[Consensus on the clinical diagnosis, treatment and prevention of cancer treatment-induced thrombocytopenia in China (2023 edition)].

Cancer treatment-induced thrombocytopenia (CTIT) is a common adverse event during anti-tumor treatment, of which incidence is related to tumor classification, regimens, course of chemotherapy, etc. CTIT may result in a series of events including bleeding, dose intensity reduction, chemotherapy delay, and in severe cases, even the need for platelet transfusion, ultimately affecting the implementation of treatment plan, increasing the cost of treatment, reducing treatment effect and quality of life, and leading to a poor prognosis. The treatment of CTIT should first identify the cause, assess the risk of bleeding, and then adopt treatment strategies according to the cause and severity of CTIT. The main treatments of CTIT include platelet transfusion, application of various types of platelet-producing drugs, and measures to reduce the additional loss of platelets. Among them, platelet-producing drugs mainly refer to platelet-stimulating factors, including recombinant human thrombopoietin (rhTPO), recombinant human interleukin 11(rhIL-11), and thrombopoietin receptor agonists (TPO-RAs). In addition, traditional Chinese medicine also has some assistance in raising platelets. Pharmacological prophylaxis in high-risk patients may help reduce the incidence and severity of CTIT. This consensus aims to support Chinese oncologists in the diagnosis and treatment of CTIT in China, reduce the risk of bleeding and improve the quality of life of patients.

Use of Sodium Bicarbonate Purge Solution in Impella Devices for Heparin-Induced Thrombocytopenia.

Heparin purge solution is recommended to be used in Impella devices to prevent biomaterial buildup and subsequent device dysfunction. The use of sodium bicarbonate purge solution in an Impella device is described in two patients with heparin-induced thrombocytopenia (HIT). The first case details a patient with severe mitral regurgitation and cardiogenic shock who had an Impella CP placed who developed HIT. Heparin purge solution was replaced by sodium bicarbonate purge solution in addition to systemic direct thrombin inhibitor (DTI) initiation. There was no significant change in Impella purge pressure or flow over the 13 days of Impella use. The second case describes a patient who developed an acute myocardial infarction and subsequent cardiogenic shock for which an Impella CP was placed who also developed HIT. Heparin purge solution was replaced by sodium bicarbonate purge solution. There was no significant change in purge pressure, flow, or motor current spikes over 11 days of use. In conclusion, we describe the successful use of a novel sodium bicarbonate purge solution utilized in patients with HIT for Impella management alone and in combination with systemic direct thrombin inhibitor therapy. This resulted in no protein deposition in the device gaps or device dysfunction.

Application of a clinical decision rule and laboratory assays in pediatrics: Adult heparin-induced thrombocytopenia.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is rare among pediatric patients. The diagnosis of HIT depends upon clinical decision tools to assess its pretest probability, supported by laboratory evidence of anti-platelet factor 4 (anti-PF4)/heparin antibodies. AIMS: To compare the use of the 4Ts score clinical decision tool, clinical characteristics, and laboratory findings between pediatric and adult patients with suspected HIT. METHODS: We compiled all pediatric patients in our center for whom HIT testing was performed during the years 2015-2021. These were compared with a cohort of consecutive adult patients. Laboratory diagnosis of HIT was performed with particle gel immunoassay (PaGIA) as screening test and confirmed by an automated latex-enhanced immunoturbidimetric assay (LIA) and/or by functional flow cytometry assay (FCA). RESULTS: The cohort included 34 children (under 18 years) and 105 adults. Adults mostly received heparins for thromboembolism prophylaxis and treatment (72.4%, n = 76), and were more frequently treated with low-molecular-weight heparin (LMWH). Children were mostly exposed during cardiopulmonary bypass and extracorporeal membrane oxygenation (ECMO, 61.8%, n = 21), and were more frequently treated with unfractionated heparin (UFH). Compared with adults, children had significantly higher 4Ts scores. Nevertheless, adults had a slightly higher rate of a positive diagnosis of HIT. Six out of 16 adults with confirmed HIT presented with thrombosis (37.5%), whereas all three pediatric patients with HIT presented with thrombosis (p = .087). CONCLUSIONS: 4Ts scores are higher in children compared with adult patients for whom laboratory tests for HIT were obtained. A potentially higher incidence of thrombosis in children with HIT may be attributable to the severity of underlying illness.

