired idiopathic or congenital TTP. Based on currently available data, the favoured PE regimen is daily PE [involving replacement of 1-1.5 times the patient's plasma volume with fresh-frozen plasma (FFP)] until remission. Adverse events of treatment are mainly related to central venous catheters. The potential reduction of plasma related side-effects, such as transfusion-related acute lung injury (TRALI) or febrile transfusion reactions by use of solvent-detergent treated (S/D) plasma instead of FFP is not established by controlled clinical studies. Uncontrolled clinical observations and the hypothesis of an autoimmune process in a significant part of the patients with acquired idiopathic TTP suggest a beneficial effect of adjunctive therapy with corticosteroids. Other immunosuppressive treatments are not tested in controlled trials and should be reserved for refractory or relapsing disease. There is no convincing evidence for the use of antiplatelet agents. Supportive treatment with transfusion of red blood cells or platelets has to be evaluated on a clinical basis, but the transfusion trigger for platelets should be very restrictive. Further controlled, prospective studies should consider the different pathophysiological features of thrombotic microangiopathies, address the prognostic significance of ADAMTS13 and explore alternative exchange fluids to FFP, the role of immunosuppressive therapies and of new plasma saving approaches as recombinant ADAMTS13 and protein A immunoadsorption.

Severe nose bleeding after intake of acetylsalicylic acid: von Willebrand disease type 2A. Case 9.

This case report of a school boy with a history of severe and repeated episodes of epistaxis presents a short overview of the clinical and laboratory findings which lead to confirm the suspected diagnosis of von Willebrand disease (vWD). Suspicion of defective primary haemostasis should arise when unusual (because of their number or duration) mucosal bleeds appear in an otherwise normal and healthy patient. Because of its definitive inhibitory effect on platelet aggregation, acetylsalicylic acid (more than other non-steroidal anti-inflammatory drugs exerting unselective inhibition of cyclooxygenase) is a strong factor in triggering or sustaining the bleeding disorders in these patients. Among the congenital disorder of primary haemostasis, vWD is by far the most frequent one. The difficulties of laboratory diagnosis of vWD are stressed; the promises and pitfalls of new in vitro methods for measuring primary haemostasis (PFA-100 analyzer) are discussed. An accurate diagnosis of the specific type of vWD is of critical importance for correct patient management as well as for genetic counseling.

Familial clustering of high factor VIII levels in patients with venous thromboembolism.

High levels of factor VIII (FVIII) but not von Willebrand factor (vWF) are known to increase the risk for venous thromboembolism. Whether high FVIII levels originate from hereditary defects or from acquired conditions remains unanswered. The objective of our study was to investigate whether there is evidence for familial clustering of elevated FVIII levels in families in which >/=1 member has been affected by a thromboembolic event and had reproducibly high FVIII levels. We investigated FVIII levels in 361 patients with previous venous thromboembolism. FVIII levels were measured by a chromogenic assay; the cutoff value was defined as the 98th percentile of FVIII plasma levels of 266 blood donors. vWF levels were determined by an enzyme immunoassay. After exclusion of known causes of FVIII elevation, such as the acute thrombotic event itself; inflammation; malignancy; liver, renal, or vascular disease; surgery; or pregnancy, we included 17 patients with unexplained, reproducibly high FVIII levels. The investigation was also extended to these patients' relatives. Multiple regressive analysis of blood donors and asymptomatic family members showed that the affiliation with a family in which 1 member suffered from venous thromboembolism and had reproducibly high FVIII levels is the second most important predictor for FVIII levels. Familial clustering was analyzed by the Houwing-Duistermaat familial aggregation test. After adjustment for the influence of age, sex, blood group, and vWF, FVIII levels were significantly (P:=0.038) clustered within families. In conclusion, FVIII levels seem to be familially determined in families in which a member showed high FVIII levels after previous venous thromboembolism.

[Measures for allogeneic blood conservation in surgery]. / Fremdblutsparende Massnahmen in der operativen Medizin.

The aim of all efforts to reduce the need of allogeneic blood transfusions is to avoid associated risks. There should particularly be a favourable effect according to the rate of transfusion-transmitted virus infections and immunological side-effects. The acceptance of an individually adjusted lowest haematocrit level and the minimisation of intra-operative blood loss by the application of optimal surgical techniques are among the most essential strategies to reduce or even avoid allogeneic blood transfusions. In addition the following interventions are generally accepted: Preoperative autologous blood donation, where appropriate supported by erythropoietin Preoperative haemodilution, where appropriate supported by erythropoietin Intra- and postoperative blood salvage Topical or systemic pharmacologic interventions to accelerate haemostasis Controlled hypotension Efficacy and indication of the different measures always depend on the individual circumstances of the specific patient. Therefore one should develop an individual approach for every case. In this context the most important subjects are an optimal coordination and if required an appropriate combination of the discussed methods. Algorithms which preoperatively allow approximate calculation of expected transfusion need may be a meaningful tool to facilitate blood conservation planning. However, at the same time one must consider that all strategies to reduce allogeneic transfusion needs are also associated with particular risks. Therefore one has to weigh carefully the pros and cons prior to their application, including the possible alternative of allogeneic transfusion in one's decision making process.

