**1. Introduction**

Heparin-induced thrombocytopenia type II (HIT II) is a severe, life-threatening, immunological drug reaction. HIT II is an important side effect of heparin, the most commonly used anticoagulant agent. As opposed to bleeding caused by heparin overdose, some patients develop a paradoxical complication of heparin treatment – thromboembolism. According to the clinicallaboratory characteristics, there are two types of HIT: type I (HIT I) and type II (HIT II). HIT I is the result of non-immunologic, direct interaction of heparin with the platelet surface. It occurs in approximately 10% of the patients in the first several days of heparin treatment. Thrombocytopenia is mild and resolves within several days with the continuation of heparin therapy. Thromboembolic complications usually do not occur; therefore, it is of minor clinical significance. Contrary, HIT II is immunologically induced (antibody-mediated) and a lifethreatening side effect of heparin therapy, often associated with thromboembolic complications [1]. The HIT may occur during the treatment with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). All patients receiving heparin are exposed to the development of anti-heparin antibodies, irrespective of heparin dosage (prophylactic or therapeutic), type (UFH or LMWH), and method of administration (subcutaneous or intravenous). Since heparin is also used for flushing intravenous lines, it may lead to the development of anti-heparin antibodies in patients who do not receive subcutaneous or intravenous heparin [1, 2]. HIT most often develops in intensive care patients, hemodialyzed patients, and cardiosurgical and orthopedic patients, who usually receive heparin. Heparin-induced thrombocytopenia (HIT) is a clinical-pathologic syndrome diagnosed based on clinical findings and laboratory evidence of antibodies directed to the heparin and platelet factor 4 complex (H-PF4). HIT II may also be defined as a transitory, autoimmune, and heparin-induced thrombocytopenia. Reaching the diagnosis of HIT is a complex process, because thrombocytopenia in patients receiving heparin may be caused by numerous other factors. Although clinical assessment is very important in suspecting HIT, laboratory diagnosis plays the key role in providing evidence for the diagnosis of HIT II [3–5]. HIT II occurs in 0.1–5.0% heparin-treated patients, predominantly in those receiving UFH. It commonly develops after 5–10 days of therapy, but it may also occur earlier during the treatment course if the patient has been exposed to heparin within the previous 100 days (early form). HIT II rarely develops after 20 or more days from the start of the therapy (late form). In HIT II, platelet count decreases by more than 50% from the baseline and ranges from 20 × 109 /L to 100 × 109 /L. HIT II patients are at high-risk of thromboembolic complications, venous and/or arterial, and allergic reactions. In HIT II, thromboembolic complications usually include deep-vein thrombosis and pulmonary embolism, but they also include arterial occlusion of the extremities, myocardial infarction, stroke, and necrosis and organ damage. Vein thrombosis may be found by duplex ultrasound in more than 50% of the patients with no clinical signs or symptoms of thrombosis [1–4]. In one-fourth of the HIT II patients, an allergic reaction may develop within 5–30 min after intravenous heparin administration (fever, chills, and respiratory distress). Rarely, an erythematous plaque or necrosis with pronouncedly painful skin may be observed. Complications related mortality rate was high (20–30%), but it has been significantly reduced in recent years due to the early diagnosis and treatment of HIT with heparin alternative [5, 6].

**1.1. Heparin**

index [6].

**2. Pathophysiology**

cal laboratory indicators.

Heparin is a polymer of varying chain size. Two forms of heparin are used as paharmaceuticals: unfractionated heparin (UFH) that has not been fractionated to sequester the fraction of molecules with low molecular weight, and low molecular weight heparin (LMWH), which undergone fractionation. Either UFH or LMWH can be used in the prevention of thromboembolic events LMWH is preferable. Heparin binds to the enzyme inhibitor antithrombin III (AT) via a specific pentasaccharide sulfation sequence contained within the heparin polymer. The formation of a ternary complex between AT, thrombin, and heparin results in the inactivation of thrombin, factor Xa, and other proteases. In contrast, antifactor Xa activity requires only the pentasaccharide binding site. The highly negative charge density of heparin contributes to its very strong electrostatic interaction with thrombin. For this reason, heparin's activity against thrombin is size-dependent, with the ternary complex requiring at least 18 saccharide units for efficient formation. The rate of inactivation of these proteases by AT can increase by up to 1000-fold due to the binding of heparin. The size difference of heparin has led to the development of low-molecular-weight heparins (LMWHs) and, more recently, to fondaparinux as pharmaceutical anticoagulants. Fondaparinux is a synthetic pentasaccharide, whose chemical structure is almost identical to the AT binding pentasaccharide sequence that can be found within polymeric heparin and heparan sulfate. LMWHs and fondaparinux target anti-factor Xa activity rather than AT activity, with the aim of facilitating a more suitable regulation of coagulation and an improved therapeutic

Heparin-Induced Thrombocytopenia (HIT) http://dx.doi.org/10.5772/intechopen.78024 103

The pathophysiologic mechanism of HIT II is mediated by the formation of heparin-platelet factor 4 (PF4) complexes. The PF4 is a positively charged heterodimer found in platelet alpha granules, and heparin is a negatively charged molecule. The formation of heparin-PF4 complex results in the change in the tertiary structure of the PF4 and exposure of neo-peptide, which elicits the formation of antibodies, usually IgG isotype. The immune heparin-PF4-IgG complexes activate platelets via Fc y IIa receptors. The antibodies may bind to monocytes, which then release tissue factor, the most potent blood clotting factor. Activated platelets release procoagulant microparticles and PF4. Antibodies recognize the complexes, bind to the endothelial cells, and activate the coagulation cascade, which leads to the formation of thrombin and eventually thrombosis. The ability of HIT antibodies to strongly activate platelets

HIT II is most often caused by IgG antibodies targeting heparin-PF4 complex. In patients with HIT antibodies present in the blood, re-administration of heparin causes a rapid decrease in the platelet counts (within hours) to extremely low values. In heparin-treated patients, platelet count should be monitored before and during therapy. Before the specific laboratory evidence of anti-heparin antibodies, the probability of HIT should be determined using clini-

even in the absence of heparin may cause heparin-independent HIT II [7–9].