The Protective Effect of Sweet Potato Root Tuber on Chemotherapy-Induced Thrombocytopenia.

SCOPE: Sweet potato (Ipomoea batatas L.) is one of the leading crops worldwide, containing high nutritional components such as fiber and polyphenols. Root tuber of Simon 1 (SIMON), a cultivar of sweet potato, is a folk food in China with a hemostasis function but lacking experimental data support. METHODS AND RESULTS: Now the protective effect of SIMON on chemotherapy-induced thrombocytopenia (CIT), a serious complication of cancer treatment, is investigated for the first time by a CIT mouse model induced by intraperitoneal injection of carboplatin. As a result, SIMON raises the number of peripheral platelets, white blood cells, and bone marrow nucleated cells in CIT mice significantly. Besides, carboplatin-induced atrophy of the thymus, spleen, and disordered metabolism of the inflammatory immune system and glycerophospholipids are also reversed by SIMON. Phytochemical analysis of SIMON indicates 16 compounds including eight phenolic derivatives, which might be associated with its anti-CIT bioactivity. CONCLUSION: Sweet potato (SIMON) may be an efficient function food in the prevention of bleeding disorders.

Initial trough concentration may be beneficial in preventing linezolid-induced thrombocytopenia.

We assessed whether prospective therapeutic drug monitoring to optimise the therapeutic range could prevent linezolid-induced thrombocytopenia. This prospective interventional study was conducted from September 2017 to October 2020 among 37 adult patients receiving linezolid. Patients were administered one of the following two initial dosages: 600 mg twice or once daily for patients with a creatinine clearance rate of ≥50 or <50 mL/min, respectively. Linezolid dosage adjustment was performed on days 3-5 based on the trough concentration. The serum linezolid levels in 22 and 15 patients were within and above the therapeutic range (2-7 µg/mL), respectively. The incidence of thrombocytopenia was significantly lower among patients whose linezolid levels were within the therapeutic range (4.5%;1/22) than in those whose levels were above the therapeutic range (80%; 12/15). It is important to maintain the linezolid level within the therapeutic range at the first therapeutic drug monitoring to prevent thrombocytopenia.

Scientific premise for the involvement of neutrophil extracellular traps (NETs) in vaccine-induced thrombotic thrombocytopenia (VITT).

Following on from the devastating spread of COVID-19, a major global priority has been the production, procurement, and distribution of effective vaccines to ensure that the global pandemic reaches an end. However, concerns were raised about worrying side effects, particularly the occurrence of thrombosis and thrombocytopenia after administration of the Oxford/AstraZeneca and Johnson & Johnson's Janssen COVID-19 vaccine, in a phenomenon being termed vaccine-induced thrombotic thrombocytopenia (VITT). Similar to heparin-induced thrombocytopenia (HIT), this condition has been associated with the development of anti-platelet factor 4 antibodies, purportedly leading to neutrophil-platelet aggregate formation. Although thrombosis has also been a common association with COVID-19, the precise molecular mechanisms governing its occurrence are yet to be established. Recently, increasing evidence highlights the NLRP3 (NOD-like, leucine-rich repeat domains, and pyrin domain-containing protein) inflammasome complex along with IL-1ß and effete neutrophils producing neutrophil extracellular traps (NETs) through NETosis. Herein, we propose and discuss that perhaps the incidence of VITT may be due to inflammatory reactions mediated via IL-1ß/NLRP3 inflammasome activation and consequent overproduction of NETs, where similar autoimmune mechanisms are observed in HIT. We also discuss avenues by which such modalities could be treated to prevent the occurrence of adverse events and ensure vaccine rollouts remain safe and on target to end the current pandemic.

Transfusion of fresh washed platelets does not prevent experimental polymicrobial-induced septic shock in mice.

