Lipoproteins, statins and septic haematology patients

The recent review by Cohen and Drage (2011) provides a very thorough and practical approach to the management of sepsis in haematology patients. However, two points were possibly overlooked in this comprehensive article – (i) the important role of biphasic activated partial thromboplastin waveform (BPW) as an early predictor of sepsis, and (ii) the increasingly recognized, beneficial effects of the cholesterol-lowering agents, statins, in septic and critically ill patients. BPW was demonstrated initially by our group (Toh et al, 2003) and later confirmed by several other investigators to be an early predictor of sepsis. More importantly, this abnormal laboratory phenomenon has been shown to correlate with the development of disseminated intravascular coagulation (DIC), probably the worst complication of sepsis (Downey et al, 1998). BPW is an abnormality of the optical transmission waveform obtained during measurement of the activated partial thromboplastin time as part of the routine coagulation screen and, as such, is an inexpensive, rapid, and repeatable tool. BPW is also beneficial with respect to the clinical deterioration of a haemato-oncology patient, to decide whether the worsening condition is related to infection or systemic inflammatory response secondary to other causes, such as chemotherapy-related adverse events. In an 8-month study of 187 consecutive intensive care patients (not specific to haematology) with analyses of BPW, procalcitonin and C-reactive protein (CRP), BPW on day one was significantly more abnormal in patients with severe sepsis or septic shock than in patients with systemic inflammatory response syndrome (Chopin et al, 2006). Two other clinical conundrums in patients with neutropenic fever are the development of clinical signs of sepsis without microbiology proven evidence of infection; and negative blood culture results in the presence of sepsis. Hussain et al (2008) analysed 49 consecutive neutropenic haematological patients over a 10month period and identified the biphasic transmittance waveform (bTW; derivation of BPW) as a rapid marker of sepsis. Interestingly, the bTW results preceded the blood culture results by up to three days, a crucial time in patients with severe sepsis. Thus, BPW can be helpful in deciding the need for antimicrobial therapy in these patients and avoid their unnecessary prescription, reducing the risks of cytopenias, renal impairment and clostridium difficile-associated diarrhoea. The review elaborates on procalcitonin as a marker of severe sepsis. However in addition to lack of availability in many hospitals, and high cost, procalcitonin has not fared as well as BPW in predicting severe sepsis. In the study by Chopin et al (2006), among the comparison between C-reactive protein (CRP), procalcitonin and BPW, the latter was more accurate for differentiating patients with severe sepsis and septic shock, with 90% sensitivity and 92% negative predictive value. A more recent paper commented on the combination of BPW and procalcitonin to fare even better, with sensitivity of 79%, specificity of 96% and negative predictive value of 96% for the diagnosis of sepsis (Zakariah et al, 2008). The molecular basis responsible for the development of BPW has been shown by our group to be due to calcium-dependent formation of a complex of CRP and very low-density lipoprotein (VLDL). Given that BPW correlates with poor outcome in septic patients, drugs that affect lipids and CRP levels (e.g. statins) may modify the CRP-VLDL complex formation and thus the sepsis phenomenon, proving to be a cost-effective therapeutic strategy in these situations. Statins have been increasingly identified to have more than just lipid-lowering properties, some of which have beneficial effects in septic and critically ill patients. The two crucial properties in this regard are their anti-inflammatory potential and effects on the coagulation system. Inflammation-coagulation crosstalk is a key component determining the development of DIC and thus, the outcome of septic patients. As such, modifying both these factors can be beneficial in the clinical course of septic patients, as evidenced by the systematic review and meta-analysis of statins for the prevention and treatment of infections. (Tleyjeh et al, 2009). It should however be stressed that further large-scale trials are required before statins can be accepted for anti-infective purposes, possibly in conjunction with existing antimicrobial therapies and should not be considered replacements for these agents in critically-ill haematology subjects. The beneficial effect of statins in critically ill haematology patients may go beyond just the ‘anti-infective’ properties. These agents are increasingly recognized to be relevant in preventing the development of venous thromboembolism (VTE; Glynn et al, 2009). VTE is a prominent cause of morbidity and mortality in critically ill patients and strict thromboprophylaxis protocols are in place in most units. However, haematology patients present additional challenges in that many of these patients are thrombocytopenic, making pharmacological anticoagulation difficult, and have additional risk factors of malignancy and chemotherapeutic agents, which can lead to anticoagulation failure. In these circumstances, statins can be favourable with their absent myelosuppressive effects and minimal drug interactions. correspondence