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Heparins and Heparinoids: Occurrence, Structure and Mechanism of Antithrombotic and Hemorrhagic Activities

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Heparins and Heparinoids: Occurrence, Structure and Mechanism of Antithrombotic and Hemorrhagic Activities 1 HEPARINS AND HEPARINOIDS: OCCURRENCE, STRUCTURE AND MECHANISM OF ANTITHROMBOTIC AND HEMORRHAGIC ACTIVITIES Helena B. Nader*, Carla C. Lopes, Hugo A.O. Rocha, Elizeu A. Santos and Carl P. Dietrich Current Pharmaceutical Design vol 10 number 9, 951-966 (2004) Abstract: The correlation between structure, anticloting, antithrombotic and hemorrhagic activities of heparin, heparan sulfate, low molecular weight heparins and heparin-like compounds from various sources that are in use in clinical practice or under development is briefly reviewed. Heparin-like molecules composed exclusively of iduronic acid 2-O-sulfate residues have weak anticloting activities, whereas molecules that contain both iduronic acid 2-O sulfate, iduronic acid and small amounts of glucuronic acid, such as heparin, or mixed amounts of glucuronic and iduronic acids (mollusk heparins) possess high anticloting and anti-Xa activities. These results also suggest that a proper combination of these elements might produce a strong antithrombotic agent. Heparin isolated from shrimp mimics the pharmacological activities of low molecular weight heparins. A heparan sulfate derived from bovine pancreas and a sulfated fucan from brown algae have a potent antithrombotic activity in arterial and venous thrombosis model "in vivo" with a negligible activity upon the serine-proteases of the coagulation cascade "in vitro". These and other results led to the hypothesis that antithrombotic activity of heparin and other antithrombotic agents is due at least in part by their action on endothelial cells stimulating the synthesis of an antithrombotic heparan sulfate. All the antithrombotic agents derived from heparin and other heparinoids have hemorrhagic activity. Exceptions to this are a heparan sulfate from bovine pancreas and a sulfated fucan derived from brown algae, which have no hemorrhagic activity but have high antithrombotic activities "in vivo". Once the structure of these compounds are totally defined it will be possible to design an ideal antithrombotic. INTRODUCTION plasma proteins and lipids, and cells. The red The leading causes of death in the United cells seem not to be a target for antithrombotic States are diseases that involve heart and blood agents, but on the other hand, white cells and vessels, and as a consequence thrombosis [1]. platelets are deeply involved in thrombus The incidence of death for this disease in 1991 formation. was almost two times higher than the next in line, The protease network in coagulation, namely, cancer (Fig. 1). Possibly, with the fibrinolysis and kallikrein-kinin system is introduction of antithrombotic agents, particularly shown in Fig. 2. This cascade of events consists heparin and its derivatives, death by heart of a series of activation of serine proteases and diseases have decreased substantially (about modulation by specific inhibitors, called 30%) in 2000 when compared to malignant serpins. The ultimate goal of the coagulation cancer, which has increased in the last ten years. system is the formation of clot that consists on Nevertheless, heart diseases are still the main the limited proteolysis of a soluble protein from cause of death [1]. This explains the efforts to plasma (fibrinogen) into an insoluble protein discover and develop specific and more potent (fibrin). antithrombotic agents. The anticloting and antithrombotic activity of heparin includes the blood itself, composed of 2 DISEASES OF THE CANCER HEART 1991-500,000 1991-975,000 1999-553,000 1999-725,000 2000-555,000 2000-700,000 CHRONIC OBSTRUCTIVE LEADING CAUSES OTHER CAUSES PULMONARY 400,000 DISORDER OF MORTALITY 1991-90,000 IN USA 1999-124,000 2000-124,000 PULMONARY TRAUMA/ACCIDENT DISEASE (FLU) 90,000 1991-80,000 1999-64,000 2000-62,000 Fig. (1). Causes of Death in USA. Heparin acts as anticoagulant compound disaccharide of αD-glucosamine 2-6-disulfate- because it forms a ternary complex with βD-glucuronic or αL-iduronic acid as shown in antithrombin III and the different serine proteases Fig. 3 [3]. Large variations occur among of the coagulation cascade. The inhibition of heparins isolated from invertebrates and of thrombin by antithrombin is accelerated by more heparins isolated from different tissues and than 1,000 times in the presence of heparin. species of vertebrates (See below). Heparin is also capable of potentiating the effect of another serpin that is called heparin cofactor II that is specific for thrombin. It also releases and OCCURRENCE OF HEPARIN IN increases the synthesis of TFPI (tissue factor VERTEBRATES AND INVERTEBRATES pathway inhibitor) by endothelial cells. Heparin was the first compound used as Whereas heparan sulfates are ubiquitous anticoagulant and antithrombotic