Diagnostic testing for differential diagnosis in Thrombotic Microangiopathies

Abstract

Thrombotic microangiopathies (TMAs) are multiple disease entities with different etiopathogeneses, characterized by thrombocytopenia, microangiopathic hemolytic anemia (MAHA) with schistocytosis, variable symptoms including fever, and multi-organ failure such as mild renal impairment and neurological deficits. The two paradigms of TMAs are represented on one hand by acquired thrombotic thrombocytopenic purpura (TTP) and on the other by hemolytic uremic syndrome (HUS). The differential diagnosis between these two paradigmatic forms of TMA is based on the presence of either frank renal failure in HUS or a severe deficiency (<10%) of the zincprotease ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) in TTP. ADAMTS13 is an enzyme involved in the proteolytic processing of von Willebrand factor (vWF), and its deficiency results in formation of highmolecular-weight vWF-rich microthrombi in the environment of the microvasculature. The presence of these ultra-large vWF multimers in the microcirculation can recruit platelets, promoting multi-organ ischemic lesions. The presence of ADAMTS13 activity at >10% could rule out the presence of a TTP form. However, it is often difficult to differentiate either a TTP or HUS clinical scenario presenting with typical symptoms of TMA. There are in fact several additional diagnoses that should be considered in patients with ADAMTS13 activity of >10%. Widespread inflammation with endothelial damage and adverse reactions to drugs play a central role in the pathogenesis of several forms of TMA, and in these cases, the differential diagnosis should be directed at the underlying disease. Hence, a correct etiologic diagnosis of TMA should involve a critical illness, cancer-associated TMA, drug-induced TMA, and hematopoietic transplant-associated TMA. A complete assessment of all the possible etiologies for TMA symptoms, including acquired or congenital TTP, will allow for a more accurate diagnosis and application of a more appropriate treatment.

From angiotensin-converting enzyme 2 disruption to thromboinflammatory microvascular disease: A paradigm drawn from COVID-19

“…data from ongoing clinical trials will be crucial to discover targeted effective treatments. Focusing on the similarities between human SARS-CoV-2 infection and other diseases [18,19,24,37,51], and addressing the consequences of COVID-19, especially among patients prone to chronic inflammatory conditions such as cardiovascular diseases [52,53], will contribute to overall progress and to preparedness against a virus that is expected to hang around for some years [24]. Independently from SARS-CoV-2, we believe current COVID-19 data consolidate a widely unrecognised paradigm of potentially fatal thromboinflammatory microvascular disorders.…”

“…Inflammatory activation, lymphopenia and thrombocytopenia reported in severe COVID-19 resemble another potentially fatal syndrome triggered by viral infections, characterised by leukopenia, macrophage hyperactivity, multiorgan failure and hyperinflammation, i.e., secondary haemophagocytic lymphohistiocytosis [18]. The blood stigmata of severe COVID-19 are compatible with lymphopenia secondary to cytokineinduced complement activation and with thrombocytopenia secondary to VWF hypersecretion and microvascular thrombosis [2,8,9,18,19]. COVID-19 lymphopenia is characterised by reduced circulating CD4+ and CD8+ T-lymphocytes and is related to both cytokine levels and adverse prognosis [20].…”

“…Importantly, thrombotic microangiopathy is reported as a distinctive feature of COVID-19 respiratory insufficiency, being absent in influenza-related respiratory failure [5]. Activated endothelium, as well as host-defense mechanisms against viral antigens, can trigger complement activation (a crucial innate immune element) by classical, alternative or lectin pathways, through C3, C5, and generation of the C5b-9 membrane attack complex (MAC); the latter destroys target cells [2,19]; significant microvascular C5b-9 deposits have been documented in COVID-19 patients [2]. Complement activation, while attempting to neutralise infection through cell lysis, also has proinflammatory, chemotactic, anaphylotoxic and prothrombotic repercussions and can induce T-lymphopenia ( Fig.…”

“…Complement activation, while attempting to neutralise infection through cell lysis, also has proinflammatory, chemotactic, anaphylotoxic and prothrombotic repercussions and can induce T-lymphopenia ( Fig. 1) [2,19,37].…”

“…A systemic endothelial microangiopathy in SARS-CoV-2 infection is further supported by elevated circulating inflammatory and prothrombotic factors, particularly VWF, an established marker of endothelial dysfunction [12][13][14]; patients with classical thrombotic microangiopathy accumulate prothrombotic high molecular weight VWF multimers [19,37]; in COVID-19 patients requiring invasive mechanical ventilation, VWF levels 3-to-4 fold higher than the upper normal limit have been reported [38]; interestingly, nonhaemostatic functions of VWF include complement activation [37]; in turn, complement hyperactivation, which has been documented in moderate and severe COVID-19 [39], can lead to thrombotic microangiopathy [19]. The shift in RAS balance toward Ang II, likely induced by the SARS-CoV-2 interaction with vascular ACE2 [5,24,25], may be a further trigger for VWF release [29].…”