Targets of anticoagulants within the coagulation cascade
Application of heparin during hemodialysis requires an initial loading dose and followed by a maintenance dose. Although the heparin dosage has not been standardized in the United States and Japan, the European best practice guidelines for HD recommend administering 50 IU/kg UFH into the arterial access needle for an initial loading dose. The maintenance dose of heparin is 800–1500 IU/h, given via constant infusion into the arterial line using an infusion pump (EBPG Expert Group on Haemodialysis 2002a). Alternatively, the maintenance dose can be given as repeated bolus injection. During intermittent HD, the patient is systemically anticoagulated. This maintenance infusion is stopped 30–60 min before the end of treatment to reduce bleeding times from fistula puncture sites, if needed (Kessler et al. 2015; Fischer 2007).
In UFH dose adjustment, activated coagulation time (ACT: 80–120 s) or activated partial thromboplastin time (aPTT: 24–40 s) adjusts to 1.5–2.0 times above normal range.
In patients at high risk of bleeding, UFH still is the most frequently used agent for anticoagulation in the world. The earliest approach was regional heparinization of the dialysis circuit. Based on the ability of protamine to neutralize the anticoagulant effect of heparin, this technically complex method has been abandoned to other methods such as use of low-dose heparin or heparin-free dialysis (Kessler et al. 2015; www.uptodate.com/contents/hemodialysis-anticoagulation).
The heparin-free hemodialysis protocol requires pretreating both the dialyzer and blood lines with 2000–5000 units of heparin contained in a liter of normal saline. The heparinized saline is flushed from the extracorporeal lines prior to the start of the dialysis treatment so that heparin is not administered to the patient. Extracorporeal blood flows are rapidly increased to 250–500 mL/min and maintained throughout the treatment, and 25–30 mL saline flushes are administered every 15–30 min into the arterial tubing line (www.uptodate.com/contents/hemodialysis-anticoagulation).
The minimum-dose heparin hemodialysis protocol usually involves boluses of 500 units of heparin every 30 min to keep the activated clotting time >150 but <200 s. Alternately, a continuous infusion of heparin with frequent activated clotting time (ACT) monitoring can be used to achieve the same degree of anticoagulation (www.uptodate.com/contents/hemodialysis-anticoagulation).
Side effects of heparin are increased bleeding risk, heparin-induced thrombocytopenia (HIT), hypertriglyceridemia, anaphylaxis, hyperkalemia, and possibly bone mineral disease. HIT is a life-threatening complication associated with heparin treatment, where antibodies to heparin–platelet complexes can lead to platelet activation and aggregation. The diagnosis of HIT is primarily based on the course of reduction in platelet count and/or the development of thromboembolic event during treatment with heparin. HIT may develop in two distinct forms, type I and type II. HIT type I is a nonimmune heparin-associated thrombocytopenia, within the first 2–3 days of heparin therapy. Direct heparin-induced degranulation of platelets can result in a modest reduction in platelet count (<100,000/mL). Platelet count increases subsequently even though heparin use is continued. HIT type II which is an immune-mediated disease may present from 4 to 10 days after initiating heparin therapy. There is antibody formation against the complex of heparin and platelet factor (Fischer 2007; www.uptodate.com/contents/hemodialysis-anticoagulation).
If HIT is suspected, any form of heparin including LMWH or heparin flushes have to be stopped, including any “heparin lock” solutions for dialysis or other catheters. Furthermore, the European best practice guideline recommends the use of therapeutic doses of an alternative nonheparin anticoagulant in patients with strong suspicion of HIT. Candidates are the direct thrombin inhibitors lepirudin, argatroban, or bivaluridin or the antithrombin-dependent factor Xa inhibitors, danaparoid, or fondaparinux (EBPG Expert Group on Haemodialysis 2002b). Furthermore, nafamostat mesilate is selected in Japan.
7.1.3 Low-Molecular-Weight Heparin (LMWH)
LMWH is recommended over UFH as anticoagulation in the European best practice guidelines for hemodialysis. Nevertheless, LMWH is used in Europe and Japan; in contrast the use of LMWH remains limited in the United States.
LMWH is produced by chemical or enzymatic cleavage of UFH to molecular size from 4000 to 8000 Da. Commonly used LMWH are dalteparin, tinzaparin, enoxaparin, nadroparin, parnaparin, reviparin, and others.