INTRODUCTION: The specific role of platelets during sepsis is not yet fully understood, probably related to the paradox of platelets being potentially beneficial but also deleterious via their thrombotic functions. OBJECTIVE: To evaluate the impact of thrombocytopenia on septic shock in mice and to investigate whether transfusion of fresh washed platelets, either fully functional or with impaired hemostatic properties, might have beneficial effects. METHODS: Septic shock was induced by cecal ligation and puncture (CLP). Experimental depletion of circulating platelets was induced with a rat anti-mouse GPIbα monoclonal antibody. Transfusion of either wild-type washed platelets, platelets treated with the antiplatelet drugs acetylsalicylic acid (ASA) and clopidogrel, or GPIIbIIIa-deficient washed platelets treated with ASA and clopidogrel was performed 4 h after CLP surgery. RESULTS: Depletion of circulating platelets negatively affected septic shock, worsening systemic inflammation, coagulopathy, organ damage, and mortality, raising the question of whether a higher platelet count could be protective. Transfusion of fully functional platelets or platelets with combined treatment with ASA and clopidogrel, with or without additional GPIIbIIIa deficiency, afforded an immediate return of circulating platelet counts to their initial values before surgery. However, transfusion of each of the three types of platelets did not prevent arterial hypotension, inflammatory response, coagulopathy, and organ damage during septic shock. CONCLUSION: Depletion of circulating platelets negatively affects septic shock, while transfusion of washed platelets has no significant beneficial effect in mice.

Efficacy of Aidi Injection and Brucea javanica Oil Emulsion Injection in Rectal Cancer during CapeOX Adjuvant Chemotherapy.

BACKGROUND: Adjuvant chemotherapy with CapeOX regimen is widely used in resected rectal cancer, which brings benefits to patients. But drug-related toxicities are severe during this process; thus, survival outcomes may potentially be affected. This study explored the efficacy of two Chinese herbal injections, Aidi injection (ADI) and Brucea javanica oil emulsion injection (BJOEI), as adjuvant drugs in CapeOX adjuvant chemotherapy on rectal cancer patients. METHODS: A total of 240 cases were enrolled in this retrospective study. 80 cases received CapeOX with ADI (the ADI group), 80 cases received CapeOX with BJOEI (the BJOEI group), and the rest 80 cases received CapeOX alone (the control group). After four cycles' chemotherapy, adverse reactions (ADRs) and quality of life (QOL) were analyzed. Then, patients received follow-up for at least one year, and the endpoint was disease-free survival (DFS). RESULTS: All patients completed at least four cycles' adjuvant chemotherapy. The incidence of leukopenia and thrombocytopenia was significantly lower in the ADI group; the incidence of nausea was significantly lower in the BJOEI group; the incidence of hand-foot syndrome was significantly lower in both the ADI group and BJOEI group. Significant difference was found in the control group regarding the Karnofsky Performance Status (KPS) scores prior and posttreatment. No difference was found among three groups regarding one-year DFS. CONCLUSION: As adjuvant drugs for rectal cancer during CapeOX chemotherapy, ADI shows advantages in decreasing leukopenia and thrombocytopenia, while BJOEI results better in remitting nausea. Both two CHIs had positive impacts on decreasing hand-foot syndrome and the maintenance of patients' QOL. It is worthy of further study and promotion for CHIs.

Outcomes after targeted treatment based on somatic tumor genetic testing for women with gynecologic cancers.

OBJECTIVE: Molecular tumor profiling and next-generation sequencing are being increasingly utilized, but there are limited data on the therapeutic implications and potential benefits of targeted treatments. We aim to characterize gynecologic oncology patients referred for somatic tumor genetic mutation testing and assess survival outcomes, efficacy, and toxicities of those receiving targeted therapy. METHODS: We conducted a retrospective chart review of gynecologic oncology patients referred for somatic tumor testing by next generation sequencing between 1/1/2012-8/23/2019. The primary objective was to compare overall and progression free survival between those treated with targeted therapy (group 1) versus traditional treatment (group 2). RESULTS: Most patients (70%) had additional treatment options available based on actionable mutations. The median number of somatic mutations identified was 5 (range 0-53). Patients in group 1 had more actionable somatic mutations (median 2 versus 0, p < 0.001). There was no difference in OS (median 64 versus 76 months, p = 0.97) or PFS (median 2 versus 8 months, p = 0.05) between the groups. While fewer patients in group 1 experienced neuropathy (0 versus 5, p = 0.02), grade I/II thrombocytopenia (7 versus 13, p = 0.03), grade III/IV thrombocytopenia (0 versus 4, p = 0.02), and grade III/IV neutropenia (1 versus 9, p = 0.002), all other non-hematologic toxicities were similar in the two groups. CONCLUSIONS: Most gynecologic cancer patients have actionable mutations and may benefit from a personalized targeted therapy treatment plan. Next generation sequencing can be used to identify clinically actionable mutations in gynecologic cancers and guide the selection of treatments, thereby expanding treatment options without worsening survival or toxicity.

