Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious respiratory virus that can lead to venous/arterial thrombosis, stroke, renal failure, myocardial infarction, thrombocytopenia, and other end-organ damage. Animal models demonstrating end-organ protection in C3-deficient mice and evidence of complement activation in humans have led to the hypothesis that SARS-CoV-2 triggers complement-mediated endothelial damage, but the mechanism is unclear. Here, we demonstrate that the SARS-CoV-2 spike protein (subunit 1 and 2), but not the N protein, directly activates the alternative pathway of complement (APC). Complement-dependent killing using the modified Ham test is blocked by either C5 or factor D inhibition. C3 fragments and C5b-9 are deposited on TF1PIGAnull target cells, and complement factor Bb is increased in the supernatant from spike protein–treated cells. C5 inhibition prevents the accumulation of C5b-9 on cells, but not C3c; however, factor D inhibition prevents both C3c and C5b-9 accumulation. Addition of factor H mitigates the complement attack. In conclusion, SARS-CoV-2 spike proteins convert nonactivator surfaces to activator surfaces by preventing the inactivation of the cell-surface APC convertase. APC activation may explain many of the clinical manifestations (microangiopathy, thrombocytopenia, renal injury, and thrombophilia) of COVID-19 that are also observed in other complement-driven diseases such as atypical hemolytic uremic syndrome and catastrophic antiphospholipid antibody syndrome. C5 inhibition prevents accumulation of C5b-9 in vitro but does not prevent upstream complement activation in response to SARS-CoV-2 spike proteins.

The antiphospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy morbidity in the presence of antiphospholipid antibodies, including anti-β2-glycoprotein-I (anti-β2GPI), that are considered central to APS pathogenesis. Based on animal studies showing a role of complement in APS-related clinical events, we used the modified Ham (mHam) assay (complement-dependent cell killing) and cell-surface deposition of C5b-9 to test the hypothesis that complement activation is associated with thrombotic events in APS. A positive mHam (and corresponding C5b-9 deposition) were present in 85.7% of catastrophic APS (CAPS), 35.6% of APS (and 68.5% of samples collected within 1 year of thrombosis), and only 6.8% of systemic lupus erythematosus (SLE) sera. A positive mHam assay was associated with triple positivity (for lupus anticoagulant, anticardiolipin, and anti-β2GPI antibodies) and recurrent thrombosis. Patient-derived anti-β2GPI antibodies also induced C5b-9 deposition, which was blocked completely by an anti-C5 monoclonal antibody, but not by a factor D inhibitor, indicating that complement activation by anti-β2GPI antibodies occurs primarily through the classical complement pathway. Finally, patients with CAPS have high rates of rare germline variants in complement regulatory genes (60%), compared with patients with APS (21.8%) or SLE (28.6%) or normal controls (23.3%), and have mutations at a rate similar to that of patients with atypical hemolytic uremic syndrome (51.5%). Taken together, our data suggest that anti-β2GPI antibodies activate complement and contribute to thrombosis in APS, whereas patients with CAPS have underlying mutations in complement regulatory genes that serve as a “second hit,” leading to uncontrolled complement activation and a more severe thrombotic phenotype.

With timely and effective treatment, most patients with thrombotic thrombocytopenic purpura (TTP) survive their acute episode. In addition to the risk of relapse, TTP survivors have higher all-cause mortality than the general population and increased rates of chronic morbidities including hypertension, depression, and mild cognitive impairment. We conducted this retrospective-prospective cohort study to determine the incidence and prevalence of stroke after recovery from acute TTP and to test the hypothesis that lower ADAMTS13 activity after recovery from TTP is associated with an increased risk for stroke during remission. Of 170 consecutive patients treated for TTP at the Johns Hopkins Hospital between 1995 and 2018, 14 (8.2%) died during the index episode and 19 were followed for less than one month after recovery. Of the remaining 137 patients, 18 (13.1%) developed stroke unrelated to an acute TTP episode over a median observation period of 3.08 years, which is 5-fold higher than the expected prevalence of 2.6% from an age- and sex-matched reference population (P= 0.002). ADAMTS13 activity during remission was measured in 52 patients and was >70% in 44.2%, 40-70% in 23.1%, 10-39% in 25%, and 70%) and in 27.6% (8 of 29) patients with low ADAMTS13 activity ({less than or equal to} 70%) (P=0.007). In conclusion, stroke is common after recovery from TTP and is associated with reduced ADAMTS13 activity during remission. Key Points Stroke is more common in TTP survivors than in a age- and sex-matched reference US population. Lower ADAMTS13 activity during clinical remission after recovery from TTP is associated with stroke.

Immune thrombocytopenia (ITP) occurs with an incidence rate of 1.6 to 3.9 per 100,000 patient-years, which increases with age and has a slight female preponderance. ITP is termed acute, persistent or chronic when its duration is 12 months, respectively. In this narrative review, we discuss the clinical manifestations of ITP in children and adults. ITP is asymptomatic in some patients; however, when present, bleeding is the most common symptom and can be mild as in petechiae, purpura and epistaxis, or severe and even life threatening in cases of intracranial haemorrhage, and massive gastrointestinal or urinary tract bleeding. A platelet count <10–20 × 10⁹/L, advanced age and prior minor bleeding are risk factors for major bleeding, which is also more common in the months following a new diagnosis of acute ITP. Fatigue and impaired health-related quality of life are also manifestations of ITP that often improve with treatment and improvement in platelet counts. Over long-term follow-up, ITP is also associated with an increased risk of venous and arterial thromboembolism, haematologic malignancy and overall mortality than the general population. Die Immunthrombozytopenie (ITP) tritt mit einer Inzidenzrate von 1,6 bis 3,9 pro 100.000 Patientenjahre auf, die mit zunehmendem Alter zunimmt und ein geringes Überwiegen der Frauen aufweist. ITP wird als akut, persistent oder chronisch bezeichnet, wenn die Dauer 12 Monate beträgt. In dieser narrativen Übersichtsarbeit diskutieren wir die klinischen Erscheinungsformen von ITP bei Kindern und Erwachsenen. ITP ist bei manchen Patienten asymptomatisch; Blutungen sind jedoch, wenn vorhanden, das häufigste Symptom und können mild sein, wie bei Petechien, Purpura und Epistaxis, oder sogar schwer oder gar lebensbedrohlich bei intrakraniellen Blutungen oder massiven Blutungen im Gastrointestinal- oder Harntrakt. Eine Thrombozytenzahl <10–20 × 10⁹ / L, ein fortgeschrittenes Alter und frühere geringfügige Blutungen sind Risikofaktoren für starke Blutungen, die auch häufiger in den Monaten nach einer neuen Diagnose einer akuten ITP auftreten. Erschöpfung und Beeinträchtigung der gesundheitsbezogenen Lebensqualität sind auch Manifestationen von ITP, die sich häufig durch Behandlung und Erhöhung der Thrombozytenzahl verbessern. Im langjährigen Follow-Up ist ITP auch mit einem höheren Risiko für venöse und arterielle Thromboembolien, hämatologischer Malignität und Gesamtmortalität verbunden als in der allgemeinen Bevölkerung.