It is recommended to use thromboprophylaxis, most commonly with low-molecular-weight heparins (LMWHs), as a part of critical care. Nonetheless, despite pharmacological thromboprophylaxis, the incidence of DVT is still 5–15%. The guidelines for thromboprophylaxis are based on studies conducted in medical and surgical patients whereas much less data are available from ICU patients. However, standard thromboprophylaxis in critically ill patients may lead to ineffective anticoagulation.
The main objective of this thesis was to study how to make thromboprophylaxis safer and more effective in critically ill patients. In addition, the association of critical illness with blood coagulation was investigated. The coagulation status was mainly evaluated in patients with aneurysmal subarachnoid hemorrhage (aSAH) who are considered high-risk patients for VTE. At the same time, the risk of bleeding persists, which makes the delivery of anticoagulation particularly challenging.
This thesis consists of four studies. Study I was a systematic review of the literature, examining 18 original publications where LMWH thromboprophylaxis had been monitored with an anti-Xa level measurement in critically ill patients. The anti-Xa levels in critically ill patients were lower in comparison with ward patients. However, no association was seen with clinical adverse events, e.g., bleeding or VTE.
In Study II and III, the route of anticoagulation administration was investigated in a randomized controlled study. Forty ICU patients were randomized to receive 40 mg of enoxaparin thromboprophylaxis either as a continuous intravenous infusion (CII) over 24 hours or as a subcutaneous bolus (SCB) every 24 hours for 72 hours. In Study II, the maximum concentration of anti-Xa was higher with SCB dosing of enoxaparin at 0–24 and 0–72 hours than attained with CII. However, at the final trough level at 72 hours, the anti-Xa level was higher with CII.
In Study III, additional blood clotting parameters were analyzed; these included prothrombin fragment 1+2 (F1+2), antithrombin, fibrinogen, and D-dimer. Moreover, the formation of thrombin was assessed with a calibrated automated thrombogram from a subset of patients. The F1+2 levels were lower when CII thromboprophylaxis was used than with SCB. These results may indicate a more pronounced anticoagulation with CII thromboprophylaxis.
In Study IV, coagulation changes after aSAH were examined by rotational thromboelastometry (ROTEM). This study was a prospective observational study conducted in 17 aSAH patients and 16 elective neurosurgical patients as controls. The main result was that after aSAH, the blood coagulation increased, and this could be measured by ROTEM. The increment in blood coagulation seemed to be further associated with a worse neurological outcome.
In conclusion, the reported anti-Xa levels with LMWH thromboprophylaxis were not related to clinical events in ICU patients. When LMWH thromboprophylaxis was given as an SCB, the maximum anti-Xa concentrations were higher than with CII. However, the CII led to a higher final trough level of anti-Xa and to more pronounced factor Xa inhibition. These effects of CII suggest that it results in more continuous anticoagulation in ICU patients than can be attained with SCB. Blood coagulation increased after aSAH and associated with worse neurological outcomes.
The doctoral dissertation of M.D. Annukka Vahtera in the field of anaesthesiology and intensive care medicine titled Thromboprophylaxis with Low-Molecular-Weight Heparin in Critically Ill Patients will be publicly examined in the Faculty of Medicine and Health Care at Tampere University on Friday 25 September 2020 starting at 12 o'clock in Finn-Medi 5 building auditorium, Biokatu 12. The Opponent is Docent Pirjo Mustonen from University of Eastern Finland. The Custos will be Professor Arvi Yli-Hankala.
The dissertation is available online at
http://urn.fi/URN:ISBN:978-952-03-1510-8
Photo: Irina, Valokuvaamo Luova