**5. Treatment**

Treatment of HIT patients is complex. In severely ill, heparin-treated patients who develop HIT II, there is often a misbalance of antithrombotic molecules including protein C, antithrombine III, thrombomodulin, and others. If there is a lack of these regulators, their substitution may increase the anticoagulant effect of heparin alternatives [16]. Clinical assessment plays a key role not only in discerning the platelet count decrease caused by anti-heparin antibodies from the platelet count decrease caused by the underlying disease but also in the selection of anticoagulant agent [17].

According to the clinical practice guidelines on antithrombotic therapy and prevention of thrombosis, if there is laboratory evidence of anti-heparin antibodies, heparin should be discontinued immediately, and replaced by some other non-heparin anticoagulant. Most commonly used alternative anticoagulants are: direct thrombin inhibitors, heparinoids, and factor Xa inhibitors (**Table 3**) [17].

Hirudin is a direct inhibitor of thrombin and acts independently of cofactors such as antithrombin. (19) Therefore, hirudin may be more effective in the presence of platelet-rich thrombi. Hirudin can also inhibit thrombin bound to fibrin or fibrin degradation products.


**Table 3.** Alternative anticoagulants for treatment of heparin- induced thrombocytopenia type II (HIT II).

Lepirudin is a recombinant hirudin and is a highly specific direct and irreversible inhibitor of thrombin. One molecule of lepirudin binds with one molecule of thrombin. Lepirudin is almost exclusively excreted by the kidneys and hence systemic clearance of lepirudin is dependent on the glomerular filtration rate. The drug should be avoided in hemodialysis patients and those with acute renal failure with creatinine clearance <15 ml min−1 (normally 120 ml min−1) or serum creatinine >528 μmol liter−1. The 2006 British Guidelines recommend lepirudin, recombinant protein, and direct thrombin inhibitor to be used as heparin alternatives [12].

of tests, heparin-induced platelet activation (HIPA), and serotonin-release assay (SRA) are the most commonly used tests. They have lower sensitivity, but higher specificity than the first group of tests. In addition to, EIA test result, OD value is also obtained. OD <1.000 indicates the presence of clinically significant antibodies and a high-risk of thromboembolic complications. OD ranging from 0.400 to 0.999 and low clinical 4T indicate low thrombogenic activity of the antibodies and subclinical HIT. Monitoring antibody titres using OD values is used in the preoperative preparation of patients with previously confirmed HIT II; the surgery in which heparin is given is performed after the antibody titter decreases or the test results

To exclude other causes of thrombocytopenia, differential diagnosis should include pseudo thrombocytopenia (artifact), massive pulmonary embolism, disseminated intravascular coagulation (DIK), sepsis, other drug-induced thrombocytopenia (e.g. by GP IIb/IIIa inhibitors), autoimmune or alloimmune thrombocytopenia, post-transfusion purpura, diabetic ketoaci-

Treatment of HIT patients is complex. In severely ill, heparin-treated patients who develop HIT II, there is often a misbalance of antithrombotic molecules including protein C, antithrombine III, thrombomodulin, and others. If there is a lack of these regulators, their substitution may increase the anticoagulant effect of heparin alternatives [16]. Clinical assessment plays a key role not only in discerning the platelet count decrease caused by anti-heparin antibodies from the platelet count decrease caused by the underlying disease but also in the selection of

According to the clinical practice guidelines on antithrombotic therapy and prevention of thrombosis, if there is laboratory evidence of anti-heparin antibodies, heparin should be discontinued immediately, and replaced by some other non-heparin anticoagulant. Most commonly used alternative anticoagulants are: direct thrombin inhibitors, heparinoids, and factor

Hirudin is a direct inhibitor of thrombin and acts independently of cofactors such as antithrombin. (19) Therefore, hirudin may be more effective in the presence of platelet-rich thrombi. Hirudin can also inhibit thrombin bound to fibrin or fibrin degradation products.

Direct thrombin inhibitors (DTI) Hirudin, lepirudin, bivaluridin argartoban

**Table 3.** Alternative anticoagulants for treatment of heparin- induced thrombocytopenia type II (HIT II).

Direct oral anticoagulants(DOACs) Dabigatran, apixaban, rivaroxaban Other Intravenous gamma globulins (IVIG)

Heparionoides Danaparoid Factor Xa inhibitors Fondaparinux

dosis, and antiphospholipid syndrome with thrombocytopenia [16].

become negative [14, 15].

