Dr. Jeffrey s.c. Tsang

11/10/99

Heparin was first discovered by a medical student McLean in 1916 when he isolated it from dog liver. The name ‘heparin’ was given by his teacher Howell. It was thought at that time that it was the substance that maintained the blood fluid. Heparin remains the main drug for anticoagulation during dialysis since its available for use in the past sixty years. It contains a mixture of acidic mucopolysaccharides with potent electronegative charge. They have different sizes with molecular weights in the range 5000 - 30,000. It acts mainly by inhibiting Factor Xa and accelerate the action of Anti-thrombin III activities. Commercially they are isolated from porcine intestinal mucosa and beef lung. In clinical use we have to consider the following points.

There is no hard data or universal accepted recommendation as to how much heparin is suitable for haemodialysis treatment. Various methods of heparinization has been performed for hemodialysis with clinical satisfactory results. These include the following methods.

1. Intermittent Heparinization with heparin given as bolus doses.
2. Flush the dialysis circuit with heparin-saline and use continuous heparinization after start haemodialysis.
3. Loading dose and continuous maintenance dose of heparin.

Methods to monitor the effect of heparinization varies from no monitoring to various bedside whole blood clotting time and plasma clotting time done in the laboratory. The difficulty is exemplified by the following observations.

1. Clinical heparins are chemically heterogeneous. There are considerable batch and brand variations.
2. Procoagulants like acute phase reactants, platelet factor 4, tumour necrotic factors present in patient may neutralize the effect of heparin.
3. Antibiotics may decrease the synthesis of Vit-K dependent Clotting Factors.
4. Duration of haemodialysis, blood flow rate and type of membrane use may affect the amount of heparin required for haemodialysis.

 

 

Dr. Jeffrey s.c. Tsang 11/10/99

Anticoagulation in Haemodialysis

5. Short dialysis with high blood flow rate of nowadays dialysis require less total dose of heparin used as compared with previous long dialysis treatment. Although heparinization is unsatisfactory but usually clinical satisfactory result is obtained.
6. Low dose heparinization is possible in cases with bleeding.
7. Heparin free dialysis without saline flush is possible with normal patient on haemodialysis.

In spite of these observations which indicate two extreme conditions, one which

do not require any anti-coagulant and the other requires more anti-coagulant, heparinization is usually required for majority of dialysis to carry out smoothly.

Nevertheless, an understanding of the use of heparin guided by its objective response ( the clotting time ) will be extremely helpful for its use in difficult situation like management of patient with bleeding tendency, prolong heparinization in continuous hemodialysis treatment and regional heparinization. The following points should be considered before heparinization.

1. The effect of the drug is measured as the response to the drug not its concentration. Therefore, it can not be given as a ratio of the body weight.
2. The half-life of the drug is around 60 minutes. Therefore to maintain the response of the drug, we have to give a maintenance dose.
3. The commonly accepted value of two and a half times control value of Activated Partial Thromboplatin Time (APTT) is derived from traditional practice for therapy of thrombotic episodes such as deep vein thrombosis. One should not confuse the patient’s baseline clotting time ( clotting time before heparinization ) with the control value ( pool plasma ). This value is not freely transplantable to other methods of performing clotting time.

Dr. Jeffrey s.c. Tsang 11/10/99

1. Monitoring Methods.

Since heparin affects the extrinsic pathways of coagulation cascade, it is usually measured by Lee & White ( LW ) clotting time, Activated Partial Thromboplastin Test APTT ( KPTT ) and Activated Clotting Time ( ACT ). Other more sophisticated test like Anti-Xa level and protamine titration test may be used. But measuring the level of heparin in blood or level of anti-Xa does not equate to the degree of anticoagulation. Since they are more complicated and more expensive, so they are rarely used.

APTT is usually done by central laboratory. It uses citrated plasma. Add contact activating agents like kaolin and phospholipids make from rabbit or bovine brain. Then recalcify it to induce coagulation. Phospholipid from biological source is notoriously difficult to standardized. It is best to buy a whole year supply of APTT reagent of the same batch number and calibrate it with heparin and pool plasma before use. Calibration will be a problem if we use bedside whole blood for test.

Lee & White clotting time is usually criticized by the laboratory people as insensitive bedside method, labour intensive and can not done in batches. Some of these inadequacy in fact is a necessity if we consider monitoring heparinization for haemodialysis. For example, bedside monitoring is almost a must if we want frequent monitoring. Ability to be done in batches is a concern of the laboratory people not that of the dialysis people. Insensitivity of the test lies in inadequate activation of the clotting factors. Activation of blood coagulation is by contact with glass surface and air. In the real world of dialysis treatment, the blood in the dialysis circuit clots because it makes contact with foreign surfaces like blood tubing, dialysis membrane and air. Lee & White method is therefore closest to what is actually happening. Sensitivity and accuracy can be improved with machines, like CM II, Hemochron machines.

 

 

Dr. Jeffrey s.c. Tsang 11/10/99

Anticoagulation in Haemodialysis

 

ACT uses the principle of increase contact activation with celite particles. The accuracy of temperature control, use of chemically clean test tubes and the presence of a magnet of doubtfully clean surface, standardization of size of the magnet and effect of its presence on blood clotting all raise concern. However, it has been successfully used to monitor heparinization during haemodialysis.

2. Setting Limits.

We must have an idea about the upper and lower limit of the response to heparin. These limits depend on the method of monitoring. If we borrow the traditional method of heparinization for treatment of thrombotic events, then it is 1.5 to 2.5 times pooled serum value for APTT. Reported limits for ACT is between 200 to 250 seconds and CM II modified LW is 4 to 6 minutes.

