Many other substances of pharmacological interest have been characterized and described [ 28 ]. Among different anticlotting molecules from leeches and involved in the coagulation cascade, fibrinolysis, or on the platelet aggregation process, three substances have been the main focus of investigation. They are hirudin a thrombin inhibitor [ 29 ], antistasin factor Xa inhibitor [ 30 ], and decorsin an antagonist of the llb-llla glycoprotein of the platelet membrane [ 31 ].
The amino acid sequences of these substances, together with studies of inhibitory activities from different molecules and designs of the three-dimension structure have been determined, and, then, the structural similarity of these molecules was observed, allowing for the design of a structure motif L.
However, the mechanisms of action of these inhibitors and important epitopes for the connection to their respective targets are distinct [ 32 ], demonstrating the relevance of the many inhibition mechanisms on clotting processes, as well as the evolution of these processes. Many of these substances that come from leeches have been developed by the industry, as targets for different therapies and in different clinical trial stages.
Thrombin is a key enzyme on the pathogenesis of coronary acute thrombosis. Therapies with heparin, an indirect thrombin inhibitor, have been used during the last four decades. Search for new alternatives has demonstrated that the development of direct thrombin inhibitors DTIs is a translational success story; an example in which the combination of scientific ingenuity, structure-based design including leech molecules models , and rigorous clinical trials has created a new class of anticoagulants that has improved patient care [ 33 ].
Hirudin was discovered on the salivary glands of the Hirudo medicinalis leeches in [ 34 ], and its role as a powerful antithrombotic drug started to be investigated on the s. Markwardt in started studies with hirudin as a direct agent on the inhibition of thrombin DTI , and these studies have been progressing significantly [ 28 , 29 ]. Hirudin is a natural peptide with a simple chain, featuring 65 with three disulfide bridges and one residue of sulfated tyrosine amino acid residues.
Part of its N-terminal region is globular and very compact, due to the presence of three disulfide bridges. On the other hand, the C-terminal region is made up of a great number of negatively charged residues [ 35 , 36 , 37 , 38 ]. More than years after its discovery, the cDNA of hirudin was cloned and the recombinant rH obtained in large scale on Escherichia coli [ 39 ], on Saccharomyces cerevisiae [ 40 ], and, more recently, on Acremonium chrysogenum [ 41 ].
Its way of action has been extensively compared to low-molecular-weight heparins. Preclinical evaluation and rH clinical selection of analog forms have been improved on the last years [ 43 ]. The complex formed between hirudin and thrombin involves the three amino acid residues from the N-terminal region, which link near to the active site, and the C-terminal tail is linked to the fibrinogen-linking site.
Crystallographic studies have shown that 10 residues of amino acids of the C-terminal portion residues 55—65 react with the anion present on the exosite of thrombin, an important region for linking to fibrinogen. These types of interaction explain why hirudin links only to thrombin and not to the blood semiproteases [ 44 ]. A significant advance was reached with the resolution of the tridimensional structure of hirudin, which allowed for the understanding and development of recombinants equivalent to this protein rH.
The increase of interest on protein inhibitors also was due to studies that demonstrated thrombocytopenia induced by heparin. The use of rH has been promising in patients with unstable angina [ 46 ]. Lepirudin Refludan is an rH, and it was the first direct thrombin inhibitor DTI licensed for treatment of thrombosis complicating HIT and associated thromboembolic disease in order to prevent further thromboembolic complications [ 47 ].
It is given as an intravenous infusion with or without a bolus, and its dosing is dependent on body weight. It is renally excreted and dose adjustments are required in patients with renal impairment [ 48 ]. Significant limitations to its use are its narrow therapeutic window and potential for increased bleeding events [ 49 ].
Besides, it is a drug that forms immunogenic complexes and causes a delay in renal excretion causing its accumulation [ 50 , 51 ]. Therefore, during the treatment, the dose adjustment based on aPTT is recommended. Although not common, anaphylaxis can also occur in patients with hirudin-induced antibodies during the re-exposition to drug [ 52 ]. To date, there are no reports of antidotes that reverse these effects of DTIs [ 53 ].
There are recent reports that lepirudin has been discontinued from the market [ 54 , 55 ]. Desirudin Iprivask is also an rH, with very similar characteristics as lepirudin. Both rH are structurally identical except for their N-terminus sequences, which are Leu1-Tyr2 in lepirudin and Val1-Val2 in desirudin. It reversibly binds to the active thrombin site of free and clot-associated thrombin. Desirudin is able to inhibit different actions of thrombin as fibrin formation, activation of coagulation factors V, VII, and XIII, and platelet aggregation, resulting in a dose-dependent prolongation of aPTT.
