The control patients had at least the combination of cardiovascular failure necessitating vasoactive

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1 ELECTRONIC SUPPLEMENTARY MATERIAL Material and methods Patients The control patients had at least the combination of cardiovascular failure necessitating vasoactive medication, respiratory failure necessitating mechanical ventilation, and renal failure necessitating renal replacement therapy [6]. Criteria for initiating CAVHD were one or more of the following: decreasing urine production and increasing serum creatinin levels above.8 mg/dl (50 µmol/l) or serum urea nitrogen of more than 70 mg/dl (5 mmol/l); MODS and/or hemodynamic instability with fluid retention and an increasing serum creatinin level above. mg/dl (00 µmol/l) or serum urea nitrogen of more than 56 mg/dl (0 mmol/l); oligo-anuria despite maximum diuretic treatment in the presence of sufficient hydration; insufficient water clearance (unacceptable positive fluid balance and increasing tissue oedema) or an unacceptable increase of central venous pressure and wedge pressure despite maximum conventional treatment with diuretics and fluid restriction; insufficient and unacceptable electrolyte clearance, particularly of serum potassium, or metabolic acidosis despite maximal conventional treatment [5,7]. Anticoagulation management In our hospital, heparin sodium (Heparine Leo, Leo Pharmaceutical Products BV, Weesp, The Netherlands) was used for intravenous administration. In the operating theatre, 5,000-50,000 U of heparin was used for anticoagulation of the extracorporeal circuit for cardiopulmonary bypass (CPB) for cardiac surgery patients. For central vascular surgery, 5000 U of heparin was used at the beginning of a procedure. In the ICU, all arterial lines were flushed with NaCl 0.9% containing 500 U of heparin per 500 ml per day. For anticoagulation of the extracorporeal circuit of CAVHDF, 5000 U of heparin was administered as a bolus followed by continuous intravenous administration of 5,000 U/50 ml targeted at a prolongation of the aptt ratio patient/human normal plasma of (Cephotest, Nycomed Pharma AS, Oslo, Norway). 1

2 Nadroparin calcium (Fraxiparine, Sanofi-Synthelabo BV, Maassluis, The Netherlands) was only used for subcutaneous administration for venous thromboprophylaxis 1 dd 850 U. No monitoring of coagulation parameters was used. Danaparoid sodium (Orgaran, Organon BV, Oss, The Netherlands) was administered subcutaneously dd 750 U for venous thromboprophylaxis, by intravenous bolus administration of 50 U for anticoagulation of the extracorporeal circuit of intermittent hemodialysis, and by continuous intravenous administration of U/50 ml for anticoagulation of the extracorporeal circuit of hemofiltration. For CAVHDF, the compassionate patient dosing schedule (Organon B.V., Oss, The Netherlands, January 1996) was used advising an intravenous bolus of 500 IU followed by a maintenance infusion of U/hr in order to maintain plasma anti-xa levels between IU/ml [9]. The efficacy and safety of this schedule was assessed in a series of 6 consecutive patients [10]. Anti-Xa levels were determined by a classic clotting assay (Staclot Heparin, Diagnostica Stago, Asnieres, France). Acenocoumarol (Sintrom mitis, Novartis Pharma BV, Arnhem, The Netherlands) was administered by nasogastric tube or orally. The international normalised ratio (INR) was used for monitoring the anticoagulation effect. Target values were for primary and secondary prevention of venous thrombo-embolism, atrial fibrillation and a heart valve bioprosthesis, for a mechanical heart valve prosthesis, and for primary and secondary prevention of arterial thrombo-embolism. The administration of coumadins was not combined with heparin-like anticoagulants whenever possible. When HIT was suspected, UFH or nadroparin calcium was stopped and blood samples were drawn for laboratory testing with an outwash period of 4 hours for UFH and of 48 hours for nadroparin calcium. Due to the procoagulant state of HIT it was indicated to continue anticoagulant therapy. When it was regarded as safe, danaparoid sodium was started and monitored by anti-xa levels [9,11,1]. When the platelet count had normalised, acenocoumarol was started with an overlap with danaparoid sodium of at least three days. Danaparoid sodium was stopped when INR.0 for two consecutive days. In case of (suspicion of) danaparoid sodium cross-reactivity, danaparoid sodium was stopped and a new blood sample was drawn after