Comprehensive TCM treatments combined with chemotherapy for advanced non-small cell lung cancer: A randomized, controlled trial.

OBJECTIVE: We conducted this study to evaluate the efficacy and safety of traditional Chinese medicine (TCM) in advanced non-small cell lung cancer (NSCLC) patients who underwent chemotherapy. DESIGN: This was a prospective, open-label, randomized controlled trial. NSCLC patients at stage IIIA, IIIB, or IV were randomly assigned to either TCM plus chemotherapy or chemotherapy alone. The comprehensive TCM treatment consisted of Kang Ai injection, herbal decoction, and Zhenqifuzheng capsules. The primary endpoint was quality of life (QOL) measured by the Functional Assessment of Cancer Therapy-Lung version 4.0. The secondary endpoints were chemotherapy completion rate, tumor response, and adverse events. All assessments were done at baseline, the third week, and the sixth week. RESULTS: Thirty-nine participants were randomly assigned to the treatment group and 36 to the control group. The QOL scores were significantly improved in the treatment group compared with those of the control group in social well-being (cycle 1, P = .048; cycle 2, P = .015), emotional well-being (cycle 1, P = .047; cycle 2, P = 4.29E-05), and functional well-being (cycle 1, P = .030; cycle 2, P = .003), while the QOL scores in the above 3 domains declined in the control group (P < .05). Both groups had a decline in the physical well-being score (cycle 1, P = .042; cycle 2, P = .017) and lung cancer symptom score (cycle 1, P = .001; cycle 2, P = .001) after 2 courses of intervention. The deterioration in physical well-being and lung cancer symptoms was noticeably smaller in the treatment group (P < .05). There were significant differences between the 2 groups in social well-being, emotional well-being, functional well-being, lung cancer symptom domain, and the total score (P < .05). Patients in the treatment group had a significantly lower incidence of platelet reduction than the control group (P = .028) after 2 cycles of treatment. No significant difference in nonhematological adverse events (AEs) was observed. CONCLUSION: This study illustrated that comprehensive TCM treatment could promote the QOL of NSCLC patients, alleviate symptoms, and reduce the AEs caused by chemotherapy, verifying the synergistic and attenuating effects of TCM in NSCLC patients undergoing chemotherapy. TRIAL REGISTRATION: Chinese Clinical Trial Registry (www.chictr.org.cn): ChiCTR-TRC-13003637.

Argatroban versus heparin in patients without heparin-induced thrombocytopenia during venovenous extracorporeal membrane oxygenation: a propensity-score matched study.

BACKGROUND: During venovenous extracorporeal membrane oxygenation (vvECMO), direct thrombin inhibitors are considered by some potentially advantageous over unfractionated heparin (UFH). We tested the hypothesis that Argatroban is non-inferior to UFH regarding thrombosis and bleeding during vvECMO. METHODS: We conducted a propensity-score matched observational non-inferiority study of consecutive patients without heparin-induced-thrombocytopenia (HIT) on vvECMO, treated between January 2006 and March 2019 in the medical intensive care unit at the University Hospital Regensburg. Anticoagulation was realized with UFH until August 2017 and with Argatroban from September 2017 onwards. Target activated partial thromboplastin time was 50 ± 5seconds in both groups. Primary composite endpoint was major thrombosis and/or major bleeding. Major bleeding was defined as a drop in hemoglobin of ≥ 2 g/dl/day or in transfusion of ≥ 2 packed red cells/24 h, or retroperitoneal, cerebral, or pulmonary bleeding. Major thrombosis was defined as obstruction of > 50% of the vessel lumen diameter by means of duplex sonography. We also assessed technical complications such as oxygenator defects or pump head thrombosis, the time-course of platelets, and the cost of anticoagulation (including HIT-testing). RESULTS: Out of 465 patients receiving UFH, 78 were matched to 39 patients receiving Argatroban. The primary endpoint occurred in 79% of patients in the Argatroban group and in 83% in the UFH group (non-inferiority for Argatroban, p = 0.026). The occurrence of technical complications was equally distributed (Argatroban 49% vs. UFH 42%, p = 0.511). The number of platelets was similar in both groups before ECMO therapy but lower in the UFH group after end of ECMO support (median [IQR]: 141 [104;198]/nl vs. 107 [54;171]/nl, p = 0.010). Anticoagulation costs per day of ECMO were higher in the Argatroban group (€26 [13.8;53.0] vs. €0.9 [0.5;1.5], p < 0.001) but not after accounting for blood products and HIT-testing (€63 [42;171) vs. €40 [17;158], p = 0.074). CONCLUSION: In patients without HIT on vvECMO, Argatroban was non-inferior to UFH regarding bleeding and thrombosis. The occurrence of technical complications was similarly distributed. Argatroban may have less impact on platelet decrease during ECMO, but this finding needs further evaluation. Direct drug costs were higher for Argatroban but comparable to UFH after accounting for HIT-testing and transfusions.