It is the only fixed-dose subcutaneously administered DTI approved by FDA for postoperative prevention of VTE in patients undergoing elective hip replacement surgery [ 56 ]. Eriksson and collaborators published two clinical studies comparing the efficacy and safety of desirudin 15 mg s.
After 8—12 days of treatment, desirudin proved to be superior to both heparin anticoagulants, while showing a similar safety profile [ 57 , 58 ]. Recently, desirudin was also under investigation as a potential anticoagulant for patients with heparin induced-thrombocytopenia HIT with or without thrombosis.
This is a small, randomized, open-label trial comparing the clinical efficacy, safety, and economic utility of fixed-dose s. However, just as lepirudin, desirudin is also renally excreted; there is still a risk of accumulation if the renal function is impaired [ 59 ].
Bivalirudin, formerly named Hirulog, is not properly a molecule from leech, but is a synthetic peptide 20 amino acids [ 60 ] and bivalent analog of hirudin with a thrombin inhibition activity nearly times weaker than that of hirudin [ 61 ].
Unlike the rH, the binding of bivalirudin to thrombin is reversible, and after the binding, the inhibitor is slowly cleaved by thrombin. Then, thrombin activity is only transiently inhibited and its enzymatic activity is restored. This reversible relationship between bivalirudin and thrombin can be seen as a benefit, once may contribute to its decreased bleeding risk when compared with rHs [ 62 , 63 ].
Another advantage of bivalirudin was demonstrated in animal studies, where bivalirudin presented a wider therapeutic index than rHs, and an additional advantage of bivalirudin was its lack of immunogenicity [ 64 ].
Bivalirudin has been further studied in other kind of surgeries, but has not been further developed for these indications. Some examples of clinical studies with bivalirudin were as an alternative to heparin in coronary artery bypass [ 68 , 69 ] in a dose-finding study for VTE prevention in patients after hip or knee surgery [ 70 ] and for the treatment of calf vein thrombosis [ 71 ].
Besides hirudin, other thrombin inhibitors less studied have been isolated from leeches. Among them are a granuline-similar peptide [ 73 ], bufrudin [ 74 ], theromin [ 75 ], and haemadin [ 76 ]. Haemadin and theromin are inhibitors and do not present homology in their sequences with the other inhibitors described up to now in all animal kingdom.
Haemadin was isolated from the Haemadipsa sylvestris , leech, and it is a 5 kDa peptide with a Ki of fM, kinetically less efficient than hirudin 21 fM [ 76 , 77 ].
In addition, in literature, we can find only studies about crystal of haemadin and formation of haemadin-thrombin complex, nothing more besides [ 78 , 79 ]. It is homodimer 67 amino acid residues, with 16 cysteines that share 8 disulfide bridges. Just like hirudin, the N-terminal sequence of theromin is highly negatively charged and its C-terminal portion is very compact, due to 10 residues of cysteine present on the sequence.
Hence, considering the low identity on the general sequence between theromin and the peptides of this family, it is difficult to include theromin as a new member of the mentioned family.
However, comparisons of sequences have been made between theromin and four different serine-protease inhibitors isolated from T. It can also be added that among the leeches from the Theromyzon genus, three other thrombin inhibitors were also described [ 84 ]. In fact, Merck Company, in , deposited patents for different applications observing three thrombin inhibitors with masses of 3, 9, and 14 kDa [ 28 ].
This 9 kDa inhibitor features a pI of 4. While FXa inhibition has emerged as a convenient pathway for management of VTE, currently three FXa inhibitors are available for anticoagulation management—rivaroxaban, apixaban, and edoxaban [ 85 ].
New researches about FXa inhibitors of hematophagous animals constantly have been sought. Antistasin was the first factor Xa inhibitor described that originates from leeches. It is a 15 kDa protein isolated from the salivary glands of the Mexican leech H. Soon after, a homologous protein, ghilanten, was isolated from the H. Of the nine residues of the C-terminal — , domain portion four was positively charged [ 86 ], and their active site was located on domain I [ 88 , 89 , 90 ].
The cDNA of antistasin was cloned [ 89 ] and the recombinant protein expressed in system of baculovirus vector in insect cells [ 90 ]. Pharmacological studies were carried out, and data showed that the protein remains active after 30 h of injection in animals.
