Global Haemostasis in Critically Ill Patients with Sepsis: Evidence for a Prothrombotic State.
Authors: Collins P. , Lewis S. , Macartney N. , Stephenson E. , Davies R. , Lees S. , Saayman A. , Macchiavello L. , Findlay G. 
Published: October 2019

Activation of haemostasis in sepsis may lead to microvascular thrombosis and progression to multiorgan failure (MOF). Almost all critically ill patients with sepsis have abnormal coagulation screens but these are unlikely to adequately represent the state of a patient’s haemostatic system and global assays may be more useful. Normal controls (n=32) and critically ill patients with sepsis (n=39) were recruited. Coagulation factors, antithrombin (AT) and protein C (PC) were measured. Thrombin generation was measured using the calibrated automated thrombogram (CAT) in platelet rich (PRP) and poor (PPP) plasma. Low dose tissue factor (6pM) activated whole blood Rotem® was measured and the first derivative of the trace gave a velocity of clot firmness.

Haemostatic changes in sepsis compared to normal controls Controls Controls mean (SD) Sepsis mean (SD) P Apparent effect of change PT (s) 11.7 (0.5) 19.7 (5.9) 0.001 Anticoagulant aPTT (s) 27 (3.4) 44.1 (18.2) 0.001 Anticoagulant Fibrinogen g/l 2.8 (0.57) 5.3 (2.1) 0.001 Prothrombotic FII IU/dl 100 (12.1) 64 (32.2) 0.001 Anticoagulant FV IU/dl 116 (22.9) 96 (55.2) 0.03 Anticoagulant FVII IU/dl 130 (31.1) 58 (33.5) 0.001 Anticoagulant FVIII IU/dl 107 (31.5) 242 (96) 0.001 Prothrombotic FIX IU/dl 101 (16.5) 112 (51.3) NS Neutral FX IU/dl 123 (16.6) 75 (42.1) 0.001 Anticoagulant FXI IU/dl 116 (15.7) 80 (41) 0.001 Anticoagulant FXII IU/dl 125 (27.8) 56 (29.4) 0.001 Neutral PC % 127 (20) 66 (37) 0.001 Prothrombotic AT IU/dl 103 (8) 64 (29) 0.001 Prothrombotic CAT in PRP Lag time (min) 17 (8) 30 (23) 0.02 Delayed ETP (nM.min) 1395 (488) 1270 (573) NS Neutral Peak thrombin (nM) 76 (40) 55 (31) 0.02 Anticoagulant Time to peak (min) 32 (12) 50 (29) 0.001 Delayed CAT in PPP Lag time (min) 2.4 (0.9) 5.1 (5.4) 0.001 Delayed ETP (nM.min) 1681 (281) 1645 (442) NS Neutral Peak thrombin (nM) 454 (100) 343 (146) 0.001 Anticoagulant Time to peak (min) 4.2 (1.2) 6.8 (6.6) 0.001 Delayed Low dose tissue factor Rotem Clot time (s) 818 (271) 1170 (766) 0.04 Delayed Alpha angle (°) 51 (12) 67 (17) 0.005 Prothrombotic MCF (mm) 51 (12) 67 (17) 0.001 Prothrombotic Max vel (mm/s) 6.5 (3.0) 10.9 (7.4) 0.005 Prothrombotic Time to Vmax (s) 1040 (334) 1079 (650) NS Neutral AUC 51 (12) 62 (24) 0.001 Prothrombotic

The results show that despite decreased levels of factors II, V, VII, XI and XII (correlation with decreased albumin, P<0.01, suggesting synthetic dysfunction as well as consumption); global measures of haemostasis show delayed but preserved or enhanced overall thrombin generation and clot formation. We hypothesise that the raised FVIII and normal FIX offset the decreased levels of other factors to maintain total thrombin generation which is delayed due to slowed formation of sufficient initial thrombin to activate FV, VIII and XI and stimulate expression of platelet phospholipids. Raised fibrinogen (correlation with CRP, P<0.001), important in the whole blood Rotem-based method, contributes to the prothrombotic state. The global assays are not sensitive to AT and PC and may underestimate the prothrombotic state. These data suggest that haemostatic changes in sepsis are predominantly prothrombotic and may be important in microvascular thrombosis and progression MOF.