Hemostasis during low molecular weight heparin anticoagulation for continuous venovenous hemofiltration: a randomized cross-over trial comparing two hemofiltration rates.
BACKGROUND
Renal insufficiency increases the half-life of low molecular weight heparins (LMWHs). Whether continuous venovenous hemofiltration (CVVH) removes LMWHs is unsettled. We studied hemostasis during nadroparin anticoagulation for CVVH, and explored the implication of the endogenous thrombin potential (ETP).


METHODS
This cross-over study, performed in a 20-bed teaching hospital ICU, randomized non-surgical patients with acute kidney injury requiring nadroparin for CVVH to compare hemostasis between two doses of CVVH: filtrate flow was initiated at 4 L/h and converted to 2 L/h after 60 min in group 1, and vice versa in group 2. Patients received nadroparin 2850 IU i.v., followed by 380 IU/h continuously in the extracorporeal circuit. After baseline sampling, ultrafiltrate, arterial (art) and postfilter (PF) blood was taken for hemostatic markers after 1 h, and 15 min, 6 h, 12 h and 24 h after converting filtrate flow. We compared randomized groups, and 'early circuit clotting' to 'normal circuit life' groups.


RESULTS
Fourteen patients were randomized, seven to each group. Despite randomization, group 1 had higher SOFA scores (median 14 (IQR 11-15) versus 9 (IQR 5-9), p = 0.004). Anti-Xa art activity peaked upon nadroparin bolus and declined thereafter (p = 0.05). Anti-Xa PF did not change in time. Anti-Xa activity was not detected in ultrafiltrate. Medians of all anti-Xa samples were lower in group 1 (anti-Xa art 0.19 (0.12-0.37) vs. 0.31 (0.23-0.52), p = 0.02; anti-Xa PF 0.34 (0.25-0.44) vs. 0.51 (0.41-0.76), p = 0.005). After a steep decline, arterial ETPAUC tended to increase (p = 0.06), opposite to anti-Xa, while postfilter ETPAUC increased (p = 0.001). Median circuit life was 24.5 h (IQR 12-37 h). Patients with 'short circuit life' had longer baseline prothrombin time (PTT), activated thromboplastin time (aPTT), lower ETP, higher thrombin-antithrombin complexes (TAT) and higher SOFA scores; during CVVH, anti-Xa, and platelets were lower; PTT, aPTT, TAT and D-dimers were longer/higher and ETP was slower and depressed.


CONCLUSIONS
We found no accumulation and no removal of LMWH activity during CVVH. However, we found that early circuit clotting was associated with more severe organ failure, prior systemic thrombin generation with consumptive coagulopathy, heparin resistance and elevated extracorporeal thrombin generation. ETP integrates these complex effects on the capacity to form thrombin.


BACKGROUND
Clinicaltrials.gov ID NCT00965328.
Oudemans-van Straaten
Heleen M
HM
Department of Intensive Care Medicine, Onze Lieve Vrouwe Gasthuis, 1091 AC Amsterdam, The Netherlands. h.m.oudemans-vanstraaten@olvg.nl
van Schilfgaarde
Muriel
M
Molenaar
Pascal J
PJ
Wester
Jos Pj
JP
Leyte
Anja
A
D018806:APACHE; D058186:Acute Kidney Injury / Q000628:therapy*; D000328:Adult; D000368:Aged; D000925:Anticoagulants / Q000627:therapeutic use; D001777:Blood Coagulation; D016638:Critical Illness; D018592:Cross-Over Studies; D015951:Factor Xa / Q000032:analysis; D005260:Female; D006440:Hemofiltration / Q000379:methods*; D006487:Hemostasis / Q000187:drug effects*; D006495:Heparin, Low-Molecular-Weight / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D017762:Nadroparin / Q000493:pharmacokinetics / Q000627:therapeutic use; D010314:Partial Thromboplastin Time; D011446:Prospective Studies; D018805:Sepsis / Q000150:complications; D012770:Shock, Cardiogenic / Q000150:complications; D013917:Thrombin / Q000502:physiology
D000925:Anticoagulants; D006495:Heparin, Low-Molecular-Weight; D017762:Nadroparin; D013917:Thrombin; D015951:Factor Xa