Besides this, when tested in different thrombosis models, antistasin proved superior to heparin [ 91 ]. Administration of recombinant antistasin in rabbits with atherosclerosis in the femoral artery, as an example, demonstrated reduction of restenosis after balloon angioplasty [ 91 ].
Besides this, chimeric peptides corresponding only to domain I were also tested, and it was checked that domains II and III do not feature any intrinsic inhibitory activity over factor Xa, and also do not contribute to activity of domain I [ 86 ]. The most powerful synthetic peptide derived from antistasin corresponds to amino acids 27—49, with a disulfide bridge ATS29—47 ; this peptide was able to inhibit factor Xa with a Ki of 35 nM.
The cDNA bp encodes 82 amino acids polypeptide with 16 of them being cysteines preceded by 19 residues representing the signal peptide. Therefore, just as other inhibitors, therostasin is expressed and kept in cells from the salivary glands of leeches [ 82 ]. Vizottin is a FXa inhibitor from the salivary complex of the leech Haementeria vizottoi. It has shown anticoagulant effects in human plasma, prolonging the recalcification time in a dose-dependent manner IC50 40 nM.
Vizottin was able to induce blood incoagulability in FX-deficient plasma, whereas in normal and reconstituted plasma, vizottin doubled the prothrombin time at nM. It is a compound which is also able to inhibit FXa in the prothrombinase complex and Gla-domain less FXa. The authors demonstrated that the inhibition of FXa by vizottin is through binding to the active site rather than an exosite.
The structure of this molecule still need to be better studied [ 93 ]. A FXa inhibitor has been described in leech that are proven not part of the antistasin-family, the Lefaxin. This inhibitor was obtained from the salivary glands of the Brazilian leech, Haementeria depressa. It is a competitive inhibitor of FXa with a Ki of 3.
It has a simple chain with 30 kDa and pI of 5. Among the FXa inhibitors from leeches, antistasin was the one that came closest to drug development; however, it did not get there. Even if these natural substances, as antistasin, are not being directly used in the human medical clinic, it was through the study of them that synthetic molecules focused on FXa were and are still being designed. This has provided potent and selective tools for evaluating the potential role of FXa in various diseases.
In addition, these advances have been instrumental in defining the biology of FXa and have aided in the discovery of specific receptors and intracellular signaling pathways for FXa that may be important in the progression of, or the response to, various diseases [ 95 ]. Leech antiplatelet protein LAPP is a specific inhibitor by collagen pathway from Haementeria officinalis leech salivary glands.
It has around 13 kDa and pI 4. In spite of this, rLAPP inhibits platelet deposition to cross sections of human atherosclerotic coronary arteries [ 99 ], and studies in baboons proved that rLAPP did not block collagen graft thrombosis, suggesting that inhibition of collagen alone is not enough to prevent thrombosis, possibly because TF exposure plays an important role in the model [ ]. The crystal structure of LAPP has been determined and consists of a C-terminal domain which is very compact and a disordered N-terminal region [ ].
Calin is isolated from the salivary secretion of the European leech H. The recombinant Saratin was obtained in yeasts Hansenula polymorpha [ ] and it is being commercialized by BioVascular which has developed this product to GMP standards and is evaluating the effects in clinical studies [ ]. To date, in the literature, only a few animal studies have been published, where it has been given alone or together with other drugs in glaucoma rabbit models [ , ].
Saratin, when administrated alone in rat carotid endarterectomy model, significantly decreased platelet adhesion, intimal hyperplasia, luminal stenosis, and thrombosis. This inhibitor did not increase suture line bleeding or bleeding times, and did not decrease platelet counts.
In this study, the authors also have concluded that Saratin may serve as a topical agent to be used for the site-specific inhibition of thrombosis and intimal hyperplasia after vascular manipulation [ ].
Disintegrins were first discovered in snake venoms where they are very well studied, and were instrumental in our understanding of integrin function and also for the development of antithrombotic drugs [ ].
However, this molecule class also has been found in bloodsucker animals. In leeches, there are two more studied molecules with this profile, decorsin and ornatin. This disintegrin, like snake family of inhibitors, has six cysteines and an RGD motif near its C-terminus.
The secretion of decorsin in the salive of this animal probably is one of its strategy to keep host blood flowing or to keep ingested blood from clotting, as leeches store ingested blood for long periods of time [ 31 ].
The structure of decorsin was determined by nuclear magnetic resonance NMR and it is interestingly similar to that of hirudin from Hirudo medicinalis leech [ 32 ]. Studies with the recombinant protein demonstrated that the native disulfide bonds are required for the optimal GPIIb-IIIa antagonist activity of the ornatin [ ].