Research on clinical characteristics and prognostic analysis of heparin-induced thrombocytopenia after surgery for acute type a aortic dissection.

PURPOSE: The present study aimed to explore the clinical characteristics of heparin-induced thrombocytopenia (HIT) after surgery for acute type A aortic dissection and perform a relevant prognostic analysis. METHODS: After continuous observation and analysis of 204 patients who underwent acute type A aortic dissection, we found that blood platelets decreased significantly after surgery and that these patients can be suspected to suffer HIT based on relevant 4Ts scores. For these suspected HIT patients, a latex particle-enhanced immunoturbidimetric assay was conducted to detect heparin-induced antibodies. Perioperative clinical data of patients in HIT and non-HIT groups were recorded as were blood platelet counts, HIT antibody test results, 4Ts scores, thromboembolic complications, clinical prognosis and outcomes. RESULTS: In the present study, 38 suspected HIT patients, 16 HIT patients and 188 non-HIT patients were selected in the clinical setting. Among them, HIT patients were found to have prolonged cardiopulmonary bypass time (223 min on average vs. 164 min) and delayed aortic cross-clamp time (128 min on average vs. 107 min), and these differences between HIT patients and non-HIT patients were significant (P < 0.05). Additionally, the HIT group required longer operation time and higher dose of heparin, but showing no statistical differences (P > 0.05). The transfusions of blood platelets in the HIT group and non-HIT group were 18.7 ± 5.0u and 15.6 ± 7.34 u, respectively. In the HIT group, the mechanic ventilation time and the length of ICU stay were longer comparing the non-HIT group(P < 0.05), though no significant differences in total length of stay or In-hospital mortality were observed (P > 0.05). The incidence of continuous renal replacement therapy in HIT group was higher than the non-HIT group (P < 0.05). Additionally,there were no significant differences in 24-h postoperative drainage or reoperation for bleeding in both group(P > 0.05). However, the HIT antibody titer in the HIT group was significantly higher than that in the Suspected HIT group (2.7 ± 0.8 U/mL vs. 0.3 ± 0.2 U/mL) (P < 0.05). Among patients diagnosed with HIT, the incidence of thromboembolism reached 31.5%.For example, two HIT patients newly developed thromboembolism in both lower extremities,and three patients experienced cerebral infarction. CONCLUSIONS: After surgery for acute type A aortic dissection, HIT patients developed postoperative complications, the duration of ventilatory support and length of ICU stay were extended, and the incidence of thromboembolism increased. HIT antibody detection and risk classification should be implemented for high-risk patients showing early clinical characteristics.

Treatment and outcomes of heparin-induced thrombocytopenia (HIT) in patients with neoplasm, a case series.