3 an outwash period of 48 hours for laboratory testing. When indicated, therapy with plasmapheresis was instituted with tri-sodium citrate anticoagulation [13]. Heparin-induced thrombocytopenia, thrombosis and hemorrhage The clinical criteria for HIT by Sheridan were used to support our clinical suspicion of HIT [14]. HIT was classified as follows: definite HIT: thrombocytopenia develops in patient while receiving heparin, and other causes of thrombocytopenia are excluded. Thrombocytopenia recurs when the patient is rechallenged with heparin; or thrombocytopenia plus acute arterial thrombosis, with other causes of arterial thrombosis excluded; probable HIT: thrombocytopenia develops in patient while receiving heparin; and other causes of thrombocytopenia are excluded, i.e. blood culture is negative; other drugs excluded; possible HIT: patient fulfills second criteria, but the thrombocytopenia resolves during continued heparin therapy; or patient fulfills second criteria, but thrombocytopenia does not recur with subsequent administration of heparin (negative rechallenge); unlikely HIT: thrombocytopenia develops in patient while receiving heparin, but another cause for the thrombocytopenia is found; or the thrombocytopenia does not resolve after heparin is discontinued. Laboratory confirmation of HIT was performed by the platelet aggregation test (PAT) with platelet rich plasma from healthy platelet donors in absence of spontaneous platelet aggregation. A blood sample was drawn from an indwelling arterial catheter and directly transported to the laboratory packed in ice. Patient plasma and donor platelets were incubated with adenosine 5 -diphosphate (ADP) as a reference for the reactivity of the platelets for aggregation. Subsequently patient plasma and donor platelets were incubated with NaCl 0.9% without heparin and a high concentration of heparin in which the aggregation should be absent. Then patient plasma and donor platelets were incubated with increasing concentrations of 0.1 U/ml and 100 U/ml of UFH, nadroparin calcium, or danaparoid sodium. When platelet aggregation occurred 5% of the reference aggregation with ADP, the test was regarded as positive according to the criteria of Chong [15]. Bleeding complications were classified as clinically important major and clinically important minor bleeds according to Landefeld s Bleeding Severity Index [16]. This method of 3

4 classification of bleeding complications is based on criteria for the amount, rate and clinical consequences of bleeding and has been shown to be highly reproducible. Clinically important major bleeding according to this classification was defined as overt bleeding that was fatal, lifethreatening, potentially life-threatening, or acute or subacute and led to severe or moderate blood loss or to intervention to stop the bleed. Minor bleeding included other overt bleeding from an internal site, such as gastrointestinal bleeding, hemoptysis, and gross hematuria. Bruising, injection or venepuncture hematoma, and microscopic hematuria were not considered clinically important minor bleeds. Results Thrombo-embolic complications HIT group. Treatment with danaparoid sodium in 16 patients did not result in a significant decrease of the incidence of TEC. Before treatment with danaparoid sodium 3/16 (18.8%) of patients suffered TEC and during treatment with danaparoid sodium 5/16 (31.3%) suffered TEC (Fisher exact test p=0.69). Treatment with CAVHDF was not significantly associated with the occurrence of TEC (Fisher exact test p=1.0). Hemorrhagic complications HIT group. Thirteen patients experienced a single episode of bleeding, patients experienced episodes of bleeding, and patients experienced 3 episodes of bleeding. Simultaneous bleeds at different sites occurred in patients. In 9 patients the occurrence of bleeding complications was during treatment with UFH and nadroparin calcium, in 9 patients during treatment with danaparoid sodium, and in 1 patient bleeding complications occurred in both treatment episodes. Treatment with danaparoid sodium in 16 patients did not result in a significant increase of the incidence of bleeding complications. During treatment with danaparoid sodium 8 major and 3 minor bleeding complications occurred and during treatment with UFH and LMWH 7 major and 3 minor bleeding complications occurred (Fisher exact test: all bleeds p=1.0; major bleeds p=1.0; and minor bleeds p=1.0). 4

5 Three out of 17 HIT patients with bleeds had used concomitant coumadins for prohylaxis. The first patient was treated with intermittent hemodialysis and did only receive intermittent boluses of heparin for anticoagulation of the extracorporeal circuit; at the time of the bleeding complication, INR was.1. The second patient was treated with hemofiltration intermittently; at the time of the bleed, INR was 1.4. The third patient did not have acute renal failure and was not treated with renal replacement therapy; at the time of the bleed INR was 1.7 and.9. 5

6 TS1. Course of platelet count day 1-14 of ICU admission. Day of ICU HIT group Control group p-value admission (0 patients) (0 patients) (16-56) 108 (34-18) (11-16) 96 (8-06) (10-16) 84 (13-55) (16-143) 81.5 (7-180) (13-18) 81 (5-190) (16-170) 106 (7-189) (-194) 131 (53-91) (18-49) 118 (55-78) (6-199) 14.5 ( ) (48-130) (76-484) (5-01) (86-56) (56-136) (98-64) (73-) 04 ( ) (74-179) 18.5 (10-408) TS1. Platelet counts are given as median and range; p-values are derived from the Mann-Whitney rank sum test. Legend: ICU denotes intensive care unit; HIT denotes heparin-induced thrombocytopenia 6

7 TS. Localisation of bleeds in HIT patients. Site Numer of bleeds Abdomen 10 Digestive tract Oesophagus Stomach/duodenum Rectum 5 1 Spleen 1 Liver 1 Abdominal wall 1 Retroperitonuem 1 Muscle Catheter-related arterial venous 4 Total 5 Legend: HIT denotes heparin-induced thrombocytopenia. 7