A clinically important adverse drug reaction, heparin-induced thrombocytopenia (HIT), is induced by antibodies specific for complexes of the chemokine platelet factor 4 (PF4) and the polyanion heparin. Even heparin-naive patients can generate anti-PF4/heparin IgG as early as day 4 of heparin treatment, suggesting preimmunization by antigens mimicking PF4/heparin complexes. These antibodies probably result from bacterial infections, as (1) PF4 bound charge-dependently to various bacteria, (2) human heparin-induced anti-PF4/heparin antibodies cross-reacted with PF4-coated Staphylococcus aureus and Escherichia coli, and (3) mice developed anti-PF4/heparin antibodies during polymicrobial sepsis without heparin application. Thus, after binding to bacteria, the endogenous protein PF4 induces antibodies with specificity for PF4/polyanion complexes. These can target a large variety of PF4-coated bacteria and enhance bacterial phagocytosis in vitro. The same antigenic epitopes are expressed when pharmacologic heparin binds to platelets augmenting formation of PF4 complexes. Boosting of preformed B cells by PF4/ heparin complexes could explain the early occurrence of IgG antibodies in HIT. We also found a continuous, rather than dichotomous, distribution of anti-PF4/heparin IgM and IgG serum concentrations in a cross-sectional population study (n ‫؍‬ 4029), indicating frequent preimmunization to modified PF4. PF4 may have a role in bacterial defense, and HIT is probably a misdirected antibacterial host defense mechanism. (Blood. 2011;117(4): 1370-1378) IntroductionThe chemokine platelet factor 4 (PF4, CXCL4) is stored within platelet ␣-granules 1 and released during platelet activation. Although its biologic role is poorly understood, PF4 commands attention in clinical medicine because it binds charge-dependently to the anticoagulant heparin, one of the most frequently used anticoagulants in clinical medicine, thereby neutralizing heparin's anticoagulant effect, 2,3 but also forming highly antigenic multimolecular complexes. [4][5][6] The resulting antibody response 7 induces the most frequent immune-mediated adverse drug reaction involving human blood cells, heparin-induced thrombocytopenia (HIT). 8 The pathogenic antibodies bind to PF4/heparin complexes at the platelet surface, and the resulting immune complexes induce Fcreceptor-mediated platelet activation and enhanced thrombin generation. 8 In a subset of patients, this causes thrombocytopenia and triggers paradoxical thrombosis, which is aggravated by continuation of heparin treatment.The immune response of HIT has several atypical features. Even in patients who receive heparin for the first time, there is rapid induction (as early as 4 days) of anti-PF4/heparin antibodies of IgG isotype. Moreover, IgG antibodies are the predominant class of immunoglobulins formed. 9,10 We and others discovered that up to 50% of patients after cardiopulmonary bypass surgery and 20% to 30% of orthopedic surgery patients (many of whom have not been previously exposed to heparin) devel...

Key Points• FcgRIIA activation is key for platelet aggregation in response to bacteria, and depends on IgG and aIIbb3 engagement.• PF4 binds to bacteria and reduces the lag time for platelet aggregation.Bacterial adhesion to platelets is mediated via a range of strain-specific bacterial surface proteins that bind to a variety of platelet receptors. It is unclear how these interactions lead to platelet activation. We demonstrate a critical role for the immune receptor FcgRIIA, aIIbb3, and Src and Syk tyrosine kinases in platelet activation by Staphylococcus aureus, Streptococcus sanguinis, Streptococcus gordonii, Streptococcus oralis, and Streptococcus pneumoniae. FcgRIIA activation is dependent on immunoglobulin G (IgG) and aIIbb3 engagement. Moreover, feedback agonists adenosine 59-diphosphate and thromboxane A 2 are mandatory for platelet aggregation. Additionally, platelet factor 4 (PF4) binds to bacteria and reduces the lag time for aggregation, and gray platelet syndrome a-granule-deficient platelets do not aggregate to 4 of 5 bacterial strains. We propose that FcgRIIA-mediated activation is a common response mechanism used against a wide range of bacteria, and that release of secondary mediators and PF4 serve as a positive feedback mechanism for activation through an IgG-dependent pathway. (Blood. 2014;123(20):3166-3174)

Financial restrictions and a stronger focus on outcomes assessment require rational decisions regarding the allocation of resources in the health-care system. Such decisions are based on medical, ethical, and economic considerations. Management of the health-care system requires both a medical and an economic orientation at the overall societal level and regarding the selection of appropriate health-care services in hospitals and ambulatory practices. The practical application of health economic methods can be an important tool assuring more transparency and in validating necessary decisions.The methods made available by health economic research represent a rational approach for a structured resource allocation in the health-care system and facilitate the process of a relative assessment of various treatment methods with each other. Although the focus of such studies frequently rests on pharmaceuticals, health economic evaluation methods are suitable for all medical services, procedures, and health-care programs. But, what is assessed from which perspective,

The positively charged chemokine platelet factor 4 (PF4) forms immunogenic complexes with heparin and other polyanions. Resulting antibodies can induce the adverse drug effect heparin-induced thrombocytopenia. PF4 also binds to bacteria, thereby exposing the same neoantigen(s) as with heparin. In this study, we identified the negatively charged lipopolysaccharide (LPS) as the PF4 binding structure on Gram-negative bacteria. IntroductionBesides their pivotal role in hemostasis, platelets are involved in host defense against pathogens and in modulation of immune reactions. This function of platelets occurs either indirectly through their interaction with endothelial cells and leukocytes 1,2 or directly by secretion of antimicrobial substances from platelet storage granules and lysosomes. 3,4 Recently, we have shown that the chemokine platelet factor 4 (PF4), which is stored within platelet ␣-granules, plays a role in bacterial host defense by inducing a humoral immune response to PF4-coated bacteria. 5 During bacterial infections, platelets are activated 6,7 and release positively charged PF4, which can bind in a charge-dependent manner to the bacterial surface, thereby inducing neoepitopes. The formation of antigenic PF4 clusters is probably the result of neutralization of the positive charge of PF4 by polyanions, 8 which allows narrowing of the distance between single PF4 tetramers down to 3 to 5 nm. This creates linear, ridge-like complexes and exposes new antigenic epitopes on PF4. 9 Antibodies to PF4/polyanion complexes bind to PF4 on the bacterial surface, leading to opsonization and increased phagocytosis of PF4-coated bacteria. 5 As PF4 is capable of binding to a large variety of bacteria, the antibody response to PF4/polyanion complexes constitutes a very broad reactive defense mechanism and could represent an evolutionary interface between innate and specific immunity. Antibodies induced by PF4 clusters would be an example of antibodies with a limited target antigen repertoire that nevertheless could result in binding to a large variety of bacteria when these bacteria are coated with PF4. 5 In medicine, research on the immune reaction to PF4/polyanion complexes to date has primarily focused on its role in causing an adverse reaction to the anticoagulant heparin as PF4 forms immunogenic complexes with heparin on platelet surfaces. Anti-PF4/polyanion antibodies bind to these PF4/heparin complexcoated platelets and induce Fc-receptor-dependent platelet activation, 10,11 leading to intravascular consumption of platelets, associated potentiation of in vivo thrombin generation, and the prothrombotic syndrome, heparin-induced thrombocytopenia (HIT).We and others have recently demonstrated the prevalence of anti-PF4/heparin antibodies of the IgM class in up to 20% and of the IgG class in up to 6% of the general population and in a slightly lower number of normal blood donors. 5,12 These antibodies are highly significantly associated with periodontitis, one of the most prevalent human infections, often associate...

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