As described in this chapter, various thrombin inhibitors from hematophagous animals together with other kind of anticoagulant as FXa inhibitor and anti-platelets not only maintain anticoagulant potential of the salivary gland secretions but also play a role of blood preservatives in the gut channel of the bloodsuckers. On the other hand, little is known on the degradation of fibrinogen and fibrin by secretions of bloodsuckers.
Factor XIIIa promotes the covalent crosslinking of fibrin polymers and incorporation of proteins into the fibrin network and thus the thrombus can be stable and relative resistance to plasmin-mediated degradation.
Tridegin was discovered in salivary glands of blood-sucking leech, Haementeria ghilianii. It is a highly specific inhibitor of factor XIIIa with about 7 kDa, this inhibitor works with effective concentrations in the nanomolar range [ ]. It was also related the presence of transcripts similar to tridegin in some transcriptome analysis of other leeches specie [ 12 ], but the obtaining of new molecules from leeches with this function was not yet published. Some tridegin analog peptides have been synthesized and analyzed for their action improvement, but so far, nothing very relevant has been exposed [ ].
Although not used in clinical trials on its recombinant form T , a derivative of tridegin is being marketed by more than one company for use in laboratory research. Hementin is responsible for proteolysis of blood fibrinogen with formation of products which block conversion of fibrinogen into fibrin catalyzed by thrombin; this molecule was discovered in salivary gland from Haementeria ghilianii [ ]. Since fibrinogen is involved in the formation of platelet clot, hementin is able to prevent the platelet aggregation induced by ADP and collagen; on the other hand, it can also induce disaggregation of platelet aggregation induced by ADP, but not collagen [ ].
Hementin can lyse fibrin clots; but its fibrinolytic activity is less potent than the fibrinogenolytic one. It does not influence the activity of other plasma proteins [ ].
Study of lysis of clots formed from PRP revealed that in the presence of tridegin the effect of fibrinolytic enzymes was the same as in PPP, whereas lysis of platelet-containing clots occurred slower. Thus, the importance of the platelets in the resistance of plasma clots to fibrinolytic enzymes and also the importance of cross-linking in this process [ ].
Considering that both molecules are obtained in the same leech species, it was suggested that hementin and tridegin have a synergic action in feeding process of Haementeria ghilianii. They may be considered as promising thrombolytic agents. However, their activities differ somewhat in terms of kinetics and with regard to the structure of the fibrin ogen fragments they may produce.
Cleavage by HT of fibrinogen A-alpha, gamma, and B-beta chains, in that order, produces fragments differ from those produced by plasmin. HT was also able to degrade cross-linked fibrin although at a lower rate as compared to fibrinogen.
HT is a plasminogen-independent fibrino geno lytic metalloproteinase that degrades fibrinogen faster than fibrin, prevents the coagulation and destroys fibrin clots in vitro [ ]. Destabilase was discovered in salivary glands from Hirudo medicinalis and it was able to hydrolyze the epsilon- gamma-glutamyl -lysine bonds as a result of fibrin stabilization by FXIIIa in the presence of calcium ions [ ].
It was characterized as a polyfunctional molecule and is a unique representative of invertebrate lysozymes. This molecule combines the properties of endo-s-lysyl-y-glutamyl isopeptidase D-dimer monomerase , lysozyme, and chitinase and simultaneously is also a non-enzymatic antimicrobial agent. Its ability to hydrolyze endoisopeptide bonds formed by transglutaminases, which are involved in many pathological conditions, including thrombosis, causes this enzyme to become a focus to seek its use in practice [ ], on the other hand, none was presented after that.
The substrate of destabilase is the D-D-dimer, a protein of kDa that contains fragments of all three chains of monomer fibrin alpha, beta, and gamma and there is a nonlinear dependence of the reaction rate on substrate concentration.
The crosslinked fibrin is also a substrate of destabilase, which catalyzes hydrolysis of isopeptide bonds connecting gamma-gamma and alpha-alpha-chains of this protein [ , ].
Recently, a study demonstrated an optimization procedures related to the expression, isolation, and purification of active destabilase isoforms mlDL-Ds1, 2, 3 using an Escherichia coli expression system, where their muramidase, lytic, isopeptidase and antimicrobial activities were detected and compared. Analyses of the tested activities revealed that all isoforms had almost identical patterns of pH and ionic strength effects.