106 Anticoagulant Drugs

**5. Treatment**

anticoagulant agent [17].

Xa inhibitors (**Table 3**) [17].

Bivalirudin is a direct thrombin inhibitor and an analogue of the peptide fragment hirugen, which is a compound derived from hirudin. Unlike lepirudin, the binding of bivalirudin to thrombin is reversible. Bivalirudin binds specifically to the catalytic site and substrate-binding site of thrombin. The US Food and Drug Administration (FDA) has approved bivalirudin for use in patients undergoing coronary angioplasty with unstable angina who are also on aspirin therapy [18].

Argatroban is a direct competitive synthetic inhibitor of thrombin. It binds reversibly to the thrombin catalytic site and therefore, inhibits reactions that are catalyzed or induced by the presence of soluble and clot-bound thrombin. When given i.v. and is metabolized in the liver by cytochrome P450 enzymes it is 100% bioavailable. Unchanged drug is excreted in the urine (16%) and feces (14%). It is eliminated as its metabolite in the feces (65%), presumably through biliary secretion, and in the urine (22%) [17].

It should be taken into account that all non-heparin anticoagulants may also lead to anaphylactic reaction and bleeding. However, unlike heparin, there is no known antidote for these agents and laboratory monitoring of their effects and antibody cross-reactivity is difficult (anti-Xa activity and ellagic time are not standard laboratory tests for hemostasis), in addition to the high price of the substance.

Danaparoid is a low molecular weight heparinoid. It is a mixture of dermatan sulfate, glycosaminoglycans, and chondroitin sulfate. A favorable outcome in 90% of patients with HIT is associated with the use of danaparoid. The main activity of danaparoid is against factor Xa, with the anti-Xa: the anti-IIa ratio of 22:1 resulting in inhibition of fibrin formation. There is a 10–20% cross-reactivity rate with HIT antibodies in vitro although it is less common in vivo. [18].

Coumarin agents (e.g. warfarin) are contraindicated in acute HIT II, because they increase the risk of microvascular thrombosis, necrosis, and gangrene. Replacing UFH with LWMH is also contraindicated in the treatment of HIT II due to the antibody cross-reactivity [12, 13, 18].

Most guidelines suggest the use of argatroban over other nonheparin anticoagulants in patients with HITT and renal insufficiency, and the use of bivalirudin over other nonheparin anticoagulants or heparin plus antiplatelet agents in patients with acute HIT or subacute HIT who require urgent cardiac surgery (Grade 2C) [12, 18, 19].

Recently, the most commonly used agent has been fondaparinux, a synthetic and selective factor Xa inhibitor, which rarely causes anti-heparin antibody cross-reactivity. Clinical experience shows it has beneficial effects in the prevention of thromboembolic complications. The fondaparinux results are an important step in developing the recommendations for the use of alternative agents to heparin, although randomized studies are needed [20, 21].

The use of oral direct thrombin inhibitors in the treatment of HIT II (dabigatran, rivaroxaban, and apixaban) also holds promise. The effectiveness of rivaroxaban in HIT patients was assessed in several studies showing no cross-reactivity with anti-heparin antibodies. Moreover, there was no PF4 release from platelets, as opposed to enoxaparin-LWMH [22, 23]. HIT can be managed with danaparoid in post-cardiac surgery patients. However, in absence of any increase of platelet count after 3–5 days of danaparoid therapy and/or occurrence of a new thrombotic event, danaparoid cross-reactivity with heparin should be suspected and replaced with direct thrombin inhibitor [24].

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There is a dozen of evidence that in some patients with severe HIT II refractory to standard treatment immediate and sustained respond could be achieved by the admission of intravenous gamma globulin (IVIg), most probably mediated by inhibition of platelet activation [25].

According to the literature data, prophylactic platelet transfusions in thrombocytopenic HIT patients are contraindicated. Since spontaneous bleeding in HIT is rare, and platelet transfusions may potentially increase the risk of thrombosis, their use is recommended in case of life-threatening bleeding. Contrary, there is not clear evidence suggested that platelet transfusions should be avoided in a critically ill bleeding patient with HIT. [26].

In a couple of studies, platelet transfusion was administered prophylactically to prevent bleeding in post-surgery patients. These patients experienced no new thrombotic complication but expected post-transfusion platelet count increment was not achieved. Furthermore, previous deep venous thrombosis progressed after platelet transfusion and subsequently led to death in one patient [27].