LMWH shows a stronger affinity to inhibit factor Xa and low specificity to thrombin, because most of the molecules do not contain enough saccharide units to bind both ATIII and thrombin and have different actions in terms of their anti-IIa activity compared with blocking factor Xa activation (Fig. 7.1). However, action of LMWH depends on the length of the polysaccharide chain, and, hence, all LMWHs do not show the same inhibitory profile. In common practice, doses are adjusted by monitoring measurement of anti-factor Xa activity (aPTT and ACT are unreliable) or clotting of the extracorporeal circuit, and most are effective when given as a single bolus dose at the start of a standard 4-h session.
Benefits of LMWH include higher bioavailability (less nonspecific binding to platelets and plasma proteins), improved lipid profile, reduced risk of hyperkalemia and osteoporosis, and lower incidence of HIT type II. Additional benefits of LMWH are expected to be high-bleeding-risk patients in Japan, but meta-analysis found no decreased risk of bleeding compared with UFH when it is used for anticoagulation in long-term hemodialysis (Kessler et al. 2015).
7.1.4 Direct Thrombin Inhibitors
Direct thrombin inhibitors are anticoagulants that bind directly to thrombin and do not require natural cofactors to inhibit the clotting cascade. Instead, they directly bind to and block thrombin, the final key enzyme within the coagulation process inducing the conversion of soluble fibrinogen to insoluble fibrin (Fischer 2007).
Argatroban is a synthetic peptide derived from arginine, with a molecular weight of 527 Da and acts as a reversible direct thrombin inhibitor by binding to the thrombin active site. Argatroban does not require the cofactor antithrombin III for antithrombotic activity (Fig. 7.1). For hemodialysis, a loading dose of 10 mg/h, followed by a maintenance infusion of 2 μg/kg/min or 5–20 mg/h, is titrated to achieve an aPTT of 1.5–2.5. To prevent excessive bleeding from fistula needle sites, the infusion should be stopped 30 min before the end of the dialysis session.
Lepirudin is a recombinant form of the natural anticoagulant hirudin, with a molecular weight of 6.9 Da. It has been administered as a single bolus at the start of hemodialysis or as a continuous infusion. However, lepirudin use has been limited because of a prolonged half-life in dialysis patients of >35 h, leading to bleeding complications with repetitive use.
7.1.5 Regional Anticoagulation
Regional anticoagulation is not necessarily the mainstream of anticoagulation therapy for hemodialysis. The earliest approach to anticoagulation for patients at high risk of bleeding was regional heparinization of the dialysis circuit. Based on the ability of protamine to neutralize the anticoagulant effect of heparin, this technically complex method has been abandoned to other methods such as use of low-dose heparin or heparin-free dialysis (Kessler et al. 2015).
In regional citrate anticoagulation, sodium citrate is administered in the arterial line to bind calcium, an important cofactor in the coagulation cascade, to inhibiting coagulation of the circuit (Fig. 7.1). The ability of the blood coagulation is restored by the use of a calcium infusion administered via the venous line. However, regional anticoagulation with citrate and calcium infusions is too tedious and expensive for routine use and thus often is limited to the intensive care setting.
7.1.6 Nafamostat Mesilate (NM)
NM is the most common anticoagulant used for the patients at high risk of bleeding in Japan. NM is a serine protease inhibitor with a half-life of 5–8 min, acts predominantly as a regional anticoagulant by inhibiting thrombin, factor Xa and factor XIIa, and also has effects on the kinin system, fibrinolysis, and platelet activation (Fig. 7.1). The maintenance dose of NM is 20–40 mg/h, given via constant infusion into the arterial line using an infusion pump, and no initial bolus is needed. In NM dose adjustment, ACT or aPTT adjusts to 1.5–2.0 times above normal range. Rarely, most important side effects of NM are anaphylactoid reactions. Severe anaphylactic shock develops immediately after the treatment has started. In addition, it is important to observe the patient, 5–10 min after the treatment has been started.
7.1.7 Dose of Anticoagulant and Dialysis Vintage
Figure 7.2 shows the relationship between total dose of anticoagulant per session and dialysis vintage in Japan. Total dose of UFH and LMWH has increased with increasing the dialysis vintage (Fig. 7.2a). In addition, the trend is also similar in terms of total anticoagulant dose per body weight (Fig. 7.2b).
Association between total dose of UFH/LMWH per session and dialysis vintage in Japan
By contrast, Fig. 7.3 shows the association between total dose of UFH/LMWH per session and patient age in Japan. Total dose of UFH and LMWH has decreased with increasing the patient age (Fig. 7.3a). However, total anticoagulant dose per body weight was very similar in patients divided into 15-year-age groups (Fig. 7.3b).