It was determined that three isoforms possessed non-enzymatic antibacterial activity independent of their muramidase activity. It was also demonstrated, for the first time, the fibrinolytic activity of the recombinant destabilase and showed that only intact proteins possessed this activity, suggesting being an enzymatic property [ ].
Most anticoagulants from ticks are produced for the salivary glands and play essential functions during feeding. Ticks inject the saliva into the skin of a wide range of terrestrial vertebrates and absorb it along with the blood of the animal. Faced with an injury inflicted by tick bite, the animal respond by activating blood coagulation, vasoconstriction, inflammation, and tissue remodeling related to wound healing.
However, these ectoparasites have a complex and potent pharmacological mechanism to overcome the host defenses, blocking pain and itch and facilitating blood flow to allow the feeding [ 25 , , ].
Differences in the composition of tick saliva are reflected in the co-evolution between ticks and their host, the feeding strategies, the tick developmental stage, the process of penetration of the host skin, and the duration of the feeding. This can be observed between the two major families, Argasidae and Ixodidae.
The first family family Argasidae is called soft ticks. They feed fast, less than 1 h, for multiple times causing profound damage to the host skin due the deep mouthparts penetration, while hard ticks family Ixodidae feed for a prolonged period days to weeks in each developmental stage. Hard ticks have strategies to firmly attach to its host, producing large amount of cement or glue to penetrate the host skin and cause a superficial damage Metastriata ticks, e.
Females hard tick feed only once and may ingest more blood than times their initial body weight to die later after oviposition Prostriata, e. Ticks saliva has other strategies besides inhibiting blood coagulation factors, in order to facilitate the feeding. Finally, factor VIII antihemolytic factor A from the platelets and endothelial cells combines with factor IX antihemolytic factor B or plasma thromboplasmin to form an enzyme complex that activates factor X Stuart—Prower factor or thrombokinase , leading to the common pathway.
The events in the intrinsic pathway are completed in a few minutes. Both the intrinsic and extrinsic pathways lead to the common pathway , in which fibrin is produced to seal off the vessel. Once factor X has been activated by either the intrinsic or extrinsic pathway, the enzyme prothrombinase converts factor II, the inactive enzyme prothrombin, into the active enzyme thrombin.
Note that if the enzyme thrombin were not normally in an inactive form, clots would form spontaneously, a condition not consistent with life.
Then, thrombin converts factor I, the insoluble fibrinogen, into the soluble fibrin protein strands. Factor XIII then stabilizes the fibrin clot. The stabilized clot is acted upon by contractile proteins within the platelets. As these proteins contract, they pull on the fibrin threads, bringing the edges of the clot more tightly together, somewhat as we do when tightening loose shoelaces see Figure 1a.
This process also wrings out of the clot a small amount of fluid called serum , which is blood plasma without its clotting factors. To restore normal blood flow as the vessel heals, the clot must eventually be removed. Fibrinolysis is the gradual degradation of the clot. Again, there is a fairly complicated series of reactions that involves factor XII and protein-catabolizing enzymes. During this process, the inactive protein plasminogen is converted into the active plasmin , which gradually breaks down the fibrin of the clot.
Additionally, bradykinin, a vasodilator, is released, reversing the effects of the serotonin and prostaglandins from the platelets. This allows the smooth muscle in the walls of the vessels to relax and helps to restore the circulation.
An anticoagulant is any substance that opposes coagulation. Several circulating plasma anticoagulants play a role in limiting the coagulation process to the region of injury and restoring a normal, clot-free condition of blood. For instance, a cluster of proteins collectively referred to as the protein C system inactivates clotting factors involved in the intrinsic pathway. TFPI tissue factor pathway inhibitor inhibits the conversion of the inactive factor VII to the active form in the extrinsic pathway.
Antithrombin inactivates factor X and opposes the conversion of prothrombin factor II to thrombin in the common pathway. And as noted earlier, basophils release heparin , a short-acting anticoagulant that also opposes prothrombin. Heparin is also found on the surfaces of cells lining the blood vessels. A pharmaceutical form of heparin is often administered therapeutically, for example, in surgical patients at risk for blood clots. View these animations to explore the intrinsic, extrinsic, and common pathways that are involved the process of coagulation.
The coagulation cascade restores hemostasis by activating coagulation factors in the presence of an injury. How does the endothelium of the blood vessel walls prevent the blood from coagulating as it flows through the blood vessels?
