Chimerism in health, transplantation and autoimmunity

The term __chimerism__ originates from Greek mythology and refers to the creature Chimaera, whose body was in front a lion, the back a serpent and the midsection a goat. In medicine, the term chimerism refers to an individual, organ or part consisting of tissues of diverse genetic constitution. Pregnancy, blood transfusion and organ transplantation are potential causes of chimerism. In this thesis the occurrence of chimerism is investigated in different organs of healthy women, of women with the autoimmune disease Systemic Lupus Erythematosus (SLE) and of women that received a renal allograft. To demonstrate chimerism, male cells were detected in female organs by using in situ hybridization of the Y chromosome. Chimerism was found in 18% of healthy organs, in about 50% of organs derived from women with SLE and in none of the skin tumors investigated from female renal allograft recipients. In various organ types and both in women with and without sons and women with and without a transfusion history, chimerism was present. In this thesis we describe these results and review data from the ancient and recent literature. With all these data in hand, we speculate about the sources of chimerism and its implications on immunity.UBL - phd migration 201

Cerebral Venous Sinus Thrombosis Associated with Vaccine-Induced Thrombotic Thrombocytopenia—A Narrative Review

In March 2021, cerebral venous sinus thrombosis and thrombocytopenia after vaccination with adenovirus-based vaccine against SARS-CoV-2 were first reported. The underlining condition has been termed vaccine-induced immune thrombocytopenia (VITT). Anti-platelet factor 4 antibodies have been proposed as a central component of the pathomechanism. Treatment recommendations entailed immunomodulation with intravenous immunoglobulins, avoidance of heparins and avoidance of platelet transfusions. Although mortality from VITT-associated cerebral venous sinus thrombosis has decreased over time, it remains high. The aim of this narrative review is to describe different aspects of this disease according to the current state of knowledge

ST segment elevation myocardial infarction as a presenting feature of thrombotic thrombocytopenic purpura

Myocardial infarction with ST segment elevation (STE) on electrocardiography (ECG) is a common presentation in emergency rooms across the world. Myocardial injury and necrosis are infrequently the initial presentation in patients with thrombotic thrombocytopenic purpura (TTP). A 48-year-old woman presented with STE myocardial infarction from outside hospital for primary percutaneous coronary intervention. However, her clinical picture was not consistent. Rapid evaluation revealed symptoms associated with microangiopathic hemolytic anemia, thrombocytopenia, acute kidney injury with waxing and waning mental status. A diagnosis of TTP was made with low ADAMST-13 activity. Plasmapheresis was initiated along with intravenous steroid therapy. The patient had a full recovery and went home after full recovery of left ventricular ejection fraction and normal myocardial perfusion studies. Rapid evaluation is needed to identify infrequent causes of STE myocardial infarction. As swift protocols are activated in the emergency room and catheterization laboratories to ensure quality control, it is equally important to integrate all aspects of the patient's clinical and objective data to detect unusual disease entities

International Council for Standardization in Haematology (ICSH) recommendations for laboratory measurement of ADAMTS13

This guidance document was prepared on behalf of the International Council for Standardization in Haematology (ICSH), by the ADAMTS13 Assay Working Group, which comprises an international group of both clinical and laboratory experts. The document provides recommendations on best practice for the performance of ADAMTS13 assays in clinical laboratories. ADAMTS13 assays support the differential diagnosis of thrombotic microangiopathies and have utility in the management of thrombotic thrombocytopenic purpura (TTP). There are three types of assay: activity, antigen and autoantibody/inhibitor assays. Methods for activity assays differ in terms of sensitivity, specificity, precision and turnaround time. The most widely used assays involve VWF peptide substrates and either chromogenic ELISA or FRET techniques, although chemiluminescence assays and rapid screening tests have recently become available. Tests for autoantibodies and inhibitors allow confirmation of acquired, immune‐mediated TTP, while antigen assays may be useful in congenital TTP and as prognostic markers. In this document, we have attempted to describe ADAMTS13 assays and the conditions that affect them, as well as: blood collection, sample processing, quality control, standardization and clinical utility; recognizing that laboratories in different parts of the world have varying levels of sophistication. The recommendations are based on expert opinion, published literature and good clinical laboratory practice

International Council for Standardization in Haematology (ICSH) recommendations for laboratory measurement of ADAMTS13

This guidance document was prepared on behalf of the International Council for Standardization in Haematology (ICSH), by the ADAMTS13 Assay Working Group, which comprises an international group of both clinical and laboratory experts. The document provides recommendations on best practice for the performance of ADAMTS13 assays in clinical laboratories. ADAMTS13 assays support the differential diagnosis of thrombotic microangiopathies and have utility in the management of thrombotic thrombocytopenic purpura (TTP). There are three types of assay: activity, antigen and autoantibody/inhibitor assays. Methods for activity assays differ in terms of sensitivity, specificity, precision and turnaround time. The most widely used assays involve VWF peptide substrates and either chromogenic ELISA or FRET techniques, although chemiluminescence assays and rapid screening tests have recently become available. Tests for autoantibodies and inhibitors allow confirmation of acquired, immune‐mediated TTP, while antigen assays may be useful in congenital TTP and as prognostic markers. In this document, we have attempted to describe ADAMTS13 assays and the conditions that affect them, as well as: blood collection, sample processing, quality control, standardization and clinical utility; recognizing that laboratories in different parts of the world have varying levels of sophistication. The recommendations are based on expert opinion, published literature and good clinical laboratory practice

The potential impact of Covid-19 on the capacity of routine laboratory tests to detect heparin-induced thrombocytopenia.

In Covid-19, anticoagulation with heparin is often administered to prevent or treat thromboembolic events. Heparin-induced thrombocytopenia (HIT) is a severe complication of heparin treatment, caused by heparin-dependent, platelet activating anti-platelet factor 4 (PF4)/heparin antibodies. Diagnosis of HIT is based on the combination of clinical parameters, allowing to determine the pretest probability, and laboratory testing for anti-PF4/heparin antibodies and confirmatory functional assays, such as the heparin-induced platelet activation (HIPA) test.We report the case of a patient with severe Covid-19 pneumonia requiring ECMO treatment, who developed recurrent clotting of the ECMO filter and a drop in platelet count under heparin treatment. He was therefore suspected to have HIT and the anticoagulation was switched to argatroban. Despite high clinical probability and high titres of anti-PF4/heparin antibodies, the functional HIPA test was negative. Nevertheless, argatroban was continued rather than to reinstate anticoagulation with heparin. Reevaluation 7 days later then demonstrated a strongly positive functional HIPA test and confirmed the diagnosis of HIT. Under anticoagulation with argatroban the patient gradually improved and was finally weaned off the ECMO.In conclusion, this case highlights the critical importance of clinical judgement, exploiting the 4 T score, given that Covid-19 patients may present a different pattern of routine laboratory test results in HIT diagnostics. The possibility of a false negative HIPA test has to be considered, particularly in early phases of presentation. In cases of a discrepancy with high clinical probability of HIT and/or high titre anti-PF4/heparin antibodies despite a negative HIPA test, a reevaluation within 3 to 5 days after the initial test should be considered in order to avoid precipitant reestablishment of unfractionated heparin, with potentially fatal consequences