Anticoagulation for Hemodialysis

Mechanism of clotting in extracorporeal circuit:

 Clotting of blood in extracorporeal circuit may be initiated when blood comes into  contact with cannulas , lines, and the dialysis membranes.

 Steps of clotting: 1.Coating of the circuit with plasma proteins.

                             2.Platelet adherence and aggregation

                             3.Generation of Thromoxane A2.

                             4.Activation of intrinsic coagulation cascade.

                             5.Thrombin formation and fibrin deposition.

 Predisposing factors:

                         1.Reduced anti coagulant.

                         2.Reduced blood flow rate.

                         3.Increased whole blood hematocrit [EPO therapy]

                         4.Increased extracorporeal hematocrit [excessive ultrafiltration].

                         5.Blood transfusion and Lipid infusion during dialysis..

 Signs of blood clotting in the extracorporeal circuit :

                   1.Dark-colored blood

                   2.Dialyzer :-Presence of black streaks in the dialyzer

                                    -Reduced residual dialyzer  volume

                                    -Presence of clots at arterial header.

                   3.Lines -Foaming at the drip chambers and venous trap.

                               -Clot formation at the drip chambers and venous trap.

                   4.Pressure :-Increased difference between the postpump and venous pressure

                                when there is clots at arterial chamber or the dialyzer.

                                  -Increase in postpump followed by increase in venous pressure

                                if the clots are distal to the venous chamber

                                    -Increased venous pressure when venous needle is clotted

 Anticoagulants

    1- Heparin       a.Crude heparin   b.Low molecular weight heparin

    2 Antiplatelet agents

      a)Protaglandins PGI 2 , PGE 2 ,eporostemol and iloprost

       -Potent inhibitors of platelets aggregation

       -Less effective than heparin

       -Side effects include ; hypotension ,flushing, headache ,nausea and vomiting

      b)Aspirin , NSAID , Sulphinpyrazone and Ticlopidine

      -Antiplatelets + Counteract platelet factor 4 and prevent its heparin neutralizing effects

      -Not suitable to maintain anticoagulation -May be used as heparin sparing

.    3- Protease inhibitors  [Nofomostat, Gabexate]

        -Inhibitors for both coagulation/fibrinolysis cascade and platelet aggregation.

        -Adequate anticoagulant effect and reduce bleeding complications.

     4-Hirudin

        -It is polypeptide thrombin inhibitor.Unlike heparin does not require cofactor to act

        -Does not cause platelet stimulation or aggregation

• Heparin and Heparinization 

Nature of Heparin

 Heparin is an anionic sulfated mucopolysaccharide of variable molecular weight [8000 to 14000 d] .Low Molecular Weight Heparin fractions [4000-6000 d] are obtained from crude Heparin .  Heparin is strongly acidic And is neutralized by strong basic compounds such as protamine ,toluidine and quinidine . The half life is about 90 minutes and the peak anticoagulant activity is reached 5-10 minutes

 Mechanism of action:

  Heparin alone does not have anticoagulant effect. In the blood it combine with a protein fraction called heparin cofactor [antithrombin III].

 The complex of Heparin -Antithrombin III prevents  clotting at the three stages of coagulation 1-It binds and inactivate Thrombin

                   2- It binds and inactivate Activated factor X

                   3-It binds and inactivate Activated factor XI

  Low Molecular Weight Heparin [LMWH] inhibits coagulation Activated factor X , XII and kallikrin, but little inhibition on Thrombin, factor X and XI therefore PTT and thrombin time are minimally prolonged,thus reducing bleeding risk.

 Side effects :

                        Bleeding             Pruritus                Allergy   

                        Osteoporosis      Hyperlipidemia     Thrombocytopenia

  Monitoring clotting times during hemodialysis

 Several laboratory method are used:

 1-Activated partial thromboplastin time [APTT or PTT]

 2-Activated clotting time [ACT]

 3-Lee White clotting time [LWCT]

                               Baseline                        60-85 sec        120-150 sec      4-8 min

   Standard      - During dialysis               120-140          200-250            20-30

  Tight            -During dialysis                 85-105            170-190              9-16

 The goal  is to maintain the PTT or ACT at the baseline value plus 80% during dialysis and plus 40% only at the end of dialysis to minimize bleeding risk after withdrawal of access needles.

 Techniques of heparin administration

   1-Intermittent infusion

   An intravenous loading dose of heparin [25-50 units/kg of body weight] is given via the last needle placed ,and smaller maintenance doses are repeated intermittently throughout the procedure. Clotting times are monitored at intervals and the dose is adjusted accordingly.

  2-Continuous infusion

  The patient is given the loading dose followed by slowly infusion of the maintenance dose to the blood circuit at a constant rate throughout the dialysis .Clotting times are done at intervals and the rate is adjusted accordingly.

  Remarks

1-In continuous infusion the loading dose of heparin is lower than with intermittent .In the former the dose is required only to prolong the clotting times to the baseline plus 80%  while in the later it is required to prolong the clotting times to above the base line plus 80%.

2-The dose of heparin is depending on sensitivity to heparin of the individual patient ,heparin half life and potency of heparin preparation

3-For a patient with an average heparin half life of 1 hour, stopping heparin administration approximately 1 hour prior to the end of dialysis .

4-During heparinization tendency to bleed is potentated by uremic platelet dysfunction and by endothelial abnormalities.

  3- Regional heparinization:

 Administration of heparin “regionally” into the arterial line blood  and neutralizing it by administration of protamin sulfate into dialyzed blood before returns to the patient.

 Protamin is strongly basic compound acts by combining chemically with the strongly acid heparin to form a stable complex with no anticoagulant effect.

 Dissociation of heparin-protamin complex may occur up to 10 hour post dialysis causing bleeding problem, this is called heparin rebound. Flushing ,bradycardia ,hypotension ,and dyspnea are other side effects of protamin .

  4-Tight heparinization:

 Tight or low dose heparinization is indicated for patient at slight to moderate risk for bleeding e.g. pericarditis and recent surgery

Loading dose 10 units/kg  followed by small additional doses according to the target clotting times. Continuous administration is preferable in tight heparinization to avoid fluctuation in clotting during dialysis.

•  Hemodialysis without heparin [heparin free dialysis] :

 Indications In patients with high bleeding risk

       1.Pericarditis 

       2.Recent surgery with bleeding complications or it will be dangerous e.g. cardiac

             vascular , eye ,renal transplant and brain surgery

       3.Blood disease ; coagulopathy , thrombocytopenia

       4.Intracerebral hemorrhage

       5.Any active bleeding

  Methods of heparin free dialysis

  1.Heparin rinse

     a,Rinse the extracorporeal blood circuit with 3000 units heparin/liter

     b.Flush the heparin containing saline with unheparinized saline or patient blood.

  2.High blood flow rate

     Set the blood flow rate as high as possible , 250-300 ml/minute if it can be tolerated.

  3.Saline rinse Rinse the dialyzer with 100-200 ml of saline .Adjust the UF rate to remove the excess fluid