3. Baseline clotting time.

This is the clotting time before the use heparin. It is a must, for patient may have an abnormal coagulation system before dialysis. The clotting time may be prolonged and do not require any heparin.

4. Loading Dose.

In the event when the patient’s baseline clotting time is well below the lower limit. A bolus dose is needed to bring the clotting time to the desired value. The desired value reflects the response to the desired dose of heparin .

 

 

 

 

 

 

Dr. Jeffrey s.c. Tsang 11/10/99

Anticoagulation in Haemodialysis

5. Maintenance Dose.

The loading dose of heparin will be metabolized during dialysis. In order to maintain the same amount of the ideal loading dose in the patient’s blood we must replace the amount that is lost with a maintenance dose. The maintenance dose thus depends on the consumption rate of the loading dose.

6. Adjusting the dose of heparin.

Once the correct loading dose and maintenance dose is found, usually no change is necessary unless the condition of the patient has changed.

Dr. Jeffrey s.c. Tsang 11/10/99

Low molecular weight heparin (LMWH) contains heparin in the molecular range of 2000 – 9000. Usually in the range of 4000 – 6000. It claims to act on Factor Xa and Factor IIa but not much on anti-Thrombin III and platelet function. This makes the drug retains its anti-coagulation property and yet has lower chance of bleeding. The lipoprotein lipase and hepatic lipase activity is not as mark as unfractionated heparin. This results in a decrease in serum total cholesterol, triglyceride, LDL cholesterol after prolong use of over one year as compared with unfractionated heparin. On repeated administration, there is a recruitment effect on Tissue Factor Pathway Inhibitor (TFPI). This may enhance bleeding tendency.

LMWHs have been characterized by their molecular weight and potency in term of anti-Factor Xa activity. But for the same anti-Factor Xa activity there is a mark variation in anti-Factor IIa activity. Seventy percent of the material in LMWH acts through TFPI and other actions unrelated to anti-Thrombin III. Therefore, all LMWHs are not interchangeable. They can not be switched on the basis of their ant-Factor Xa activity.

Tests for measuring ant-Factor Xa, anti-Factor IIa are available. A simplified test, Heptest is also available. It can be used as a bedside procedure. Since all these tests involved calibration of biological materials, they have to be calibrated by the laboratory. All these tests are expensive. Interpretation of these results will depend on the recommendation of the pharmaceutical firms for reasons given above.

Clinical use of LMWH has to follow the instructions from their supplier based on results of clinical trials. Due to its long half-life, usually one dose at the start of dialysis is enough for a four-hour dialysis treatment. The advantage is also its disadvantage is that there is no need to perform monitoring. In fragile patients, there is doubt whether this recommendation is universally suitable for them. From anti-coagulation point of view there is no significant advantage over conventional heparin.

Dr. Jeffrey s.c. Tsang 11/10/99

Manipulation can be done during dialysis due to short half live of conventional heparin. For example, the maintenance dose can be stopped anytime before the dialysis is finished depending on individual response. Overdose of conventional heparin can be neutralized by protamine, but this is not very effective for LMWH. The only clinical advantage is moderate improvement in lipid profile when used for over a year. Not all lipid abnormalities are improved and much less corrected. The lipid abnormality needs management by other means. Nevertheless, if the haemodialysis unit can afford to use LMWH, it still has an advantage in this respect. There is no strong argument for or against the use of this drug on daily routine haemodialysis treatment.

1. True heparin free with intermittent flushing of the dialysis circuit with normal saline. This acts to remove the activated clotting factors in the dialysis circuit. High blood flow is mandatory.
2. Prime the dialysis circuit and dialyzer with heparin before dialysis and perform heparin free dialysis later. Some residual heparin must be present in the dialysis circuit, depending on the amount of heparin used for priming and the amount of saline used to flush the circuit.

1. Minimal Heparinization.

This uses technique described above but with a much lower upper limit and also a lower limit more close to the baseline clotting time value. A dose of protamine to neutralize the heparin may be used at the end of dialysis treatment.

2. Lower dose of LMWH.

The supplier’s recommendation has to be followed. Individual adjustment is difficult.

 

 

Dr. Jeffrey s.c. Tsang 11/10/99

Anticoagulation in Haemodialysis

3. Regional heparinization.

1. Heparin-Protamine method. At a desired blood flow rate ( usually as low as possible, so as to use less of both of these drugs ), heparin dose is adjusted to give the desired clotting time in the dialysis circuit. The dose of protamine assumes to neutralize the heparin is used. Periodic measurement of clotting time of blood from arterial sampling port to make sure it is not elevated and clotting time of blood from venous sampling port to make sure it is elevated. Dosage of protamine and sometimes heparin has to be adjusted to achieve this result. Post-dialysis protamine has to be given intermittently for the first twelve hours to prevent rebound of anti-coagulation from dissociation of the heparin-protamine complex.
2. Citrate-Calcium Method. The principle is the same for Heparin-Protamine method. Citrate binds with calcium in the blood and blood without free ionized calcium can not clot. Citrate-Calcium complex is dialyzable and lost of calcium will occur. Calcium will be infused to keep the blood ionized calcium level within the safety range. Excess citrate not dialyzed will be returned to the body and may cause alkalosis as it is metabolized to bicarbonate through the citric acid cycle. Citrate is usually in form of Trisodium Citrate. The extra sodium load may cause hypernatremia. Hypocalcaemia may be caused by calcium lost as citrate-calcium complex in the dialysate and as formation of further complexes as excess citrate is returned to the body. The occurrence of these complications can be minimized if we use minimal amount of citrate by checking the clotting as mention above for Heparin-Protamine dialysis.