Vaccine-induced immune thrombotic thrombocytopenia presenting with normal platelet count.

Adenoviral-vector based vaccines for coronavirus disease 2019 (COVID-19) have been linked with a thrombotic syndrome, vaccine-induced thrombotic thrombocytopenia (VITT). A key clinical question is whether VITT can be reliably ruled out by the absence of thrombocytopenia. We report on three patients who presented to our institute with this syndrome. Noteworthy in our presentations are two patients who presented for medical assessment of thrombotic symptoms with a normal platelet count, one preceding and one following a period of thrombocytopenia. Prompt diagnosis of VITT is critical to prevent rapid patient decline. We provide herein a new diagnostic algorithm that we believe will help optimally capture case presentations of VITT. These cases broaden and refine our understanding of the disease process and highlight to practitioners that VITT cannot be adequately ruled out by thrombocytopenia alone.

Validation of the PLASMIC score for predicting ADAMTS13 activity <10% in patients with suspected thrombotic thrombocytopenic purpura in Alberta, Canada.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic microangiopathy (TMA) that requires prompt plasma exchange. Clinical prediction tools may facilitate decision-making in institutions with delayed turnaround time or limited access to ADAMTS13 assays. The PLASMIC score and Bentley score have been shown to predict severe ADAMTS13 deficiency with excellent sensitivity and specificity. OBJECTIVES: To validate the PLASMIC score using a population of suspected TTP, and evaluate its discriminatory power in predicting severe ADAMTS13 deficiency in comparison with Bentley score and clinical gestalt. METHODS: Adults presenting with suspected TTP in Alberta, Canada between 2008 and 2018 with available ADAMTS13 results were included. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for PLASMIC score, Bentley score and clinical gestalt. Receiver operator characteristics analysis assessed the performance of the scoring systems. RESULTS: Among 163 individuals with suspected TTP, ADAMTS13 activity was available in 117 (72%). Severe ADAMTS13 deficiency <10% was present in 62 (53%). High-risk PLASMIC score (≥6) predicted severe ADAMTS13 deficiency with a sensitivity of 81.7%, specificity 71.4%, PPV 75.4% and NPV 78.4% (c-statistic 0.80). Intermediate-high risk Bentley score (≥20) had a lower sensitivity (59.5%) and higher specificity (93.9%) with similar c-statistic (0.77). Clinical gestalt had similar sensitivity as PLASMIC score but very low specificity (16.1%). CONCLUSIONS: Both PLASMIC and Bentley scores had good discriminatory power in identifying severe ADAMTS13 deficiency in a Canadian TMA population compared to clinical gestalt. Integration into institutional clinical pathways may help supplement clinical judgment and reduce costs.

Time from suspected thrombotic thrombocytopenic purpura to initiation of plasma exchange and impact on survival: A 10-year provincial retrospective cohort study.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy (TMA) with significant morbidity and mortality. Guidelines recommend initiating plasma exchange within 4-8 h of suspected diagnosis. It is unclear what are real-world practice patterns and whether delays >8 h increases mortality. OBJECTIVES: To determine if delayed initiation of plasma exchange is associated with increased risk of death and complications. METHODS: In this retrospective cohort study, we evaluated the time from suspected diagnosis to plasma exchange in all adults presenting with suspected TTP to apheresis centres in Alberta, Canada (2008-2018). Among patients with acquired TTP, the association between delayed plasma exchange and risk of death was evaluated using Cox regression. RESULTS: Overall 190 episodes of suspected TTP were included among 163 individuals. Acquired TTP was confirmed in 61 patients. Inappropriate Emergency Department triage occurred in 59%. The median time from suspected diagnosis to first plasma exchange was 10.7 h; 59% had delayed plasma exchange >8 h, among whom plasma infusion was administered in only 45%. 36% of suspected TTP and 13% of confirmed TTP patients died. Delayed plasma exchange between 8 and 24 h was not associated with a significantly higher risk of death (adjusted hazards ratio; aHR 0.63, 95% CI 0.08-4.83) in confirmed TTP. On the other hand, the risks of death (aHR 1.40, 95% CI 0.20-9.79) and major thrombotic events (aHR 2.9, 95% CI 0.6-12.8) were markedly increased with >24 h delay. CONCLUSIONS: Our study demonstrated that TTP care in a real-world setting is discordant with expert guidelines due to multiple barriers. There is a gradient of increased mortality risk and thrombotic complications with longer treatment delays, although the study is likely underpowered.

Tissue-specific transcriptional modulation of fatty acid-binding protein genes, fabp2, fabp3 and fabp6, by fatty acids and the peroxisome proliferator, clofibrate, in zebrafish (Danio rerio).

All fabp genes, except fabp2, fabp3 and fabp6, exist as duplicates in the zebrafish genome owing to a whole genome duplication event ~230-400 million years ago. Transcription of some duplicated fabp genes is modulated by fatty acids (FAs) and/or clofibrate, a peroxisome proliferator-activated receptor (PPAR) agonist. We had also shown previously that the steady-state level of acyl-CoA oxidase 1 (acox1) mRNA, a marker of PPARα activation, was elevated in liver, intestine, heart and muscle of fish fed clofibrate demonstrating that zebrafish, unlike some fishes, is responsive to this drug. acox1 transcripts were not induced in the brain of fish fed clofibrate, which suggests this drug may not cross the blood brain barrier. Here, we investigated the effect of dietary FAs and clofibrate on the transcription of single copy fabp genes, fabp2, fabp3 and fabp6, in five tissues of inbred zebrafish. The steady-state level of fabp2 transcripts increased in intestine, while fabp3 mRNA increased in liver of fish fed diets differing in FA content. In fish fed clofibrate, fabp3 mRNA in intestine, and fabp6 mRNA in intestine and heart, were elevated. Based on these findings, modulation of fabp2, fabp3 and fabp6 transcription by FAs and/or clofibrate in zebrafish implicates control of these genes by PPAR interaction with peroxisome proliferator response elements (PPRE) most likely in fabp promoters. Moreover, transcriptional induction of these fabp genes by dietary FAs and/or clofibrate is over-ridden by a tissue-specific mechanism(s), e.g., transcriptional activator or repressor proteins.