Although surgeons often rely on the expertise of pathologists, hematologists, and blood bank personnel, some of the subtleties regarding use of blood components are critical to a surgeons’ complete care of the patient. Therefore, it is important to have an understanding of the basics of hemostasis, the clotting cascade, and fibrinolysis, as well as common disorders and coagulation abnormalities that may be encountered. In addition, it is crucial to understand the risks and benefits of transfusion therapy, the complications of said therapy, and particular situations where issues may be expected to occur. Finally, a description of heparin-induced thrombocytopenia and the use of new anticoagulants are provided.

It is accurate to state that many surgeons take for granted the safety of the U.S. blood supply, but lessons learned in other countries are illustrative. Approximately 80% of the world’s population has access to only 20% of the safe blood supply. For instance, in places such as Latin America, where donations are often non-altruistic (i.e., done for livelihood purposes), infection with human immunodeficiency virus (HIV) and hepatitis is not uncommon. Transfusion of unsafe blood products accounts for up to 16 million hepatitis B, >4 million hepatitis C, and 160,000 HIV infections per year. Up to 20% of donated blood is not tested for transmissible infections and 25% of maternal deaths can be linked to blood loss and incumbent issues related to the blood supply.

It is clear from studies that paid donors are more likely to conceal information about risky behavior. In a number of countries, achieving a donor base that is at least 50% altruistic is a difficult target to reach. The Pan-American Health Organization funded by the Gates Foundation, has attempted to ensure that the region’s blood supply is screened for hepatitis and HIV, as well as other endemic problems such as Chagas disease. In addition, centralized blood collection systems have obvious advantages over small or local banks.

An episode from 2002 in this country is illustrative of potential problems even when the blood is extensively tested. There are new viruses that become endemic and especially if the time from incubation to development of disease is long (Creutzfield-Jacob), identification and screening can be difficult. In 2002, about 4,200 people were infected with mosquito-borne West Nile virus. During this time, there were 23 cases of transfusion-transmitted infection and seven related deaths due to this virus, which was obviously not screened at that time. Soon after, nucleic acid amplification technology was adapted for detection of this virus and the threat was essentially removed. Current screening practices include review with the potential donor of risk factors as well as history of transmittable infectious disease such as hepatitis C and B, HIV 1 and 2, HTLV I and II, malaria, babesiosis, and Chagas disease. Blood is also screened for indications of underlying infection.

Although most surgeons view hemostasis as the appropriate suture and knot, clear knowledge of the clotting cascade is critical. It is very important to understand the types of factors or blood products that should be administered at any given time and what the potential issues/contraindications may be. Since each product ordered from the blood bank carries some risk, at least a basic facility with their uses is expected. Part of the overall care of the patient is based on the evaluation of preexisting “bleeding” disorders as well as those that may be acquired from complications related to surgery or new underlying disease processes. Finally, understanding the use and/or complication of the omnipresent heparin (mainly related to heparin-induced thrombocytopenia), as well as the myriad novel anticoagulants is part of excellent surgical care.

Hemostasis relies on a dynamic, minute-by-minute interactive process between platelets and coagulation complexes. When cells are injured, tissue factor (TF) is released and this activates the extrinsic pathway. This damage of the endothelium of blood vessels exposes the underlying collagen to platelets and thus, activates them. In the blood, tissue factor forms a complex with activated Factor VIIA. This complex subsequently activates IX and X. At the same time, stimulated platelets change their shape, externalizing among other enzymes, the procoagulant phospholipid platelet factor 4 (PF4). Coagulation proteins can thus, assemble on the surface of the platelets allowing acceleration of coagulation reactions. Dormant platelets do not express binding sites for coagulation factors. von Willebrand factor (vWF) is responsible for platelet adhesion by binding to glycoprotein IB. Fibrinogen forms bridges between platelets by binding to glycoprotein IIB/IIIA and adjacent stimulated platelets. This leads to a platelet plug being formed. Factor Xa can now activate Factor V. Ionized calcium and prothrombin now complex on the platelet lipid surface to initiate the catalyzation that leads to the formation of thrombin.

All coagulation, regardless of whether it is related to extrinsic or intrinsic pathway requires thrombin. Thrombin, among other things, acts to cleave fibrinopeptide A from the alpha chain of fibrinogen and fibrinopeptide B from the beta chain. This release of fibrinopeptides allows formation of fibrin monomers, which cross-link. Thrombin, in addition, activates Factor XIII, which affects a number of coagulation processes. These include acceleration of cross-linking of fibrin to make the clot harder, activation of platelets, as well as Factors V and VIII. It also cross-links other plasma proteins such as fibronectin and incorporates them into the clot. What is apparent is that many complexes/mechanisms are interacting at a given time, but derangement of just one key component can lead to disastrous problems.