agent. Heparin components of all tissue-organized animal life was isolated in 1916 by McLean in Canada from forms [4-6] heparin, has shown a very peculiar a preparation of dog liver [2]. The commercial distribution in mammalian and other vertebrate heparin preparations, introduced in the clinical tissues as well as invertebrates. Since the earlier use 60 years ago, are from hog and bovine studies, lung, intestine, and liver were the intestinal mucosa, as well as bovine lung. tissues rich in heparin from a variety of Chemical and enzymatic analyses and NMR mammals. [5-8]. Table 1 shows a systematic spectroscopy have revealed the main structural study involving nine mammalian species. These features of heparin. In our laboratory we have analyses have shown that except for rabbit shown that bovine lung heparin is mainly (80- tissues, heparin was present in lung, skin, ileum, 90%) composed of hexasaccharide repeats with lymph nodes, thymus, and appendix of all two disaccharides of αD-glucosamine, N,6- species. The absolute content of heparin varied disulfate-αL-iduronic acid,2-O-sulfate, and one in the different tissues. The lack of heparin in 3 INTRINSIC PATHWAY HMWK XII XIIa EXTRINSIC PATH WAY HMWK XI XIa III (Tissue factor) Phospholipid Phospholipid Antithombin III Ca++ IX Ca++ VII IXa VIIa VIIIa Phospholipid/ Ca++ Protein Ca X + Protein S Xa X Va Protein C TFPI Phospholipid/ Ca++ + Thrombomodulin Prothrombin Thrombin II IIa Heparin Cofactor II tPA Fibrinogen Fibrin XIIIa Plasmin Plasminogen Polymerization Depolymerization (Clot) (Fibrinolysis) Fig. (2). Coagulation cascade. rabbits was correlated with the absence of mast contact with the environment or in organs that cells in the species [8]. The amounts of the function as internal barriers against infection heparins isolated from mammalian and other and foreign bodies. vertebrate's tissues are also shown in Table 1. A The anticoagulant activity and molecular large variation on the concentration of heparin weight of some mammalian heparins is shown among species is evident. Thus, bovine and dog in Table 2. It is interesting that the anticoagulant tissues contain the highest amounts of heparin. In activity varied from 60 up to 200 I.U./mg. non-mammal vertebrates the amounts of heparin Likewise the molecular weight of the heparins is considerably less. An interesting characteristic depending on the tissue of origin also shows a is that heparin is mainly distributed in tissues in large variation (11 kDa up to >150 KDa). 4 CH2OSO3H CH2OSO3H COOH CH2OSO3H O O O O O O COOH COOH COOH o o O O OH OH O OH OH O OH OH O----R1 OH OSO3H NSO3H OSO3H NSO3H NSO3H n Fig. (3). Basic hexasaccharide unit of heparin. Table 1. Distribution of heparin in mammalian and other vertebrates TISSUE VERTEBRATE SPECIES (µg/g dry tissue) Rb GP Rat Dog Cat Pig Bov H Ck Sk Lizd Frg Fish Shrk Lung <1 70 67 217 63 211 300 8 0.5 0.3 0 0.64 0.03 Liver <1 <1 <1 141 1 <1 50 <1 0 0 0.02 0.77 1.32 0 Ileum <1 27 1 400 87 113 1015 32 0.5 0.9 0.23 0 0 0 Kidney <1 4 <1 2 6 <1 26 <1 0.1 0 0 0.46 0.29 Aorta <1 <1 9 102 <1 2 150 <1 Brain <1 <1 <1 <1 <1 <1 <1 <1 0 0 0 0 0 0 Muscle <1 <1 36 9 <1 5 2 <1 0 0 0 11.4 0 0 Spleen <1 <1 <1 11 <1 <1 19 <1 0 11.9 Skin <1 <1 175 15 63 2 108 39 0.4 0 0 0 0 0 Lymph n. <1 11 5 160 74 242 180 41 Thymus <1 112 20 20 10 286 35 Appendix <1 17 38 20 47 Branchia 0.03 0 Rb, rabbit, GP, guinea pig; Bov, bovine; H, human; Ck, chicken; Sk, snake; Lizd, lizard; Frg, frog; Shrk, shark As shown in Table 2 there was no correlation a matter of controversy [16]. The peculiar between molecular weight and anticoagulant distribution of heparin between fetal and adult activity of the heparins. All these results imply tissues raised again the question of whether that heparins have a large structural variation these heparins were related to the presence of depending of their origin. In invertebrates heparin mast cells. Studies on the concentration of is found in few species, namely, mollusks heparin and content of mast cells in different (eulamelibranchia), crustacean, annelid, tunicate fetal and adult bovine tissues [17] have shown and possibly urochordate [4, 9, 10-12] (Table 3) that a good correlation between the mast cell Again the anticoagulant activity and molecular number and heparin concentration could be weight varied according to the species analyzed. obtained in all tissues analyzed. A few differences could be observed among the mast HEPARIN AND MAST CELLS cell from the different tissues. The mast cells in adult ileum were usually larger and contained Since the discovery of mast cells by Paul more granules when compared with the mast Ehrlich [13] and that the metachromatic activity cells from fetuses. In fetal spleen, the mast cells of these cells with basic dyes was related to were distributed homogeneously in the whole heparin [14,15], the question whether this organ whereas in adult spleen the mast cells compound was only confined to the mast cells or were only found in the capsule.
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