Depletion of neutralising antibodies resensitises a secondary non-responder to botulinum A neurotoxin.

The objective was to evaluate whether removal of neutralising antibodies potentially resensitises a secondary non-responder to botulinum neurotoxin A (BoNT/A). Neutralising antibodies directed against BoNT/A are produced during long term treatment with BoNT/A-hemagglutinin complex in up to 10% of patients with cervical dystonia. These patients become secondary non-responders. Other serotypes of BoNT are not yet generally available and may also bear the risk of inducing antibody formation. Plasma exchange (PE) (one treatment cycle) and immunoadsorption on a protein A column (IA-PA; three treatment cycles) was employed over 15 months to remove neutralising antibodies from a severely disabled secondary non-responder with cervical dystonia. After plasma exchange or IA-PA, BoNT/A was reinjected. Antibodies were measured with a sensitive functional toxin neutralising test. Repeated use of plasma exchange and IA-PA depleted neutralising antibodies to below the detection limit and subsequently allowed successful BoNT/A injection into dystonic muscles. No serious side effects were found related to the depletion of IgG. In conclusion PE or IA-PA performed before BoNT/A readministration may provide an alternative strategy in treating selected secondary non-responders who are severely disabled.

Chronic inflammatory demyelinating polyradiculoneuropathy: superiority of protein A immunoadsorption over plasma exchange treatment.

We present a patient with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) who was treated regularly with plasma exchanges (PE) because response to other therapies including i.v. immunoglobulins was not adequate. To reduce nonspecific protein losses due to repeated PE and increase IgG-removal, immunoadsorption (i.a.)-therapy using sepharose-bound protein A was initiated. Retrospective analysis of clinical data including muscle strength and walking distance shows that IA led to more rapid and greater functional improvement than PE in this patient with no relevant side effects. After 3 years of therapy lymphoma was diagnosed and treated. The patient had no relapses of CIDP for 17 months, when his functional status deteriorated again necessitating further IA-therapy. It is concluded that IgG removal by IA in CIDP is more effective and has fewer complications than PE. Due to the chronic course of CIDP requiring repeated interventions IA is also not more expensive than PE.

[Changes in blood rheology and microcirculation after preparatory combined thrombocytapheresis and plasmapheresis]. / Veränderungen der Blutrheologie und Mikrozirkulation nach präparativer kombinierter Thrombozytapherese und Plasmapherese.

INTRODUCTION: Because of anticoagulation, changes in blood composition, and--perhaps--extracorporeal circulation, donor apheresis should cause alterations in hemorheology and hence in the perfusion of the microvasculature. MATERIAL AND METHODS: 19 regular blood donors were included. According to our standard protocol for automated collection of blood components with the MCS 3p cell separator, we harvested 1 unit of platelets and 2 units of plasma in each case. Prior to, 1 h after, and 24 h after donation, the following parameters were measured: total serum protein (tsp), hematocrit (hc), whole blood and plasma viscosity (wbv/pv), red cell aggregability (rca) and blood flow velocity of the nail-fold capillaries (bfv). RESULTS: The following parameters decreased 1 h/24 h after donation: tsp (p < 0.001/p = 0.008), elastic wbv (p = 0.018/p < 0.001), viscous wbv (p = 0.85/p = 0.0031), pv (p < 0.001/p < 0.001), static rca (p < 0.001/p = 0.0073), dynamic rca (p < 0.001/p = 0.017). The hc showed an initial increase (p < 0.001) with a subsequent overshooting decrease after 24 h (p < 0.001). 1 h after donation bfv raised (p = 0.0065). It decreased after 24 h and remained only slightly higher than the initial level (p = 0.27). CONCLUSIONS: Automated combined collection of platelets and plasma gives rise to: i) Improvement of rheological properties of the donor's blood and increased bfv of his nail-fold capillaries within the 1st h after apheresis. ii) 24 h after donation the improved hemorheological properties remain demonstrable, but the bfv of nail-fold capillaries declines and shows a trend toward the starting-point. iii) Taken together, this is possibly reflecting adapted hemodynamic and vasoconstrictor regulation for altered hemorheological conditions.