Either an insufficient or an excessive production of platelets can lead to severe disease or death. As discussed earlier, an insufficient number of platelets, called thrombocytopenia, typically results in the inability of blood to form clots. This can lead to excessive bleeding, even from minor wounds. Another reason for failure of the blood to clot is the inadequate production of functional amounts of one or more clotting factors.
This is the case in the genetic disorder hemophilia , which is actually a group of related disorders, the most common of which is hemophilia A, accounting for approximately 80 percent of cases. This disorder results in the inability to synthesize sufficient quantities of factor VIII. Hemophilia B is the second most common form, accounting for approximately 20 percent of cases. In this case, there is a deficiency of factor IX.
Both of these defects are linked to the X chromosome and are typically passed from a healthy carrier mother to her male offspring, since males are XY. Females would need to inherit a defective gene from each parent to manifest the disease, since they are XX. Patients with hemophilia bleed from even minor internal and external wounds, and leak blood into joint spaces after exercise and into urine and stool.
Hemophilia C is a rare condition that is triggered by an autosomal not sex chromosome that renders factor XI nonfunctional. It is not a true recessive condition, since even individuals with a single copy of the mutant gene show a tendency to bleed.
Regular infusions of clotting factors isolated from healthy donors can help prevent bleeding in hemophiliac patients. At some point, genetic therapy will become a viable option. In contrast to the disorders characterized by coagulation failure is thrombocytosis, also mentioned earlier, a condition characterized by excessive numbers of platelets that increases the risk for excessive clot formation, a condition known as thrombosis.
While the formation of a clot is normal following the hemostatic mechanism just described, thrombi can form within an intact or only slightly damaged blood vessel. In a large vessel, a thrombus will adhere to the vessel wall and decrease the flow of blood, and is referred to as a mural thrombus.
In a small vessel, it may actually totally block the flow of blood and is termed an occlusive thrombus. Thrombi are most commonly caused by vessel damage to the endothelial lining, which activates the clotting mechanism. These may include venous stasis, when blood in the veins, particularly in the legs, remains stationary for long periods. This is one of the dangers of long airplane flights in crowded conditions and may lead to deep vein thrombosis or atherosclerosis, an accumulation of debris in arteries.
Thrombophilia, also called hypercoagulation, is a condition in which there is a tendency to form thrombosis. This may be familial genetic or acquired. Acquired forms include the autoimmune disease lupus, immune reactions to heparin, polycythemia vera, thrombocytosis, sickle cell disease, pregnancy, and even obesity. A thrombus can seriously impede blood flow to or from a region and will cause a local increase in blood pressure. If flow is to be maintained, the heart will need to generate a greater pressure to overcome the resistance.
When a portion of a thrombus breaks free from the vessel wall and enters the circulation, it is referred to as an embolus. An embolus that is carried through the bloodstream can be large enough to block a vessel critical to a major organ. When it becomes trapped, an embolus is called an embolism. In the heart, brain, or lungs, an embolism may accordingly cause a heart attack, a stroke, or a pulmonary embolism. These are medical emergencies. Among the many known biochemical activities of aspirin is its role as an anticoagulant.
Aspirin acetylsalicylic acid is very effective at inhibiting the aggregation of platelets. It is routinely administered during a heart attack or stroke to reduce the adverse effects. Physicians sometimes recommend that patients at risk for cardiovascular disease take a low dose of aspirin on a daily basis as a preventive measure. However, aspirin can also lead to serious side effects, including increasing the risk of ulcers.
A patient is well advised to consult a physician before beginning any aspirin regimen. A class of drugs collectively known as thrombolytic agents can help speed up the degradation of an abnormal clot. However, some strokes are not caused by thrombi, but by hemorrhage.
Thus, the cause must be determined before treatment begins. Tissue plasminogen activator is an enzyme that catalyzes the conversion of plasminogen to plasmin, the primary enzyme that breaks down clots. It is released naturally by endothelial cells but is also used in clinical medicine. New research is progressing using compounds isolated from the venom of some species of snakes, particularly vipers and cobras, which may eventually have therapeutic value as thrombolytic agents.
Hemostasis is the physiological process by which bleeding ceases. Hemostasis involves three basic steps: vascular spasm, the formation of a platelet plug, and coagulation, in which clotting factors promote the formation of a fibrin clot. Fibrinolysis is the process in which a clot is degraded in a healing vessel. Anticoagulants are substances that oppose coagulation.
They are important in limiting the extent and duration of clotting. Inadequate clotting can result from too few platelets, or inadequate production of clotting factors, for instance, in the genetic disorder hemophilia.
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