Recurrent Early Filter Clotting during Continuous Veno-Venous Hemodialysis with Regional Citrate Anticoagulation is Linked to Systemic Thrombin Generation and Heparin Induced Thrombocytopenia Type II: A Retrospective Analysis

Research Article

Austin Crit Care Case Rep. 2021; 5(3): 1032.

Recurrent Early Filter Clotting during Continuous Veno-Venous Hemodialysis with Regional Citrate Anticoagulation is Linked to Systemic Thrombin Generation and Heparin Induced Thrombocytopenia Type II: A Retrospective Analysis

Khadzhynov D¹*, Slowinski T¹, Schreiber A¹, Lieker I¹, Halleck F¹, Lehner LJ¹, Kindgen-Milles D², Eckardt K-U¹, Budde K¹ and Staeck O¹

¹Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany

²Department of Anesthesiology/University Hospital Duesseldorf/Heinrich-Heine-University, Duesseldorf, Germany

*Corresponding author: Dmytro Khadzhynov, Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Charitéplatz 1, D-10117 Berlin, Germany

Received: September 01, 2021; Accepted: September 23, 2021; Published: September 30, 2021


Objective: Regional Citrate Anticoagulation (RCA) for Continuous Renal Replacement Therapy (CRRT) is widely used and leads to an excellent clottingfree filter survival. Despite strict adherence to protocols, in some cases recurrent early filter-clotting occurs. The aim of this observational study was to evaluate the underlying causes and the efficacy of interventions in patients with early recurrent filter-clotting during RCA.

Methods: In a retrospective analysis of a cohort of 1183 patients treated with RCA-CRRT we detected 12 patients with early filter-clotting unrelated to protocol violation or any obvious technical or medical reason.

Results: All patients were systemically anticoagulated with low molecular weight or unfractionated heparin for at least 24h before initiation of Continuous Veno-Venous Hemodialysis with RCA (RCA-CVVHD). During RCA, all postfilter ionized calcium concentrations were in the target range (mean 0.33±0.05 mmol/L). At the time of the first clotting event, thrombocyte counts were 168±66/ nL. After the clotting events, the systemic anticoagulation was switched to argatroban in all patients. With systemic anticoagulation using argatroban filter lifetime of RCA-CVVHD increased significantly (p<0.001) and clotting-events decreased from 0.61 to 0.10 per 24h. All patients were tested for HIT and 5/12 (42%) had a positive test for hep-PF4-antibodies. Application of argatroban significantly reduced early filter-clotting both in HIT-positive patients as well as in HIT-negative patients. At the time of the first clotting event, no patient had clinical signs of thrombosis or thromboembolism. However, during follow up a thromboembolic event occurred in three patients.

Conclusion: In patients with recurrent early filter-clotting despite strict adherence to the citrate protocol undetected HIT or other causes of thrombin activation may be present. Therefore, patients with recurrent early filter clotting in RCA-CVVHD should be screened for HIT or other conditions that may activate thrombin. A significant improvement of filter run-time can be achieved by systemic administration of a thrombin inhibitor both in patients with and without HIT.

Keywords: Continuous veno-venous hemodialysis; Regional citrate anticoagulation; Filter-clotting; Heparin induced thrombocytopenia type 2; Argatroban; Thrombin


AKI: Acute Kidney Injury; RCA: Regional Citrate Anticoagulation; CRRT: Continuous Renal Replacement Therapy; CVVHD: Continuous Veno-Venous Hemodialysis; GLA-Domain: Gamma-Carboxyglutamic Domain; HIPA: Heparin-Induced Platelet Aggregation; HIT: Heparin Induced Thrombocytopenia; ICU: Intensive Care Unit; SD: Standard Deviation; IQR: Interquartile Range


Regional Citrate Anticoagulation (RCA) has become a widely used technique in CRRT to provide an effective anticoagulation of the extracorporeal blood circuit. Compared to systemic anticoagulation with heparin, RCA prolongs filter patency, allows to waive systemic anticoagulation, and reduces bleeding risk [1]. Thus, RCA is nowadays an accepted technique for all patients and not only for those at high risk of bleeding [2].

