Anticoagulation in Children Undergoing Hemodialysis, Continuous Renal Replacement Therapy, or Apheresis Therapy

Introduction

Extracorporeal blood purification techniques are associated with clotting of the extracorporeal circuit; therefore, with the exception of some coagulation disorders, anticoagulation is mandatory. In pediatric practice, the relative surface area of the extracorporeal circuit is increased in relation to its blood volume. The use of smaller lumen diameter lines provides greater surface contact. Passage of blood through the extracorporeal circuit results in activation of leukocytes, macrophages, lymphocytes, platelets, and the complement cascade. Monocyte activation, especially in the presence of activated platelets, results in surface expression and local release of tissue factor, thus activating the coagulation cascade promoting thrombosis in the extracorporeal circuit. In pediatric patients, smaller lumen in catheter, needle, and circuit tubing results in higher resistance, more turbulent flow, and limited blood flow rates compared with adults. The type of blood purification technique has implications for the choice, use, and handling of anticoagulants. In intermittent hemodialysis (HD), anticoagulants are needed for only about 4 hours to prevent the circuit from clotting. In patients undergoing continuous renal replacement therapy (CRRT) procedures, the need for and potential risks of anticoagulants are present for a considerably longer period of time. Most commonly, clotting affects small filters, and their lifetime in CRRT is significantly shorter as compared to larger filters regardless of the type of the anticoagulant.

General Considerations

In pediatric practice, most centers use unfractionated heparin (UFH) for treatment in patients without increased risk of hemorrhagic complications because it is inexpensive and easy to handle. Some centers use low-molecular-weight heparins (LMWHs) instead for better predictability.

In patients with heparin-induced thrombocytopenia (HIT) type II (and children with type I), alternatives to heparins are recommended. In noncritically ill children with HIT, we favor argatroban, a reversible direct thrombin inhibitor (DIT) with a considerably short half-life and only a few adverse effects.

Data from adults as well as children strongly indicate regional citrate anticoagulation in patients who are actively bleeding or at risk of bleeding (e.g., within 3 days of a bleeding episode, a surgical wound, accidental wound, or tonsillectomy within the past week, or < 2 weeks from a cerebral or retinal hemorrhage).

Long-term anticoagulation in CRRT needs strict anticoagulation management and frequent anticoagulation monitoring, especially in critically ill children.

Very small children (< 10 kg body weight) need stringent anticoagulation monitoring. Because of a very slow blood flow and smaller lumen lining, they need higher anticoagulant dosing and, thus, have an increased risk of hemorrhagic complications.

Unfractionated Heparin

The anticoagulant most commonly used is UFH. It consists of a large series of glycosaminoglycans, which interact with antithrombin. Although heparin effectively reduces coagulation cascade activation and thrombin formation, it can also directly activate platelets, which results in microthrombi deposits on the dialyzer wall.

For efficient use of heparin, antithrombin is needed. Heparin is an ineffective anticoagulant in patients with low plasma antithrombin levels (e.g., children with severe liver impairment or with an inborn antithrombin deficiency). If necessary, administer antithrombin to keep levels within a normal range.

Heparin is a systemic anticoagulant with an action time of 3 to 5 minutes. It is not removed by dialysis and only partially by plasma separation. About 35% is excreted via the kidney; therefore, the half-life is increased to 50 to 70 minutes in patients with acute kidney injury or end-stage renal disease. The disparity in half-life is greatest in the extremes of age and weight, especially in children weighing less than 10 kg. Heparin is a very negatively charged molecule that adheres well to plastics.

It is important to use a properly diluted heparin solution to prevent adherence of heparin only to the inner lining of the tube. Use a minimum heparin infusion velocity of 2.0 mL/h!

Heparin can be used in children without risk of bleeding. A loading dose of 25 to 50 IU/kg or 300 to 1000 IU/m ² (maximum, 2000 IU) should be administered, followed by a maintenance dose of 10 to 30 IU/kg/h. Loading dose (or no loading dose) had no effect on the occurrence of hemorrhagic complications in children with increased bleeding risk (see the Regional Citrate Anticoagulation section). In intermittent HD, the infusion is discontinued some 30 minutes before the end of the dialysis, especially in children with shunts, to prevent excess bleeding from the puncture site.

Because there is variability between batches of UFH, bedside monitoring of its effects is crucial. Monitoring can be easily performed by using bedside whole-blood activated clotting time (ACT). ACT values significantly differ among various ACT monitoring systems (e.g., ACTester, iSTAT, Hemocron, ACT plus). ACT measurements should be performed in all patients before and while undergoing heparin therapy and tailored not only to the patient but also to the system used. For sufficient anticoagulation, ACT is aimed at 1.7- to 2.3-fold of pre heparin baseline. The activated partial thromboplastin time (aPTT) can be used but needs a laboratory test. The aim is a 1.7- to 2-fold of baseline or upper normal value. With every 10-second aPTT prolongation, the risk of bleeding complications is increased by 50%!

Although the introduction of heparin has been one of the major advances in the history of HD, its side effects can be significant. The most severe of these is bleeding. Heparin can cause allergic reactions because it is derived from pork or bovine intestine. Long-term treatment with heparin can cause osteoporosis, alopecia, and abnormal liver function test results and may promote hyperkalemia (by antagonizing aldosterone).

In case of severe bleeding complications, heparin activity can be quickly reversed: Use 1 mg protamine for every 100 IU of heparin.

Occasionally, patients can develop HIT. The more severe (antibody-mediated) type II reaction usually develops when the patient has been exposed to large doses of heparin. Type II can be observed in 2% to 3% of patients about 5 to 10 days after exposure by a significantly decreased thrombocyte count (< 50,000/μL). Instant withdrawal of heparin in type II of HIT is mandatory. Generally, in children with HIT, alternatives to UFH should be used for anticoagulation.

On dialysis, the need for a significantly increasing heparin dosage to achieve sufficient anticoagulation can be a clue to subclinical HIT (type I). Thrombocyte count can be normal or only slightly decreased. In these cases, HIT should be checked.