ANTICOAGULATION IN HAEMODIALYSIS DR. SRILATHA VADLAMUDI PROF. OF NEPHROLOGY NRI MEDICAL COLLEGE GUNTUR

OUTLINE Coagulation cascade and its inhibitors. Why the need for anticoagulation in haemodialysis? Various modalities of anticoagulation How to optimize anticoagulation and parameters for monitoring Anticoagulation in special circumstances

COAGULATION CASCADE AND ITS INHIBITORS

HAEMOSTATIC ABNORMALITIES IN RENAL INSUFFICIENCY Uremia increases bleeding tendency due to the platelet dysfunction secondary to uraemia. The usage of anticoagulants during extra corporeal therapy further increases the risk of bleeding. ESRD patients are also at increased risk of thrombosis compared to general population due to… systemic inflammation, activation of platelets and monocytes deficiency of protein C, Protein S, antithrombin

WHY ANTICOAGULATION IN DIALYSIS Haemodialysis procedure is a procoagulant state. Exposure to the artificial membranes Air blood interfaces in the chambers Turbulent blood flows across the circuit Low blood flow rates Both extrinsic and intrinsic coagulation pathways are activated. Surface contact activated platelets and granulocytes lead to activation of coagulation cascade. Without anticoagulation, dialysis has 5-10% extracarporial circuit clotting, loss of 100-150ml of blood.

ANTICOAGULATION IN DIALYSIS RISKS Systemic anticoagulation predisposing to bleeding episodes. Anticoagulant related adverse effects such as thrombocytopenia, osteoporosis. May need monitoring of therapy which increases cost and consumes time BENEFITS Prevents circuit clotting Enhances dialysis efficacy More life for consumables and hence decreased cost. Less blood loss during dialysis

WHICH ANTICOAGULANT? Anticoagulants commonly used in dialysis interfere with plasmatic coagulation pathway. Anticoagulants act Directly on clotting factors - direct thrombin inhibitors, factor Xa inhibitors) Indirectly by activating inhibitory factors( heparin or danaproid) They have variable potency on various factors.

ANTITHROMBIN ENHANCERS UFH, LMWH and fondaparinux are called as antithrombin enhancers. They enhance the activity of antithrombin which inhibits factor Xa and thrombin. Activated antithrombin inhibits factor Xa 1000-4000 times more than endogenous AT. UFH and LMWH heparins bind thrombin where as fondaparinux doesn’t bind thrombin

ANTITHROMBIN ENHANCERS contd…

ANTITHROMBIN ENHANCERS-UNFRACTIONATED HEPARIN Ineffective against thrombin or factor Xa if they are located in a thrombus or bound to fibrin or to activated platelets. Inhibitory effect on factor Xa vs. thrombin is 1:1 The ACT is adjusted to 80% above the baseline value. Adverse effects:osteoporosis and lipid status, allergic reactions such as pruritus, and thrombocytopenia. Monitoring with aPTT, ACT, WBPTT. Platelet count

ANTITHROMBIN ENHANCERS-LOW MOLECULAR WEIGHT HEPARIN Inhibitory effect on factor Xa vs. thrombin is 2.5:1 or 3:1. The anticoagulant effect in patients with normal renal function is highly correlated with body weight, allowing use of a fixed dose per kilogram body weight. In renal failure, dosing has to be reduced. If monitoring is performed, anti-factor Xa activity needs to be measured, while aPTT and ACT are not reliable. Level of 0.5 IU/mL is recommended in the venous line of the extracorporeal circulation.

ADVANTAGES OF LMWH AND FONDAPARINUX OVER HEPARIN

OPTIMIZATION OF ANTICOAGULATION AND BIOLOGICAL MONITORING CURRENT LIMITATIONS FOR OPTIMIZATION: No evidence based guidelines regarding the dosage and the drug of choice. Which drug? UFH or LMWH Controversy exists in various guidelines EBPG – LMWH BRA – UFH CARI – no difference between UFH or LMWH NKF – lack of data in favor of LMWH

OPTIMIZATION OF ANTICOAGULATION AND BIOLOGICAL MONITORING How much dose? Regarding UFH – European and UK guidelines recommend bolus of heparin 50 units/ kg followed by 500-1500 units /hr. Regarding LMWH- no guidelines recommend the dose of drug. To be individualized basing on the molecule used and patients bleeding risk.

OPTIMIZATION OF ANTICOAGULATION AND BIOLOGICAL MONITORING ANTICOAGULATION ADEQUACY? Clinical parameters: Undercoagulation: Extremely dark blood ,shadows or black streaks in the dialyzer. Foaming with subsequent clot formation in drip chambers and venous traps. Rapid filling of transducer monitors with blood Teethering(suction) blood in the post dialyzer Rapid rise in TMP, Unexplained increase in venous pressure Presence of clots at the arterial side header of the dialyzer Overcoagulation: prolonged compression time after dialysis

OPTIMIZATION OF ANTICOAGULATION AND BIOLOGICAL MONITORING Biological parameters: No simple, inexpensive and rapid bed side test till date to assess the adequacy of anticoagulation. UFH adequacy is usually monitored by WBPTT, ACT or aPTT. LMWH monitoring requires factor Xa measurements Levels of Xa more than 0.25 units must be maintained for adequate anticoagulation. Time consuming and expensive to incorporate into daily clinical practice. Levels may be monitored in patients at high risk of bleeding.