In addition, RCA might offer benefits in patients at risk to develop a Heparin-Induced Thrombocytopenia (HIT) because a systemic anticoagulation to prevent clotting of the CRRT circuit is not necessary. Thus, the risk of HIT is reduced in patients receiving RCA. By nature, RCA is of course not a substitute for systemic anticoagulation. Therefore, for general thrombosis prophylaxis a systemic anticoagulation is mandatory and in patients with HIT, alternative anticoagulants must be initiated immediately to avoid thromboembolic complications [3,4].

In 2009, a RCA protocol for CRRT in CVVHD mode and variable treatment dose was published [5]. In a number of studies, this protocol was shown to be safe and effective with regard to the delivered dialysis dose, metabolic control as well as control of the acid-base status. In early studies, clotting-free filter survival was higher than 90% at 48 hours [5,6]. With growing experience, filter running time has increased even more. In a recent prospective multicentre study a clotting-free filter survival rate of 98% at 72 hours was observed [7]. Thus, filter-clotting has become a rare event with this RCA-CVVHD protocol [8,9].

Nevertheless, during routine use of this RCA-CVVHD protocol in critically ill patients in the Intensive Care Unit (ICU) the observation emerged that a low but noticeable number of patients showed inexplicable recurrent early filter-clotting although the postfilter ionized calcium levels were in the target range. In some of these patients, repeated clotting occurred within a few hours after starting a new circuit. Recently, Lehner et al. reported a case of premature and recurrent filter clotting during RCA, which might have been caused by development of HIT in the patient [10].

Unexpected and repeated filter clotting during CRRT with RCA might foil the proven advantages of RCA. In this retrospective analysis, we, therefore, aimed to characterize patients and conditions related to recurrent early filter-clotting that was not due to obvious reasons as RCA-protocol violation or technical failure, and to investigate the efficacy of interventions to reduce the number of clotting events in such cases.

Materials and Methods

Study design and study population

The retrospective observational single-center study was performed at the University Hospital Charité, Berlin, Germany in six intensive care units. All adult patients treated with RCA-CVVHD were included in the study.

RCA-CRRT was performed as continuous veno-venous hemodialysis (RCA-CVVHD) using the Multifiltrate device with Ultraflux AV1000S dialyzer (Fresenius Medical Care, Bad Homburg, Germany) in all patients according to the previously published protocol [5,11,12]. Routine filter change was after 72 hours, as recommended by the manufacturer, with an allowed tolerance of ±12 hours for practical reasons.

Detection of patients with recurrent early filter clotting

Databases were screened for RCA-CVVHD treatments with at least two subsequent filter-clottings occurring within the first 48 hours of a filter or one clotting event within the first 8 hours. Cases with filter-clotting due to RCA-protocol violation or technical failure were excluded.

Data collection

Patients were identified and clinical data (patient demographics, laboratory parameters, CRRT parameters and concomitant medication) were collected from three different sources: a computerized billing database (SAP HANA, SAP Deutschland, Walldorf, Germany), the patient data management system used in the ICUs (Computer Organized Patient Report Assistant (COPRA), COPRA System GmbH, Sasbachwalden, Germany) and records of the daily prescriptions of renal replacement procedures.

Testing for HIT: Screening for anti-PF4/heparin antibodies was performed by lateral-flow-immunoassay (Milenia® QuickLine HIT) and if positive confirmed by testing heparin-induced platelet aggregation (HIPA; in house).

For patients with recurrent filter-clotting the probability of HIT was calculated for the time-point of the occurrence of the first filterclotting retrospectively. Probability was estimated by 4T-scoring system [13].

Statistical analysis

Patient cohort characteristics and parameters were calculated as mean (and standard deviation [SD]) or, in case of non-parametric distribution of metric variables, as median (and interquartile range [IQR]). Differences were tested using t-tests for independent samples in case of normally distributed variables, using Mann-Whitney- Tests for skewed variables. Significance level was p=0.05. Statistical analysis was performed with IBM SPSS Statistics Version 22 (IBM Corporation, USA).


Patients with recurrent early filter-clotting

From September 2008 to January 2012 we treated 1183 patients with RCA-CCVHD. In this cohort, we identified 12 patients with recurrent early filter-clotting with a total of 147 filters used. The demographic data and clinical characteristics of these patients at time of ICU admission are shown in Table 1.