Heparin-induced thrombocytopenia (HIT) is a highly thrombogenic condition. Cancer patients are already at high risk of thrombosis. The treatment and outcomes of HIT in cancer patients are not well established. We retrospectively identified patients with active cancer who were diagnosed with HIT at our institution. Only patients with a positive HIT assay and intermediate to high 4Ts score were included. We assessed patients for baseline characteristics, HIT characteristics, non-heparin agent usage, and outcomes (recurrent thrombosis, bleeding, and death) up to 180 days after diagnosis of HIT. Between November 1, 2006 and December 31, 2016, 39 patients with active cancer received a diagnosis of HIT. Of these, 35.9% had thrombotic complications at diagnosis. Gastrointestinal cancer was the most common solid organ malignancy while myeloproliferative neoplasm (MPN) was the most common hematological malignancy. Fondaparinux was the most often used parenteral agent at any point of follow-up (87.2%), followed by argatroban (41.0%). Less than half the patients transitioned to an oral agent. The recurrent thrombosis rate was 17.9%, the bleeding rate was 20.5%, the major bleeding rate was 10.3%, and the mortality rate was 15.4% in the entire cohort. HIT in cancer patients is associated with poor outcomes.

Mediterranean Diet Maintained Platelet Count within a Healthy Range and Decreased Thrombocytopenia-Related Mortality Risk: A Randomized Controlled Trial.

There is little information on the dietary modulation of thrombosis-related risk factors such as platelet count. We aimed to assess the effects of Mediterranean diet (MedDiet) on platelet count and related outcomes in an older population at high cardiovascular risk. In participants of the PREDIMED (PREvención con DIeta MEDiterránea) study, we assessed whether an intervention with a MedDiet enriched with extra-virgin olive oil or nuts, relative to a low-fat control diet, modulated platelet count (n = 4189), the risk of developing thrombocytosis and thrombocytopenia (n = 3086), and the association between these alterations and all-cause mortality (median follow-up time: 3.0 years). Although platelet count increased over time (+0.98·109 units/L·year [95% confidence interval: 0.12; 1.84]), MedDiet interventions moderated this increase, particularly in individuals with near-high baseline count (both MedDiets combined: -3.20·109 units/L·year [-5.81; -0.59]). Thrombocytopenia incidence was lower in the MedDiet interventions (incidence rates: 2.23% in control diet, 0.91% in MedDiets combined; hazard ratio: 0.44 [0.23; 0.83]). Finally, thrombocytopenia was associated with a higher risk of all-cause mortality (hazard ratio: 4.71 [2.69; 8.24]), but this relationship was attenuated in those allocated to MedDiet (p-interaction = 0.018). In brief, MedDiet maintained platelet counts within a healthy range and attenuated platelet-related mortality in older adults at high cardiovascular risk.

Astragalus polysaccharide has a protective effect on hematopoiesis in an irradiated mouse model and decreases apoptosis in megakaryocytes.

Huangqi, the dried root of Radix Astragali, is an essential herb in Traditional Chinese Medicine and has been used to promote hematopoiesis for centuries. Astragalus polysaccharide (ASPS), the bioactive compound of Huangqi, serves a crucial role in hematopoiesis. The aim of the present study was to investigate the hematopoietic effects, in particular the thrombopoietic effects, and the molecular mechanisms of ASPS using an irradiation­induced myelosuppressive mouse model. Colony­forming unit assays, flow cytometric analysis of apoptosis, ELISAs, Giemsa staining and western blotting were performed to determine the hematopoietic and anti­apoptotic effects of ASPS. The results demonstrated that ASPS enhanced the recovery of red blood cells at day 21 following treatment, as well as platelets and white blood cells at day 14. In addition, ASPS promoted colony formation in all lineages (megakaryocytes, granulocyte monocytes, erythroid cells and fibroblasts). The morphological study of the bone marrow demonstrated that tri­lineage hematopoiesis was preserved in the ASPS­ and thrombopoietin (TPO)­treated groups compared with the control group. The overall cellularity (mean total cell count/area) of the ASPS­treated group was similar to that of the TPO­treated group. Additionally, in vitro experiments indicated that treatment with 100 µg/ml ASPS exhibited the maximum effect on colony formation. ASPS attenuated cell apoptosis in megakaryocytic cells via inhibiting the mitochondrial caspase­3 signaling pathway. In conclusion, ASPS promoted hematopoiesis in irradiated myelosuppressive mice possibly via enhancing hematopoietic stem/progenitor cell proliferation and inhibiting megakaryocytes apoptosis.

Pharmacological interventions for preventing clotting of extracorporeal circuits during continuous renal replacement therapy.