OPTIMIZATION OF ANTICOAGULATION AND BIOLOGICAL MONITORING Biological parameters: Several biomarkers are under evaluation as a marker to assess the adequacy of anticoagulation Some potent molecules include.. tissue factor pathway inhibitor transformation growth factor beta thrombin-antithrombin complex thrombomodulin, plasminogen activator inhibitor However none of the molecules proved promising till date

ANTICOAGULATION IN SPECIAL CIRCUMSTANCES Alternative anticoagulant therapies need to be considered in patients… a)Heparin induced thrombocytopenia. b) In patients with high risk of bleeding. Goal : a) to reduce the complications due to anticoagulation. b) to maintain extracorporeal circuit patency

HEPARIN INDUCED THROMBOCYTOPENIA A moderate decline in platelet count is frequently observed after commencing HD. HIT type I: a)Within the first 2 to 3 days of heparin therapy. b) Modest reduction in platelet count (100,000/mL) is frequently seen. c) Non immunologic reaction. d) direct heparin-induced degranulation of platelets. e) harmless.

HEPARIN INDUCED THROMBOCYTOPENIA contd… HIT type II: a) 4 to 10 days after initiating heparin therapy. b) Immune-mediated disease. c)Antibody formation against the complex of heparin and platelet factor 4 (‘‘HIT antibodies’’). d) Devastating disease. e) venous and arterial thromboembolism inspite of low platelet count. f) HIT presents with the highest rate of clot formation (50% within 30 days).

HEPARIN INDUCED THROMBOCYTOPENIA contd… HIT is also called the ‘‘white clot syndrome,’’ because characteristic platelet rich, white arterial thrombi are formed. Clinical features: Ischemia of one or several limbs Cerebral or myocardial infarctions. Pulmonary thromboembolism. The venous manifestations are frequently overlooked or not interpreted as a manifestation of HIT.

HEPARIN INDUCED THROMBOCYTOPENIA contd… All heparin preparations including LMWH must be stopped. A heparin free dialysis if possible to be considered. Heparin should not be used even for initial rinse of circuit in patients with HIT. Regional citrate anticoagulation can be considered to prevent extracorporial circuit anticoagulation. Alternative systemic anticoagulation: danaparoid, lepirudin, argatroban and fondaparinux

HEPARIN INDUCED THROMBOCYTOPENIA contd… Danaparoid: Heparinoid of low molecular weight (5.5 kDa) consisting of heparan sulfate (83%), dermatan sulfate, and chondroitin sulfate. Alternative anticoagulant most widely used in patients with HIT. Binds to antithrombin and heparin cofactor II. Factor Xa is more selectively inhibited than LMWH ( Xa:IIa ratio 22:1) Danaparoid has a low rate of cross-reactivity against HIT antibodies. The half-life is 25 hr in patients with normal renal function and is further prolonged in uremia. An antidote is not available. Dosage: before 1st HD: 2500 IU, 2nd HD: 2000 IU, maintain antiXa activity 0.5 to 0.8IU/ml

HEPARIN INDUCED THROMBOCYTOPENIA contd… Lepirudin: Recombinant hirudin preparation approved for the treatment of HIT. mainly eliminated by the kidneys. After a single loading dose, the patient may be therapeutically anticoagulated for 1 week or longer. No antidote, non dialysable except with high volume hemaofiltration. Hirudin constitutes a polypeptide and does not show cross-reactivity to HIT antibodies. Lepirudin levels are more reliably assessed by ecarin clotting time or chromogenic substrate assays. Dosage: 0.05 to 0.1mg/kg

HEPARIN INDUCED THROMBOCYTOPENIA contd… Argatroban: Potent arginine-derived, synthetic, catalytic site-directed thrombin inhibitor. No cross reactivity with HIT antibodies. Primary metabolism in liver. dose reduction necessary in renal and hepatic failure Periodic monitoring of the anticoagulant activity of argatroban is recommended using aPTT, the ECT, or the activated clotting time. Dose: 250microgm/kg loading dose before HD

ANTICOAGULATION IN SPECIAL CIRCUMSTANCES contd… Patients with bleeding risk: heparin free dialysis and regional citrate anticoagulation are options. HEPARIN FREE DIALYSIS: Rinse the circuit with 25-150 ml of saline repeatedly. High blood flows(250ml/min), short treatment times(2-3hrs), and usage of membranes with low thrombogenecity (polysulfone) reduces the risk of clotting in heparin free dialysis. Rinse the circuit with heparin saline prior to initiation of dialysis.

ANTICOAGULATION IN SPECIAL CIRCUMSTANCES contd… REGIONAL CITRATE ANTICOAGULATION: Good alternative in patients with high risk of bleeding who require long duration of dialysis and who cant tolerate high blood flows. Citrate infused into the arterial line chelates calcium and magnesium, and thus inhibits the coagulation cascade in the extracorporeal circulation. Before blood reinfusion, calcium is substituted into the venous line to target normal ionized calcium.

ANTICOAGULATION IN SPECIAL CIRCUMSTANCES contd.. REGIONAL CITRATE ANTICOAGULATION: Advantages: No systemic anticoagulation. Citrate is metabolized to bicarbonate in liver and helps to correct metabolic acidosis. Citrate improves the biocompatibility of dialysis membranes. Disadvantages: Complex procedure requiring monitoring of serum calcium levels. Excess citrate infusion can trigger metabolic alkalosis. Trisodium citrate can trigger hypernatremia

ALGORITHM FOR TAILORING ANTICOAGULATION Kessler et al; anticoagulation in chronic haemodialysis; seminars in dialysis, volume 28, No 5; 2015

TAKE HOME MESSAGE Anticoagulation remains key for adequate haemodialysis. Controversy still exists on the appropriate drug and their dosing regimens. Unfractionated or low molecular weight heparins are the commonly used medications. No simple bed side test to assess the adequacy of anticoagulation. Alternative anticoagualants, heparin free haemodialysis and regional citrate anticoagulation are options in high risk patients

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