Coagulation is a dynamic process and the understanding of the blood coagulation system has evolved over the recent years in anaesthetic practice. Although the traditional classification of the coagulation system into extrinsic and intrinsic pathway is still valid, the newer insights into coagulation provide more authentic description of the same. Normal coagulation pathway represents a balance between the pro coagulant pathway that is responsible for clot formation and the mechanisms that inhibit the same beyond the injury site. Imbalance of the coagulation system may occur in the perioperative period or during critical illness, which may be secondary to numerous factors leading to a tendency of either thrombosis or bleeding. A systematic search of literature on PubMed with MeSH terms 'coagulation system, haemostasis and anaesthesia revealed twenty eight related clinical trials and review articles in last 10 years. Since the balance of the coagulation system may tilt towards bleeding and thrombosis in many situations, it is mandatory for the clinicians to understand physiologic basis of haemostasis in order to diagnose and manage the abnormalities of the coagulation process and to interpret the diagnostic tests done for the same.

Overview of the coagulation system

Insulin resistance is a uniform finding in type 2 diabetes, as are abnormalities in the microvascular and macrovascular circulations. These complications are associated with dysfunction of platelets and the neurovascular unit. Platelets are essential for hemostasis, and knowledge of their function is basic to understanding the pathophysiology of vascular disease in diabetes. Intact healthy vascular endothelium is central to the normal functioning of smooth muscle contractility as well as its normal interaction with platelets. What is not clear is the role of hyperglycemia in the functional and organic microvascular deficiencies and platelet hyperactivity in individuals with diabetes. The entire coagulation cascade is dysfunctional in diabetes. Increased levels of fibrinogen and plasminogen activator inhibitor 1 favor both thrombosis and defective dissolution of clots once formed. Platelets in type 2 diabetic individuals adhere to vascular endothelium and aggregate more readily than those in healthy people. Loss of sensitivity to the normal restraints exercised by prostacyclin (PGI(2)) and nitric oxide (NO) generated by the vascular endothelium presents as the major defect in platelet function. Insulin is a natural antagonist of platelet hyperactivity. It sensitizes the platelet to PGI(2) and enhances endothelial generation of PGI(2) and NO. Thus, the defects in insulin action in diabetes create a milieu of disordered platelet activity conducive to macrovascular and microvascular events.

https://care.diabetesjournals.org/content/diacare/24/8/1476.full.pdf

Platelet Dysfunction in Type 2 Diabetes

2. Assay methodologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 2.1. Quantitation of PMP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 2.1.1. Total phosphate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 2.1.2. Radiolabeled mAb . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 2.1.3. Flow cytometry (1): direct detection by forward light scatter (FLS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 2.1.4. Flow cytometry (2): detection by mAb markers . . . . . . . . . . . . . . . . . 114 2.1.5. Flow cytometry (3): PMP quantitation . . . . . . . . . . . . . . . . . . . . . . 114 2.1.6. Other methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 2.2. Procoagulant or ‘‘functional’’ assays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 2.2.1. PF3 activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 2.2.2. Problem of unit of PF3 activity . . . . . . . . . . . . . . . . . . . . . . . . . . 114 2.2.3. Prothrombinase assays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115

Platelet microparticles: a wide-angle perspective.

Hemostasis is initiated by injury to the vascular wall, leading to the deposition of platelets adhering to components of the subendothelium. Platelet adhesion requires the presence of von Willebrand factor and platelet receptors (IIb/IIIa and Ib/IX). Additional platelets are recruited to the site of injury by release of platelet granular contents, including ADP. The "platelet plug" is stabilized by interaction with fibrinogen. In this review, I consider laboratory tests used to evaluate coagulation, including prothrombin time, activated partial thromboplastin time, thrombin time, and platelet count. I discuss hereditary disorders of platelets and/or coagulation proteins that lead to clinical bleeding as well as acquired disorders, including disseminated intravascular coagulation and acquired circulating anticoagulants.

