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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 SARsâparticularly on a critically ill patientâs contextâcould 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 plateletsâ propensity to be activated even in the absence of deliberate stimuli and to the occurrence of time-dependent storage lesions.
Abstract
Background
Heparin induced thrombocytopenia (HIT) is likely a misdirected bacterial host defense mechanism. Platelet factor 4 (PF4) binds to polyanions on bacterial surfaces exposing neoâepitopes to which HIT antibodies bind. Platelets are activated by the resulting immune complexes via FcÎłRIIA, release bactericidal substances, and kill Gramânegative Escherichia coli.
Objectives
To assess the role of PF4, antiâPF4/H antibodies and FcÎłRIIa in killing of Gramâpositive bacteria by platelets.
Methods
Binding of PF4 to proteinâA deficient Staphylococcus aureus (SA113Îspa) and nonâencapsulated Streptococcus pneumoniae (D39Îcps) and its conformational change were assessed by flow cytometry using monoclonal (KKO,5B9) and patient derived antiâPF4/H antibodies. Killing of bacteria was quantified by counting colony forming units (cfu) after incubation with platelets or platelet releasate. Using flow cytometry, platelet activation (CD62Pâexpression, PACâ1 binding) and phosphatidylserine (PS)âexposure were analyzed.
Results
Monoclonal and patientâderived antiâPF4/H antibodies bound in the presence of PF4 to both S. aureus and S. pneumoniae (1.6âfold increased fluorescence signal for human antiâPF4/H antibodies to 24.0âfold increase for KKO). Staphylococcus aureus (5.5 Ă 104cfu/mL) was efficiently killed by platelets (2.7 Ă 104cfu/mL) or their releasate (2.9 Ă 104cfu/mL). Killing was not further enhanced by PF4 or antiâPF4/H antibodies. Blocking FcÎłRIIa had no impact on killing of S. aureus by platelets. In contrast, S. pneumoniae was not killed by platelets or releasate. Instead, after incubation with pneumococci platelets were unresponsive to TRAPâ6 stimulation and exposed high levels of PS.
Conclusions
AntiâPF4/H antibodies seem to have only a minor role for direct killing of Gramâpositive bacteria by platelets. Staphylococcus aureus is killed by platelets or platelet releasate. In contrast, S. pneumoniae affects platelet viability.
Abstract
Platelets are small anucleate blood cells with a life span of 7 to 10Â days. They are main regulators of hemostasis. Balanced platelet activity is crucial to prevent bleeding or occlusive thrombus formation. Growing evidence supports that platelets also participate in immune reactions, and interaction between platelets and leukocytes contributes to both thrombosis and inflammation. The ubiquitinâproteasome system (UPS) plays a key role in maintaining cellular protein homeostasis by its ability to degrade nonâfunctional selfâ, foreign, or shortâlived regulatory proteins. Platelets express standard and immunoproteasomes. Inhibition of the proteasome impairs platelet production and platelet function. Platelets also express major histocompatibility complex (MHC) class I molecules. Peptide fragments released by proteasomes can bind to MHC class I, which makes it also likely that platelets can activate epitope specific cytotoxic T lymphocytes (CTLs). In this review, we focus on current knowledge on the significance of the proteasome for the functions of platelets as critical regulators of hemostasis as well as modulators of the immune response.
Abstract
Background
Heparins are usually produced from animal tissues. It is now possible to synthesize heparins. This provides the abilities to overcome shortages of heparin, to optimize biological effects, and to reduce adverse drug effects. Heparins interact with platelet factor 4 (PF4), which can induce an immune response causing thrombocytopenia. This side effect is called heparinâinduced thrombocytopenia (HIT). We characterized the interaction of PF4 and HIT antibodies with oligosaccharides of 6â, 8â, 10â, and 12âmer size and a hypersulfated 12âmer (S12âmer).
Methods
We utilized multiple methodologies including isothermal calorimetry, circular dichroism spectroscopy, single molecule force spectroscopy (SMFS), enzyme immunosorbent assay (EIA), and platelet aggregation test to characterize the interaction of synthetic heparin analogs with PF4 and antiâPF4/heparin antibodies.
Results
The synthetic heparinâlike compounds display stronger binding characteristics to PF4 than animalâderived heparins of corresponding lengths. Upon complexation with PF4, 6âmer and S12âmer heparins showed much lower enthalpy, induced less conformational changes in PF4, and interacted with weaker forces than 8â, 10â, and 12âmer heparins. AntiâPF4/heparin antibodies bind more weakly to complexes formed between PF4 and heparins â€Â 8âmer than with complexes formed between PF4 and heparins â„ 10âmer. Addition of one sulfate group to the 12âmer resulted in a S12âmer, which showed substantial changes in its binding characteristics to PF4.
Conclusions
We provide a template for characterizing interactions of newly developed heparinâbased anticoagulant drugs with proteins, especially PF4 and the resulting potential antigenicity.
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.
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: 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 / â„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.