[Therapeutic thrombocytapheresis--effect on hemorheologic parameters]. / Therapeutische Thrombozytapheresen--Wirkung auf hämorheologische Parameter.

Common features of all myeloproliferative diseases (CMPE) are a markedly increased number of platelets and restrictions in the subjective feeling of the patients, comprising symptoms like nausea, headache, sensory deficits and transient paresis. Meanwhile, it has been shown that platelet pheresis (mTD) does not only reduce platelet counts sufficiently but also results in an impressive relief of the subjective complaints. To test the part that rheological mechanisms play hereby, relevant rheological parameters in the blood of 22 CMPE patients and of 8 healthy platelet donors as controls were analyzed before and after treatment with an AS-104 cell separator. Concerning the viscosity of whole blood und the filterability of erythrocytes, there was seen neither a difference between the patients and the controls, nor before and after mTD. As a result of treatment of patients, the moderately raised plasma viscosity was normalized, whereas the aggregation of erythrocytes was significantly lowered. It is concluded that there is an influence of hemorheological conditions on the patient's subjective feeling. These would originate in neurological dysfunctions caused by CMPE-induced restrictions in cortical microcirculation. The erythrocyte aggregation, lowered by mTD, would cause an improvement of microcirculatory fluidity and would, in consequence, abolish the neurological symptoms.

[The diagnosis and therapy of acquired factor-VIII inhibitors in combination with lupus anticoagulants]. / Diagnose und Therapie eines erworbenen Faktor-VIII-Inhibitors in Kombination mit Lupus-Antikoagulanzien.

HISTORY AND CLINICAL FINDINGS: A 63-year-old woman, known to have a primary factor VIII inhibitor (FFI) in combination with lupus anticoagulants (LA) was hospitalised because of life-threatening bleeding from mouth and neck. INVESTIGATIONS: The activity of coagulation factor VIII was 9% under substitution, while the factor VIII inhibitor titre was 123 U/ml. A lupus anticoagulant test was positive. Antibodies against varicella-zoster virus and Epstein-Barr virus were demonstrated. The right adrenal was found to be enlarged on computed tomography. TREATMENT AND COURSE: Coagulation became normal on administration of porcine factor VIII concentrate. Three cycles of a combination of three protein A immunoadsorptions, cyclophosphamide (twice 1.0 g intravenously), IgG (30 g daily for 5 days) as well as long-term oral cyclophosphamide administration (150 mg daily) during the interval were undertaken to reduce the inhibitor and produce immuno-tolerance. The factor VIII inhibitor titre was stabilised at a low level, but factor VIII activity could not be normalised without substitution. CONCLUSIONS: The simultaneous presence of specific and non-specific inhibitors makes laboratory diagnosis and treatment more difficult. Porcine factor VIII and a combination of immunoadsorption and suppression are important components in the treatment of bleeding episodes and the production of immunotolerance.

[Storage-induced rheologic and biochemical changes in erythrocyte concentrates with added solution and possible correlations]. / Lagerungsbedingte rheologische und biochemische Veränderungen von Erythrozytenkonzentraten in additiver Lösung und deren mögliche Zusammenhänge.

Rheological integrity is one of the essentials for red blood cells (rbc) in capillary circulation. The influences of metabolical/biochemical changes of rbc on their rheological properties are well known, but (to our knowledge) until now there are no published studies, which cover both quality aspects of packed rbc (prbc) in additive solutions. According to our standard operating procedures (SOP) we prepared prbc in additive solution (SAG-M) and plasma from 16 regular blood donations. The buffy coat was discharged. Following parameters were measured on day 1, 14 and 28: extracellular pH, ATP and 2,3-DPG content of rbc, prbc-viskosity, -filterability, -aggregability and filter clogging rate. For examination of the filterability a 5% rbc-suspension in phoshate buffered solution was prepared, the remaining tests were performed with rbc-samples adjusted to a hematokrit of 40% with fresh frozen autologous plasma. In correlation with the depletion of ATP a decrease of rbc flexibility and changes of shape (for example spherocytosis) are well known from the literature. Our results confirm the assumed time dependent deterioration of rheological patterns of prbc in SAG-M, reflecting in an increase of rbc-viscosity and filter clogging rate and a decrease of rbc-filterability and -aggregability. We also observed the expected decrease of pH, ATP and 2,3-DPG during storage. The influences of biochemical changes on rheological alterations are discussed. Therefore we recommend on demand rheological examinations in addition to metabolical/biochemical analyses for an extended quality assurance program, for instance for testing new additive solutions or major changes of SOP.