/pdf/coagulation-and-bleeding-disorders-review-and-update-7qc0rl7zpu.pdf

Coagulation and Bleeding Disorders: Review and Update

Cardiovascular disease (CVD) is the major cause of morbidity and mortality in patients with diabetes Macrovascular events, including stroke, myocardial infarction (MI), and peripheral arterial disease (PAD), occur earlier than in nondiabetics and the underlying pathologies are often more diffuse and severe Diabetic arteriopathy, which encompasses endothelial dysfunction, hypercoagulability, changes in blood flow, and platelet abnormalities, contributes to the early evolution of these events Tight glucose and blood pressure control improves the vascular status of these patients by varying degrees Antiplatelet agents have also been shown to be effective in the secondary prevention of cardiovascular events In the ideal world, every risk factor would be addressed and each diabetic would have excellent glycemic control, a low normal blood pressure, a low LDL, and be prescribed an ACE inhibitor, together with aspirin and clopidogrel If this is done, this emerging epidemic of macrovascular disease will be contained

Diabetes and macrovascular disease

Mechanisms of stimulus-response coupling in platelets are as complex and varied as the compounds that elicit the responses. The complexities are compounded by feedback mechanisms from substances released or synthesized by platelets as well as by "cross-talk" between signal transduction pathways. Examples of cross-talk include the ability of epinephrine to inhibit platelet adenylate cyclase through a G protein-mediated mechanism while causing platelet aggregation by some other mechanism and the ability of cAMP to inhibit thrombin-stimulated diacylglycerol formation. Despite the complexities, certain common threads are beginning to emerge, such as the involvement of G proteins in transducing many receptor-mediated processes, the involvement of relatively few second messenger pathways and the role of calcium in many of events leading to platelet responses, and the common involvement of protein kinases in carrying out second messenger function. The latter offers a useful assay for the effect of many agonists because they lead to the phosphorylation of specific proteins that can readily be detected by radioautography. Indeed, the emphasis has shifted in the past 10 years from relatively crude measurements of platelet function such as aggregation to precise, quantifiable measurement of processes such as protein phosphorylation and calcium release, which are indicators of the fundamental mechanisms involved in platelet function and thus serve as assays of these processes. On the other hand, there are other pathways and regulators yet to be discovered, notably regarding the action of epinephrine and the regulation of phospholipase A2. In addition, certain receptors remain elusive, including those for ADP and eicosanoids. The mechanisms of action of thrombin and cathepsin G, which involve their proteolytic activities, also remain an enigma. The combination of new insights into second messenger function and the techniques of molecular biology will allow many of these problems to be resolved, providing new approaches to therapy of thromboembolic disorders.

Mechanisms of platelet activation and inhibition

The ADP-hydrolyzing enzyme apyrase inhibited platelet aggregation and phosphorylation of a 40,000 dalton platelet protein (P40) induced by 1-oleoyl-2-acetyl glycerol (OAG), indicating a dependence on secreted ADP. Apyrase also enhanced OAG-induced potentiation of forskolin or prostaglandin I2 activation of cyclic AMP formation in platelets. Cyclic AMP formation induced by OAG alone could be demonstrated in the presence of a phosphodiesterase inhibitor. Elevation of cyclic AMP level inhibits platelet aggregation so that secreted ADP may be required to inhibit OAG-activated adenylate cyclase for aggregation to proceed. In contrast, apyrase only partially affected phosphorylation of P40 and aggregation induced by the tumor promoter 12-0-tetradecanoyl phorbol-13-acetate (TPA). TPA caused marked inhibition of forskolin-stimulated cyclic AMP formation. TPA inhibition of cyclic AMP formation was largely reversed by apyrase, indicating that it was mainly due to release of ADP.

Differences in the mode of action of 1-oleoyl-2-acetyl-glycerol and phorbol ester in platelet activation.

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Mechanisms of platelet activation and inhibition

Differences in the mode of action of 1-oleoyl-2-acetyl-glycerol and phorbol ester in platelet activation.