Institut für Immunologie u. Transfusionsmedizin - Abteilung Transfusionsmedizin
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For the last two decades, heparins have been widely used as anticoagulants. Besides
numerous advantages, up to 5% patients with heparin administration suffer from a major adverse
drug effect known as heparin-induced thrombocytopenia (HIT). This typical HIT can result in deep
vein thrombosis, pulmonary embolism, occlusion of a limb artery, acute myocardial infarct, stroke, and
a systemic reaction or skin necrosis. The basis of HIT may lead to clinical insights. Recent studies using
single-molecule force spectroscopy (SMFS)-based atomic force microscopy revealed detailed binding
mechanisms of the interactions between platelet factor 4 (PF4) and heparins of different lengths in
typical HIT. Especially, SMFS results allowed identifying a new mechanism of the autoimmune HIT
caused by a subset of human-derived antibodies in patients without heparin exposure. The findings
proved that not only heparin but also a subset of antibodies induce thrombocytopenia. In this review,
the role of SMFS in unraveling a major adverse drug effect and insights into molecular mechanisms
inducing thrombocytopenia by both heparins and antibodies will be discussed.
Background
Signs of an inflammatory process have been described in major depression.
Methods
In a double-blind, randomized study of celecoxib or placebo add-on to reboxetine in 40 depressed patients, celecoxib treatment has beneficial effects. In order to evaluate the tryptophan/kynurenine metabolism and to identify predictors for remission, tryptophan (TRP), kynurenine (KYN), kynurenic acid (KYNA), and quinolinic acid (QUIN) were estimated in the serum of 32 patients before and after treatment and in a group of 20 healthy controls.
Results
KYN levels were significantly lower in patients (p = 0.008), and the QUIN/KYN ratios were significantly higher (p = 0.028). At baseline, the higher KYN/TRP ratio was predictive for remission during celecoxib add-on treatment (p = 0.04) as well as for remission in the overall patient group (p = 0.01). In the placebo group, remitters showed a higher KYNA/QUIN ratio (p = 0.032). In the overall group, remitters showed lower KYNA/KYN (p = 0.035) and QUIN/KYN (p = 0.011) ratios. The lower the formation of downstream metabolites, especially QUIN, the better the treatment outcome.
Conclusion
The high KYN/TRP ratio predicted remission after treatment with celecoxib in this small sample of depressed patients. Eventually, the KYN/TRP ratio might be a marker for those patients, which benefit from an additional anti-inflammatory treatment.
Background: We assessed the effect of the uniform donor questionnaire (UDQ) on deferral rates in first-time and repeat donors. We focused on the introduced question about unprotected sexual contact with a new partner. Another goal was a stratified comparison of the deferral rates of the donor questionnaire (DQ) and UDQ. Methods: Data on donors and deferrals using the DQ and UDQ were collected at four blood establishments. The comparison included a 2-year period by questionnaire version. For the comparison of the questionnaires, an adjusted multinomial logistic regression was performed. Results: The analysis included 260,848 donations. First-time (FTD) and repeat donations (RD) showed higher deferral rates with the UDQ (FTD +5.4%, RD +1.4%). Deferral due to a new partner was 3.0% in first-time and 0.4% in repeat donors. The majority of these occurred in the youngest age groups. The most frequent deferral criterion was ‘disease' (5.1%). Conclusion: The regression revealed stronger predictors for deferral than the questionnaire version. Especially younger age carried a higher and independent risk for deferral. The additional deferrals of mainly young first-time donors due to a new sexual partner may identify those donors with potential heterosexual risk behavior who would otherwise not be identified.
Background: Patients with mucin-producing adenocarcinoma have an increased risk for venous and arterial thrombosis. When these patients present with thrombocytopenia, disseminated intravascular coagulopathy (DIC) is often the underlying cause. Case Report: We report 2 patients who were admitted due to bleeding symptoms of unknown cause, in whom further workup revealed adenocarcinoma-induced DIC. Conclusion: In elderly patients presenting with signs of DIC, such as reduced fibrinogen levels, elevated prothrombin time, elevated D-dimer, and thrombocytopenia, without any obvious reason (e.g., sepsis), adenocarcinoma-associated coagulopathy should be considered as the underlying cause. Paradoxically, in these patients bleeding symptoms improve when the patient is sufficiently anti-coagulated with low molecular weight heparin. Treatment of the underlying disease is of central importance in controlling acute or chronic DIC associated with malignant diseases and chemotherapy should be started as soon as possible.