BACKGROUND: Acute kidney injury (AKI) is a major comorbidity in hospitalised patients. Patients with severe AKI require continuous renal replacement therapy (CRRT) when they are haemodynamically unstable. CRRT is prescribed assuming it is delivered over 24 hours. However, it is interrupted when the extracorporeal circuits clot and the replacement is required. The interruption may impair the solute clearance as it causes under dosing of CRRT. To prevent the circuit clotting, anticoagulation drugs are frequently used. OBJECTIVES: To assess the benefits and harms of pharmacological interventions for preventing clotting in the extracorporeal circuits during CRRT. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 12 September 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: We selected randomised controlled trials (RCTs or cluster RCTs) and quasi-RCTs of pharmacological interventions to prevent clotting of extracorporeal circuits during CRRT. DATA COLLECTION AND ANALYSIS: Data were abstracted and assessed independently by two authors. Dichotomous outcomes were calculated as risk ratio (RR) with 95% confidence intervals (CI). The primary review outcomes were major bleeding, successful prevention of clotting (no need of circuit change in the first 24 hours for any reason), and death. Evidence certainty was determined using the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) approach. MAIN RESULTS: A total of 34 completed studies (1960 participants) were included in this review. We identified seven ongoing studies which we plan to assess in a future update of this review. No included studies were free from risk of bias. We rated 30 studies for performance bias and detection bias as high risk of bias. We rated 18 studies for random sequence generation,ààsix studies for the allocation concealment, three studies for performance bias, three studies for detection bias,à nine studies for attrition bias,à14 studies for selective reporting and nine studies for the other potential source of bias, as having low risk of bias. We identified eight studies (581 participants) that compared citrate with unfractionated heparin (UFH). Compared to UFH, citrate probably reduces major bleeding (RR 0.22, 95% CI 0.08 to 0.62; moderate certainty evidence) and probably increases successful prevention of clotting (RR 1.44, 95% CI 1.10 to 1.87; moderate certainty evidence). Citrate may have little or no effect on death at 28 days (RR 1.06, 95% CI 0.86 to 1.30, moderate certainty evidence). Citrate versus UFH may reduce the number of participants who drop out of treatment due to adverse events (RR 0.47, 95% CI 0.15 to 1.49; low certainty evidence). Compared to UFH, citrate may make little or no difference to the recovery of kidney function (RR 1.04, 95% CI 0.89 to 1.21; low certainty evidence). Compared to UFH, citrate may reduceàthrombocytopenia (RR 0.39, 95% CI 0.14 to 1.03; low certainty evidence). It was uncertain whether citrate reduces a cost to health care services because of inadequate data. For low molecular weight heparin (LMWH) versus UFH, six studies (250 participants) were identified. Compared to LMWH, UFH may reduce major bleeding (0.58, 95% CI 0.13 to 2.58; low certainty evidence). It is uncertain whether UFH versus LMWH reduces death at 28 days or leads to successful prevention of clotting. Compared to LMWH, UFH may reduce the number of patient dropouts from adverse events (RR 0.29, 95% CI 0.02 to 3.53; low certainty evidence). It was uncertain whether UFH versus LMWH leads to the recovery of kidney function because no included studies reported this outcome. It was uncertain whether UFH versus LMWH leads to thrombocytopenia. It was uncertain whether UFH reduces a cost to health care services because of inadequate data. For the comparison of UFH to no anticoagulation, one study (10 participants) was identified. It is uncertain whether UFH compare to no anticoagulation leads to more major bleeding. It is uncertain whether UFH improves successful prevention of clotting in the first 24 hours, death at 28 days, the number of patient dropouts due to adverse events, recovery of kidney function, thrombocytopenia, or cost to health care services because no study reported these outcomes. For the comparison ofàcitrate to no anticoagulation,àno completed study was identified. AUTHORS' CONCLUSIONS: Currently,àavailable evidence does not support the overall superiority of any anticoagulant to another. Compared to UFH, citrate probably reduces major bleeding and prevents clotting and probably has little or no effect on death at 28 days. For other pharmacological anticoagulation methods, there is no available data showing overall superiority to citrate or no pharmacological anticoagulation. Further studies are needed to identify patient populations in which CRRT should commence with no pharmacological anticoagulation or with citrate.