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Caplacizumab reduces the need for therapeutic plasma exchange (TPE) during treatment for thrombotic thrombocytopenic purpura (TTP), associates with fewer required TPE, and shortens hospital stay. It is therefore recommended as part of standard care. However, the treatment effects on hemostasis may complicate initial management. We present a case of a woman with immune-mediated TTP who developed an intrathoracic hemorrhage on caplacizumab treatment after replacement of her central venous catheter. Reduced von Willebrand factor (vWF):glycoprotein Ib mutant (GPIbM) activity was reversed using vWF concentrate and the bleeding stopped. Unfortunately, vWF substitution in combination with caplacizumab discontinuation likely contributed to subsequent extensive venous thromboembolism. Risk-reducing strategies against both bleeding and thrombosis are crucial during caplacizumab treatment, and emergency vWF substitution increases the already high risk of thrombosis associated with TPE.

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In disease states with chronic inflammation, there is a crosstalk between mast cells and neutrophil granulocytes in the inflamed microenvironment, which may be potentiated by tryptase. In systemic mastocytosis (SM), mast cells are constitutively active and tryptase is elevated in blood. Mast cell activation in SM leads to symptoms from various organs depending on where the active mast cells reside, for example, palpitations, flush, allergic symptoms including anaphylactic reactions, and osteoporosis. Whether neutrophil function is altered in SM is not well understood. In the current study, we assessed nucleosomal citrullinated histone H3 (H3Cit-DNA) as a proxy for neutrophil extracellular trap release in plasma from 55 patients with indolent and advanced SM. We observed a strong trend towards a correlation between leukocyte count, eosinophil count and neutrophil count and H3Cit-DNA levels in patients with advanced SM but not in indolent SM; however, no differences in H3Cit-DNA levels in SM patients compared with healthy controls. H3Cit-DNA levels did not correlate with SM disease burden, tryptase levels, history of anaphylaxis or presence of cutaneous mastocytosis; thus, there is no evidence of a general neutrophil extracellular trap release in SM. Interestingly, H3Cit-DNA levels and leukocyte counts were elevated in a subgroup of SM patients with aberrant mast cell CD2 expression, which warrants further investigation. In conclusion, we found no evidence of global increase in neutrophil extracellular trap release in SM.

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Prophylactic platelet (PLT) transfusion is a common practice in severely thrombocytopenic patients that reduces mortality, but responses to platelet transfusions are variable and difficult to predict in individual patients. In this prospective study, we evaluated the outcome of PLT transfusions in 40 patients with haematological malignancies, linking corrected count increment (CCI) to clot formation and agonist-induced platelet activation after transfusion. The CCI was highly variable between patients and 34% showed no response (1-h CCI < 7,5). Short time since the last PLT transfusion and extended storage time of the PLT product were linked to poor transfusion response, while patient sex, C-reactive protein or the number of chemotherapy cycles prior to transfusion did not influence transfusion outcome. High CCI and good PLT responsiveness to agonist stimulation predicted efficient clot formation in rotational thromboelastometry, but transfusion did not restore poor PLT function in patients to the level of healthy controls. Our study provides new insights into factors affecting PLT transfusion outcome in haematology patients with severe thrombocytopenia, and suggests that the thrombocytopenic environment, or disease-associated factors, may hamper platelet responsiveness.

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Patients with hematological cancers often have low platelet counts because of progressing bone marrow failure or cytostatic therapy. A large fraction of those patients need platelet transfusions, which can be life-saving if bleedings occur and also allow diagnostic and therapeutic interventions. The outcomes of platelet transfusions are not always easy to predict in terms of bleeding control or increase in platelet count. Reasons could be disease-specific factors, fever, or infections leading to platelet consumption, but the immune system may also be involved, in particular, in patients previously immunized against foreign human leukocyte antigens (HLA). Mechanisms underlying immune-mediated platelet destruction in the presence of antibodies again HLA are not well understood in clinical situations. This review discusses the role of complement in platelet refractoriness, with a focus on HLA antibody-mediated platelet refractoriness. We summarize recent work in this area, discuss complement-platelet interactions in general terms, and a suggest a possible role of complement in platelet transfusion in general.

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BACKGROUND: Platelet refractoriness due to HLA immunization represents a problem in transfusion management of thrombocytopenic hematology patients. Refractory patients can be managed by HLA-selected platelet transfusions, but the optimal matching strategy is debated and how the degree of HLA mismatch influences transfusion outcome is poorly studied. STUDY DESIGN AND METHODS: We studied 32 hematology patients who received 142 matched platelet units between 2007 and 2016. Four matching strategies were compared: 1) genomic HLA typing at the two digit level, performed using polymerase chain reaction-sequence-specific oligonucleotide probing; 2) serologic "eplet score" calculated using HLAMatchmaker; 3) cross-matching using lymphocyte cytotoxicity; and 4) matching based on donor-specific antibody (DSA) specificity, determined using Luminex. A 1-hour corrected count increment (CCI) of more than 7.5 × 109 /L was considered a successful response. RESULTS: Selection of platelets with either a complete HLA match or an acceptable HLA mismatch based on genomic typing and DSA information, each predicted 86% successful transfusion responses. For HLA-mismatched transfusions, the eplet score correlated with CCI and the fraction of successful transfusions, but less well compared to DSA matching. Cytotoxic crossmatching was least predictive. For transfusions across one to four DSAs, the antibody reaction strength correlated with the 1-hour CCI, but many transfusions were successful despite the presence of DSA. CONCLUSION: A complete HLA-A and -B match or an acceptable mismatch based on DSA should guide identification of donors. Still, transfusions across DSAs are often successful, emphasizing that the presence of DSA is necessary but not sufficient for platelet clearance.

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BACKGROUND: The presence of antibodies against HLA Class I can lead to platelet (PLT) transfusion refractoriness, that is, the repeated failure to achieve adequate posttransfusion PLT count increments. PLT refractoriness can be overcome by transfusion of HLA-matched donor PLTs. A different approach is to remove HLA from the PLT surface using low pH. Previous case studies using HLA-stripped PLTs showed encouraging but inconsistent results and lacked information on the biologic effects of acid treatment on PLT function as well as sensitivity to PLT destruction in the presence of HLA antibodies. STUDY DESIGN AND METHODS: PLTs prepared from buffy coats were stripped from HLA Class I using a brief incubation at pH 2.9. Kinetics of acid stripping, viability, phenotypic alterations, and sensitivity to complement-mediated lysis and phagocytosis were determined by flow cytometry. Functional potential was evaluated using a multiplate analyzer. RESULTS: Acid-treated PLTs were viable, upregulated activation markers normally and aggregated to a similar extent as untreated PLTs in response to stimulation with three natural agonists. Acid treatment removed 70% to 90% of HLA Class I complexes from the PLT surface, which led to complete protection from HLA antibody-mediated complement lysis and reduced monocyte-mediated phagocytosis in the presence of anti-HLA in vitro. CONCLUSION: Our study fills an important knowledge gap in how acid treatment affects PLT function and interactions with immune cells, paving the way for controlled clinical trials to evaluate acid-treated PLTs as an alternative to HLA-matched donors in PLT refractoriness.

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