Association between total dose of UFH/LMWH per session and patient age in Japan
In Japan, the mean age of maintenance dialysis patients has been increasing since 1982, and there has been a notable increase in the patients aged ≥65 years (Patient Registration Committee, 2005). At the end of 2012, the patients aged ≥65 years proportion was 65.5%, clearly showing aging among Japanese patients undergoing dialysis. Similarly, at the end of 2012, the mean age of incident dialysis patients in Japan was 68.4 years (Kimata et al. 2015).
UFH/LMWH per session may be low as the proportion of elderly people in patients with dialysis less than 2 years has increased. However, dose of anticoagulant was increased with increasing the dialysis vintage. In general, most outpatient dialysis units do not regularly measure anticoagulation parameters, unless there is an issue with dialyzer clotting or prolonged bleeding following dialysis. However, it may be necessary for regular evaluation of anticoagulation dose.
7.1.8 Coagulation Due to Other Causes
Thrombosis in blood tubing, drip chambers, and dialysis membrane occur as a result of activation of platelets and coagulation cascade. Thrombus formation was macroscopically roughly classified into two types (white thrombus or red thrombus). While the appearance of red thrombus formation is a common phenomenon in every hemodialysis unit, the occurrence of white thrombus in the dialysis tubing is relatively rare (Watnick et al. 2008).
White thrombus was found in 8 out of 486 patients (1.64%) in 3 months of our observation. During rinse back at the end of dialysis, white particulate matter measuring 1–3 mm was found firmly adherent to the blood tubing line, and 3–5 mm was found in the drip chamber or/and needle cannula site.
Electron microscopy of the core of white thrombus was CD61-positive platelet-rich thrombus with a small amount of fibrin, and red thrombus had aggregated erythrocytes in the core of the clots. Additionally, the core of the red thrombus was occupied with the red blood cell and fibrin. Suburb of the core was highly consists with erythrocytes, leukocyte, and fibrinogen (Fig. 7.4) (Kimata et al. 2008).
Two types of thrombus formation in hemodialysis blood tubing lines
From the clinical records, white thrombus was found postoperatively more frequently than red thrombus. Besides, most of the phenomenon of white thrombus will calm down after a lapse of more than 4 days after surgery. In contrast, red thrombus was frequently found in cases of low blood-flow rate (<100 mL/min), high ultrafiltration rate, high hematocrit, and access recirculation. Red thrombus is almost resolved with an increase in heparin dose. However, the white thrombus occurred regardless of the type of dialyzer or blood tubing and did not resolve with an increase in heparin dose. The internal use of aspirin was the most effective for suppressing the white thrombus (Kimata et al. 2008).
UFH is the most commonly used anticoagulant because it is inexpensive and has a short half-life. Nevertheless, the dosage has not been standardized in the United States and Japan. Anticoagulation for patients at HIT, alternatives from UFH, includes direct thrombin inhibitors (argatroban and lepirudin), regional anticoagulation (citrate and nafamostat mesilate), and anticoagulation-free treatment with frequent saline flushes. Furthermore, despite changing the anticoagulant dosage or anticoagulant type, in cases of repeating the circuit coagulation, sometimes white thrombus (platelet-derived thrombus) is involved. In that case, it should be considered an antiplatelet medication, such as aspirin.
7.2 Anticoagulation in Patients on Hemodialysis
Kitasato University Graduate School of Medical Sciences, Tokyo, Japan
7.2.1 Anticoagulation in Hemodialysis Patients
During hemodialysis, blood from the body is circulated through a blood circuit outside the body (extracorporeal circulation). During the extracorporeal circulation, the blood comes in contact with artificial surfaces, such as the blood circuit and dialysis membrane, which triggers the coagulation cascade. Therefore, anticoagulation is indispensable during hemodialysis.
The first anticoagulant tried to use during hemodialysis in humans was hirudin, by Haas in 1924 (Haas 1925). In 1928, Haas tried to use heparin during batch-type hemodialysis treatment (Haas 1928). This was the first use of heparin in humans during blood purification therapy (Paskalev 2001). In 1937, Thalhimer succeeded in removing urea in dogs by extracorporeal circulation using heparin (Thalhimer 1937; Cameron 2000). In 1945, Kolff et al. were the first to succeed in rescuing patients with acute renal failure by hemodialysis (Kolff et al. 1944); they also used heparin as the anticoagulant.