#### **1.1. Heparin**

**1. Introduction**

102 Anticoagulant Drugs

from 20 × 109

heparin alternative [5, 6].

/L to 100 × 109

Heparin-induced thrombocytopenia type II (HIT II) is a severe, life-threatening, immunological drug reaction. HIT II is an important side effect of heparin, the most commonly used anticoagulant agent. As opposed to bleeding caused by heparin overdose, some patients develop a paradoxical complication of heparin treatment – thromboembolism. According to the clinicallaboratory characteristics, there are two types of HIT: type I (HIT I) and type II (HIT II). HIT I is the result of non-immunologic, direct interaction of heparin with the platelet surface. It occurs in approximately 10% of the patients in the first several days of heparin treatment. Thrombocytopenia is mild and resolves within several days with the continuation of heparin therapy. Thromboembolic complications usually do not occur; therefore, it is of minor clinical significance. Contrary, HIT II is immunologically induced (antibody-mediated) and a lifethreatening side effect of heparin therapy, often associated with thromboembolic complications [1]. The HIT may occur during the treatment with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). All patients receiving heparin are exposed to the development of anti-heparin antibodies, irrespective of heparin dosage (prophylactic or therapeutic), type (UFH or LMWH), and method of administration (subcutaneous or intravenous). Since heparin is also used for flushing intravenous lines, it may lead to the development of anti-heparin antibodies in patients who do not receive subcutaneous or intravenous heparin [1, 2]. HIT most often develops in intensive care patients, hemodialyzed patients, and cardiosurgical and orthopedic patients, who usually receive heparin. Heparin-induced thrombocytopenia (HIT) is a clinical-pathologic syndrome diagnosed based on clinical findings and laboratory evidence of antibodies directed to the heparin and platelet factor 4 complex (H-PF4). HIT II may also be defined as a transitory, autoimmune, and heparin-induced thrombocytopenia. Reaching the diagnosis of HIT is a complex process, because thrombocytopenia in patients receiving heparin may be caused by numerous other factors. Although clinical assessment is very important in suspecting HIT, laboratory diagnosis plays the key role in providing evidence for the diagnosis of HIT II [3–5]. HIT II occurs in 0.1–5.0% heparin-treated patients, predominantly in those receiving UFH. It commonly develops after 5–10 days of therapy, but it may also occur earlier during the treatment course if the patient has been exposed to heparin within the previous 100 days (early form). HIT II rarely develops after 20 or more days from the start of the therapy (late form). In HIT II, platelet count decreases by more than 50% from the baseline and ranges

/L. HIT II patients are at high-risk of thromboembolic complica-

tions, venous and/or arterial, and allergic reactions. In HIT II, thromboembolic complications usually include deep-vein thrombosis and pulmonary embolism, but they also include arterial occlusion of the extremities, myocardial infarction, stroke, and necrosis and organ damage. Vein thrombosis may be found by duplex ultrasound in more than 50% of the patients with no clinical signs or symptoms of thrombosis [1–4]. In one-fourth of the HIT II patients, an allergic reaction may develop within 5–30 min after intravenous heparin administration (fever, chills, and respiratory distress). Rarely, an erythematous plaque or necrosis with pronouncedly painful skin may be observed. Complications related mortality rate was high (20–30%), but it has been significantly reduced in recent years due to the early diagnosis and treatment of HIT with Heparin is a polymer of varying chain size. Two forms of heparin are used as paharmaceuticals: unfractionated heparin (UFH) that has not been fractionated to sequester the fraction of molecules with low molecular weight, and low molecular weight heparin (LMWH), which undergone fractionation. Either UFH or LMWH can be used in the prevention of thromboembolic events LMWH is preferable. Heparin binds to the enzyme inhibitor antithrombin III (AT) via a specific pentasaccharide sulfation sequence contained within the heparin polymer. The formation of a ternary complex between AT, thrombin, and heparin results in the inactivation of thrombin, factor Xa, and other proteases. In contrast, antifactor Xa activity requires only the pentasaccharide binding site. The highly negative charge density of heparin contributes to its very strong electrostatic interaction with thrombin. For this reason, heparin's activity against thrombin is size-dependent, with the ternary complex requiring at least 18 saccharide units for efficient formation. The rate of inactivation of these proteases by AT can increase by up to 1000-fold due to the binding of heparin. The size difference of heparin has led to the development of low-molecular-weight heparins (LMWHs) and, more recently, to fondaparinux as pharmaceutical anticoagulants. Fondaparinux is a synthetic pentasaccharide, whose chemical structure is almost identical to the AT binding pentasaccharide sequence that can be found within polymeric heparin and heparan sulfate. LMWHs and fondaparinux target anti-factor Xa activity rather than AT activity, with the aim of facilitating a more suitable regulation of coagulation and an improved therapeutic index [6].