Background: Hyperthyroidism is known to induce a hypercoagulable state. It stimulates plasma levels of procoagulative factors and reduces fibrinolytic activity. So far most of the data have been derived from patients with endogenous hyperthyroidism with a wide variability in the underlying pathogenesis and severity of the disease. Objectives: In this study we experimentally induced thyrotoxicosis in healthy volunteers to explore the effects of thyroxine excess on the plasma proteome. Using a shotgun proteomics approach, the abundance of plasma proteins was monitored before, during and after thyrotoxicosis. Methods: Sixteen healthy male subjects were sampled at baseline, 4 and 8 weeks under 250 µg/day thyroxine p.o., as well as 4 and 8 weeks after stopping the application. Plasma proteins were analyzed after depletion of 6 high-abundance proteins (MARS6) by LC-ESI-MS/MS mass spectrometry. Mass spectrometric raw data were processed using a label-free, intensity-based workflow. Subsequently, the linear dependence between protein abundances and fT<sub>4</sub> levels were calculated using a Pearson correlation. Results: All subjects developed biochemical thyrotoxicosis, and this effect was reversed within the first 4 weeks of follow-up. None of the volunteers noticed any subjective symptoms. Levels of 10 proteins involved in the coagulation cascade specifically correlated with fT<sub>4</sub>, supporting an influence of thyroid hormone levels on blood coagulation even at nonpathological levels. Conclusions: The results suggest that experimental thyrotoxicosis exerts selective and specific thyroxine-induced effects on coagulation markers. Our study design allows assessment of thyroid hormone effects on plasma protein levels without secondary effects of other diseases or therapies.
Background: Securing future blood supply is a major issue of transfusion safety. In this prospective 10-year longitudinal study we enrolled all blood donation services and hospitals of the federal state Mecklenburg-Western Pomerania. Methods and Results: From 2005 to 2015 (time period with major demographic effects), whole blood donation numbers declined by 18%. In male donors this paralleled the demographic change, while donation rates of females declined 12.4% more than expected from demography. In parallel, red cell transfusion rates/1,000 population decreased from 2005 to 2015 from 56 to 51 (-8.4%), primarily due to less transfusions in patients >60 years. However, the transfusion demand declined much less than blood donation numbers: -13.5% versus -18%, and the population >65 years (highest transfusion demand) will further increase. The key question is whether the decline in transfusion demand observed over the previous years will further continue, hereby compensating for reduced blood donation numbers due to the demographic change. The population structure of Mecklenburg-Western Pomerania reflects all Eastern German federal states, while the Western German federal states will reach similar ratios of age groups 18-64 years / ≥65 years about 10 years later. Conclusions: Regular monitoring of age- and sex-specific donation and transfusion data is urgently required to allow transfusion services strategic planning for securing future blood supply.
‘Chameleonic' Serological Findings Leading to Life-Threatening Hemolytic Transfusion Reactions
(2015)
Background: The phenomena of co-incidence of transfusion-induced allo- and autoantibodies, blockage and/or loss of red blood cell (RBC) antigens are conspicuous and may result in confusion and misdiagnosis. Case Report: A 67-year-old female was transferred to the intensive care unit due to hemolysis which developed 2 days following transfusion of three Rh(D)-negative RBC units in the presence of strongly reactive autoantibodies. Standard serological testing and genotyping were performed. Upon arrival, the patient was typed as Ccddee. Her hemolysis was decompensated, and an immediate blood transfusion was required. In addition, direct and indirect antiglobulin tests (DAT and IAT) as well as the eluate were strongly positive. Emergency transfusion of Rh(D)-negative RBCs resulted in increased hemolysis and renal failure. An exhaustive testing revealed anti-D, anti-c, CCddee phenotype and CCD.ee genotype. Three units of cryopreserved CCddee RBCs were transfused, and the patient's condition immediately improved. The discrepancy between Rh-D phenotyping and genotyping was likely caused by masking of the D-epitopes by the autoantibodies. In fact, further enquiry revealed that the patient had been phenotyped as Rh(D)-positive 6 months ago and had been transfused at that time following hip surgery. Conclusion: The phenomena of transfusion-induced autoantibodies, masked alloantibodies, antigen blockage and/or loss are rare but important features which should be considered in patients presenting with autoimmune hemolytic anemia and/or hemolytic transfusion reactions.
Platelets transfusion is a safe process, but during or after the process, the recipient may experience an adverse reaction and occasionally a serious adverse reaction (SAR). In this review, we focus on the inflammatory potential of platelet components (PCs) and their involvement in SARs. Recent evidence has highlighted a central role for platelets in the host inflammatory and immune responses. Blood platelets are involved in inflammation and various other aspects of innate immunity through the release of a plethora of immunomodulatory cytokines, chemokines, and associated molecules, collectively termed biological response modifiers that behave like ligands for endothelial and leukocyte receptors and for platelets themselves. The involvement of PCs in SARs—particularly on a critically ill patient’s context—could be related, at least in part, to the inflammatory functions of platelets, acquired during storage lesions. Moreover, we focus on causal link between platelet activation and immune-mediated disorders (transfusion-associated immunomodulation, platelets, polyanions, and bacterial defense and alloimmunization). This is linked to the platelets’ propensity to be activated even in the absence of deliberate stimuli and to the occurrence of time-dependent storage lesions.