HAEMATOLOGY
coagulation system evolved as an effector pathway of the immune response – laying down fibrin around bacteria to physically entrap them and prevent their dissemination. Thus, the endpoint of inflammation is thrombosis. In patients with Behçets and vasculitis, for example, anticoagulants do not improve outcomes; instead the inflammatory process is treated.
Hypoxia through transcription factors is also found in COVID patients, which leads to a prothrombotic state. “We are admitting patients with COVID-19 because they are hypoxic and the degree of hypoxia determines whether they end up on a ventilator in ICU or on the ward receiving supplementary oxygen,” she commented. She explained that, in patients with COVID-19 pneumonia, acute lung injury leads to a profound inflammatory state. “When we look at the histopathology of the pneumonia, we are seeing massive invasion of the lungs with macrophages and lymphocytes. We see areas of focal
haemorrhage and we also see areas where fibrin has been laid down. We know the result of acute lung injury is the cytokine storm,” commented Prof. Hunt, adding that ferritin, CRP, D-dimer and fibrinogen become extremely elevated, with a marked acute phase response.
“In all my long career, I have never seen people with such high levels of fibrinogen. It is usually 3-4g per litre…but we are seeing levels of 10-14g per litre in some patients with COVID-19,” Prof. Hunt continued. She stated that the evidence points to the fact that thrombosis is occurring secondary to inflammation and hypoxia, in COVID-19 patients, rather than this being a primary thrombotic process.
She gave her view on what is likely to be happening in COVID-19 patients: “COVID-19 enters through the ACE2 receptor on the pulmonary epithelium, but it is also on the macrophages and endothelium. There is a lack of clarity whether it is expressed in all the endothelium or just some areas in
Breakthrough in treating HLH
US researchers have revealed a potential new treatment combination for the rare immune disorder haemophagocytic lymphohistiocytosis (HLH). The condition causes severe hyperinflammation, through immune system overactivation and the production of immune signalling chemicals called cytokines. These chemicals can further activate the immune system, resulting a ‘cytokine storm’ which can lead to organ damage and death. The research was co-led by Dr. Kim Nichols from St Jude Children’s Research Hospital in Memphis, Tennessee and Dr. Michelle Hermiston from University of California San Francisco, along with colleagues at Baylor College of Medicine in Houston, Texas.
The team set out to look at how cytokines produced during HLH confer resistance to dexamethasone, one of the standard treatments for the disease. Dr. Nichols explained: “For the last 20 years, treatment for haemophagocytic lymphohistiocytosis has remained a combination of the drugs dexamethasone and etoposide. But we know that many patients either do not respond to this regimen or later relapse, so we looked into the biology to come up with a different treatment strategy. “We wanted to know whether any of the cytokines that are elevated in haemophagocytic lymphohistiocytosis contribute to dexamethasone resistance, and if so, whether blocking the signalling
of these cytokines might reverse treatment resistance.”
The researchers used cells from patients and mouse models of the disease. They found that one particular cytokine, interleukin-2, is elevated in the condition, and is “critically important to driving resistance to dexamethasone”. Interleukin-2 is produced by activated T cells and promotes their survival. JAK1/2 mediates the effects
interleukin-2 and other cytokines involved in HLH. Therefore, the team hypothesised that adding ruxolitinib, a JAK1/2 inhibitor, might reverse the disease’s resistance to dexamethasone.
They found that blocking the effect of interleukin-2 causes the T cells system to be re-sensitised to dexamethasone. They then found in animal models that the combination of dexamethasone and ruxolitinib to be significantly more effective than either drug alone at controlling HLH. Publishing their results in the journal
Blood, the researchers believe that the study provides further evidence to support testing the combination of dexamethasone and ruxolitinib in clinical trials.
Reference 1 Meyer L, Verbist KC, Albeituni S, Scull BP, Bassett R, Stroh AN, Tillman H, Allen CE, Hermiston M, Nichols KE (2020) “JAK/STAT pathway inhibition sensitizes CD8 T cells to dexamethasone-induced apoptosis in hyperinflammation.” Blood, doi: 10.1182/ blood.2020006075
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particular. I would put money on the small bowel endothelium and the large vessels. “We know that if you get COVID, it will be seven to ten days, then the minority (5-10%) will go on to get COVID pneumonia. It is at that point we are seeing these profound changes in coagulation, in inflammation and cytokine storm, with endothelial and macrophage activation. I am just waiting for the paper to say there is platelet activation too. “So, we are seeing a marked prothrombotic state due to the effects of IL1 and IL6. I am interested in why it happens in certain groups – does a pre-existing inflammatory state make COVID-19 pneumonia more likely – e.g. artherosclerosis, obesity and diabetes?” Prof. Hunt highlighted the fact that the BMI is >25 in 75% of UK patients with severe COVID-19 and obesity is common. The children that have gone on to get the inflammatory response have also tended to have a BMI of around 28. Hypertrophic adipocytes (like atherosclerosis and diabetes) induce an inflammatory state, she explained. She moved on to examine the risk of VTE in critical care. At the turn of the century, without thromboprophylaxis, the figures were around 28%. With thromboprophylaxis, this is dramatically reduced, so rates of around 10% can be expected. Risk factors include increasing age, acute infective illness, venous lines, underlying patient risk factors and immobility.
She added that the evidence shows that low molecular weight heparin is better than Unfractionated Heparin (UFH). “We have profoundly sick patients that have been ventilated, with prothrombotic status, and then we are sending them home. So, should we send them home on some form of thromboprophylaxis? We know that if we give people low molecular weight heparin after they have gone home, they have a lower rate of VTE, but the bleeding risk increases, and the overall effect is no benefit,” she commented. However, she added that trials have looked at the use of Apixiban, Rivaroxaban and Betrixiban and the data now shows that a low dose of direct oral anticoagulant (DOAC) has a positive effect. The criteria for extending prophylaxis include:
l Age ≥75 years l Past history of Cancer or VTE; or l EXtra risk factors
Known risk factors for VTE include: D-dimers
≥2 upper limit of normal range, ICU stay, or two other factors such as past history of superficial VT, obesity, varicose veins, chronic venous insufficiency, lower extremity paresis, hormone therapy, thrombophilia (congenital or acquired), concomitant use of erythropoiesis stimulating agents. Based on these criteria, Prof. Hunt suggested that COVID-19 patients should be considered for
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