**4. Management**

Principles of treatment for patient diagnosed with HIT can be outlined in the following points.


It should be stressed that stopping heparin without initiating anti- Xa inhibitors or DTI therapy is not sufficient for prevention of thrombotic complications.

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 levels.

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 thrombocytopenia.

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.


Table 3. Short description of pharmacokinetic properties of alternative anticoagulants used in treatment of HIT

**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 antidote.

**Fondaparinux**. Fondaparinux also belongs to group of indirect anti-Xa inhibitors but when compared to Danaparoid it does not have anti-thrombin properties. Half-life of Fondaparinux is 17 h. Paradoxically, Fondaparinux can trigger formation of HIT antibodies but its use is still considered to be very effective treatment of HIT.

**R-Hirudins**. Currently, there are two formulations of r-Hirudins available on the market: lepirudin and desirudin. Hirudins belong to DTI and have very high affinity to thrombin including molecules bonded to fibrin. This high affinity makes binding practically irreversible. Half-life of R-Hirudins is 80 min., they are eliminated almost exclusively by kidneys. In patients with kidney dysfunction half-life of r-Hirudins is totally unpredictable. R-hirudins are highly efficacious but treatment is complicated by high incidence of hemorrhagic complications (15%). Literature reports on several cases of lethal anaphylactic reactions complicating re-exposure to Hirudins.

**Argatroban**. When compared to Hirudins, Argatroban bindings to thrombin are reversible. Drug is primarily metabolized and excreted by liver therefore is recommended for use in patients with kidney dysfunction or failure. Frequency of major bleeding complicating argatroban therapy is 8%, more over patients treated with Argatroban have high incidence of limb amputation. Most likely it is related to difficulties in achieving therapeutic level and fact that Argatroban artificially elevates values of INR. It may compromise safe overlap and transition from Argatroban therapy to Coumadin. Experience with Argatroban used for cardiac surgical procedures is highly unfavorable.

**Bivalirudin**. Bivalirudin belongs to reversible DTI and among all agents used for HIT therapy presents most favorable pharmacokinetic profile. It has short half-life (25 min) and is primarily metabolized by plasma enzymatic degradation. It makes it drug of choice in patients with kidney and/or liver dysfunction (i.e. ICU patients). On the other hand due to plasma enzymatic degradation of bivalirudin any blood anticoagulated with this agent, which in stagnation will eventually clot. This property requires alternative approaches during CPB: the pump suckers must be replaced with cell saver and cardioplegia pump must be continuously flushed. Additionally, presence of clots in pericardium (stagnated blood) does not indicate that patient is not adequately anticoagulated. Therapy with Bivalirudin should be monitored with Ecarin Clotting Time (ECT), which is not available in many institutions. As an alternative one can use direct DTI assay or aPTT or plasma modified ACT if Bivalirudin is to be used for CPB purposes. Properties of Bivalirudin make it agent of choice for cardiac surgical procedures in HIT-positive patients who cannot be rescheduled beyond time when HIT antibodies disappear.
