**5. HIT patient for CPB**

216 Perioperative Considerations in Cardiac Surgery

The fundamental difference between heparin and Xa inhibitors or DTIs lies in the mechanism of their action. Heparin requires a cofactor, which is called antithrombin- III (ATIII), additionally it can not bind to thrombin, which is already attached to a fibrin network. A long half-life and a stable level of anticoagulation characterize indirect factor Xa inhibitors, similar to heparin since they also require ATIII. The pharmacokinetic profile of anti-Xa inhibitors makes them favorable to use in the ICU setting (one dose a day). On the other hand, the fact that they do not have antidote may complicate clinical management in case patient requires surgical intervention. Specific assays are available to measure drug

The second group of medications DTIs bind and inhibit thrombin directly by connecting to 2 active exosites. They have a short half-life and may interfere with the thrombin-induced protein C pathway. Similar to indirect Xa inhibitors, DTIs do not have an antidote, therefore their action cannot be reversed. All these agents can be safely used in patients with

Currently there are five main drugs used for HIT therapy: danaparoid, fondaparinux, bivalirudin, argatroban and hirudins. Danaparoid and fondaparinux belong to ATIIIdependent anti-Xa inhibitors, lepirudin, bavalirudin and argatroban belong to group of DTI. Danaparoid, lepirudin and argatroban are approved for treatment of HIT, bivalirudin and fondaparinux are not but have high rationale to be used for HIT therapy. Those five agents will be discussed below; additionally their brief characteristics are presented in Table 3.

**Non-thrombin Inhibitors** 

**Direct Thrombin Inhibitors** 

Table 3. Short description of pharmacokinetic properties of alternative anticoagulants used

**Danaparoid**. Danaparoid is a mixture of several glycoaminoglycans, mainly haparan sufate. It has both anti-thrombin and anti- Xa properties but later predominates. It can be given as subcutaneous or intravenous injection and has long half-life (25h). Danaparoid has a unique property; in therapeutic concentration it can inhibit platelet activation caused by HIT antibodies, stopping vicious circle of thrombotic complications. It is usually administered once a day and first dose should be given intravenously to rapidly achieve therapeutic concentration. Similar to other agents used for treatment of HIT Danaparoid has no

Danaparoid Ancrod

T1/2 Elimination 7-25 hrs 3-5 hrs, >24 hr Monitoring Anti Xa levels Fibrinogen Reversal incomplete with protamine FFP, cryo

 r-hirudin Argatroban Bivalirudin Thrombin binding Irreversible Reversible Reversible Metabolism Renal Hepatic Plasma, renal

T1/2 Elimination 40-120 min 25-50 min 25 min Monitoring aPTT, ECT aPTT, ACT ECT, kACT

levels.

thrombocytopenia.

in treatment of HIT

antidote.

One of the most challenging situations facing cardiac anaesthesiologists is intra-operative management of the patient who requires a cardiac surgical procedure who is HIT positive. Whenever possible it is recommended to delay surgery until the HIT antibodies have cleared (on average 100 days). Unfortunately, in some clinical situations it is not possible; for example: left main stenoses with symptoms of unstable angina, rapidly progressing endocarditis or heart transplantation are among the most common clinical scenarios. Among all of the presented agents (see **Table 3**), none of them is approved for anticoagulation during cardiopulmonary bypass (CPB). Therefore therapy with DTIs or indirect anti Xa inhibitors during cardiac surgery with use of CPB should be considered as an "off-label" application for these drugs. All of them have been used in different doses with varying protocols and outcomes were not always favorable. Their recommended doses and protocols for clinical use are presented in **Table 4.** When comparing all of these agents, Bivalirudin appears to offer that most favorable outcome with respect to control of anticoagulation during extracorporeal circulation. The features of Bivalirudin, which makes it a favorable agent for use with CPB are: a short half-life and metabolism that is independent from kidney and liver function. A protocol based on data from the literature and our own experience is presented in the **Appendix 1.**


Table 4. Dosages of alternative anticoagulants used for patients who are HIT positive and require cardiac surgery with the use of cardiopulmonary bypass

It should be mentioned that there are some reports in the literature recommending the use of strategies other than using a DTI or indirect Xa inhibitor for anticoagulation during CPB. The most encouraging of those are: use of plasmapheresis prior to CPB to clear all HIT antibodies followed by use of regular doses of heparin or to use a prostacyclin infusion combined with antiplatelet therapy with GPIIb/GPIIIa inhibitors.


**Appendix 1 Scheme of CPB approach with bivalirudin anticoagulation for HIT** 

Appendix 1.

218 Perioperative Considerations in Cardiac Surgery

protocols and outcomes were not always favorable. Their recommended doses and protocols for clinical use are presented in **Table 4.** When comparing all of these agents, Bivalirudin appears to offer that most favorable outcome with respect to control of anticoagulation during extracorporeal circulation. The features of Bivalirudin, which makes it a favorable agent for use with CPB are: a short half-life and metabolism that is independent from kidney and liver function. A protocol based on data from the literature

and our own experience is presented in the **Appendix 1.**

**Anticoagulant Dosages for CPB**

Infusion 7 units kg-1 h-1 iv on CPB

Ancrod Infusion 8.4 units h-1 x 12hrs preoperatively check fibrinogen

Additional bolus to maintain ECT Stop infusion before end of CPB

Stop infusion before end of CPB

Stop infusion before end of CPB

Table 4. Dosages of alternative anticoagulants used for patients who are HIT positive and

It should be mentioned that there are some reports in the literature recommending the use of strategies other than using a DTI or indirect Xa inhibitor for anticoagulation during CPB. The most encouraging of those are: use of plasmapheresis prior to CPB to clear all HIT antibodies followed by use of regular doses of heparin or to use a prostacyclin infusion

If clotting noted additional bolus 1250 units Stop infusion 45 minutes before end of CPB

Infusion 0.5 mg min-1 iv, maintain ECT > 400s

Additional 2 mg iv boluses to maintain ACT

Infusion 2.5 mg kg-1 h-1 iv, maintain ECT > 400s

Infusion 5-10 ug kg-1 min-1 iv, maintain ACT > 400s

Stop infusion preoperatively once the target fibrinogen level of

If fibrinogen > 0.8 gm L-1 restart the infusion at 2.1 units h-1

Danaparoid Bolus 125 units kg-1 iv, post thoracotomy CPB prime 3 units ml-1

levels q 4hrs

Hirudin Bolus 0.25 mg kg-1, pre cannulation

Bivalirudin Bolus 1.5 mg kg-1 iv, pre cannulation CPB prime 50mg

require cardiac surgery with the use of cardiopulmonary bypass

combined with antiplatelet therapy with GPIIb/GPIIIa inhibitors.

0.4-0.8 gm L-1 is reached

CPB prime 0.25 mg kg-1

Argatroban Bolus 0.1 mg kg-1 iv, 20 minutes pre cannulation

CPB prime 0.05 mg kg-1