The intrinsic pathway basically requires the formation of XIa from XI. This involves changes on the vascular surface and starts with XIIa converting XI to Xia, which in turn converts IX to IXa. The combination of IXa, X, calcium, and VIIIa on the platelet surface forms the x-ASE complex, which then catalyzes the conversion of Factor X to Xa. The process can occur by the contact activation system with Factor XII and prekallikrein, and also by thrombin’s interaction with negatively charged surfaces. There are multiple overlaps and amplification steps, partly based on autocatalytic nature of certain factors. The remainder of the pathway follows along with the extrinsic mechanisms.

To understand the extrinsic pathway, the critical role of tissue factor or thromboplastin needs to be delineated. Tissue factor is an integral membrane glycoprotein that is not typically expressed on vascular endothelial cells, but is noted on skin, vascular adventitia, and organ surfaces. Typically, tissue factor is exposed to flowing blood only after endothelial damage. Cell lysis leads to activation of tissue factor, which is normally in a dormant state. It may also circulate in the blood in microvesicles, typically of stimulated macrophages. These microvesicles can then fuse with and initiate coagulation-activated platelets. The end product of TF’s interactions, which are complex, is activated Factors X and IX. Since Factor X is at the center of all coagulation reactions, it is critical that both pathways lead to the production of Xa. This is made even more apparent if one focuses on the extrinsic pathway alone, since the amount of TF generated is fairly limited, partly due to the presence of tissue factor pathway inhibitor.

For any organism to have the ability to have flowing blood, heal wounds, and stop bleeding, as stated above, a very intricate set of checks and balances needs to be in place. If hemostasis, which is part of wound healing and tissue remodeling, was allowed to go unfettered, patients would not survive after any injury. Thus, innate pathways have been developed to aid in both clot elimination and fibrinolysis. In addition, these are changing second by second at a molecular level and do not just remain stagnant until some event such as a trauma occurs. Antithrombin, heparans, activated protein C and S, and tissue plasminogen activator (TPA) are a few of the critical factors involved in halting further clot, its elimination, and eventual fibrinolysis.

Antithrombin is circulating plasma protease inhibitor with two functional sites, a so-called reactive center and heparin-binding site. It forms equimolar irreversible complexes with a majority of enzymes in the clotting cascade including thrombin, Xa and IXa. The binding of endogenous or exogenous heparins or heparans to the active site produces a conformational change. The glycosaminoglycans heparan sulfate is found naturally on endothelial surfaces and contains a critical pentasaccharide that in part mediates the physiologic action of antithrombin. This allows the endothelial cells to have already activated antithrombin on their surface allowing destruction of excess thrombin in the general circulation.

Activated protein C (APC) joins with protein S on phospholipid surfaces and causes the proteolysis of Factors Va and VIIIa. Of note, protein S functions to amplify the effects of activated protein C. This is critical because this complex inactivates both prothrombinase and the intrinsic X-ase. Elucidation of the importance of APC can occur with understanding of the hematologic condition, Factor V Leiden, in which the arginine in Factor V is replaced by glutamine, thus making it not susceptible to cleavage by activated protein C. This leads to promotion of a potentially hypercoagulable state. When heterozygous, this can be “dormant,” until one develops an inflammatory state (infection, trauma, and surgical injury) in which the acute phase reactant C4B-binding protein (compliment system) is increased. Since this binds freely circulating protein S, the likelihood of thrombosis is enhanced.

Protein C and S primarily function as circulating anticoagulants; thus, as will be described further in this chapter, they become critical during periods when thrombosis exceeds fibrinolysis. This can be seen in a number of scenarios but it is easy to understand when you note that Coumadin, the most widely used anticoagulant, is initially a procoagulant since it inhibits protein C and S (short half-life) before it effects the clotting cascade factors. This is one of the main reasons patients with active heparin-induced thrombocytopenia should not receive Coumadin until they are fully anticoagulated with direct thrombin inhibitors (DTIs).

Plasminogen, a precursor to plasmin, forms a ternary complex with fibrin and TPA. This leads to generation of a very active proteolytic plasmin, which destroys fibrin, fibrinogen, and a number of other plasma proteins and clotting factors. When plasmin is active, it leads to release of fibrin degradation products; this is what is measured in the D-dimer laboratory test. TPA itself is an endothelial cell enzyme that circulates as a complex with its inhibitor plasminogen activator inhibitor one (PAI-1). TPA recognizes lysine residues on the fibrin clot and when it binds, this aligns TPA with plasminogen directly on the fibrin surface making its efficacy increase exponentially. Urokinase is also a plasminogen activator and, whereas TPA initiates and continues intravascular fibrinolysis urokinase functions
mainly in the extravascular space. PAI-1 is made both by platelets and endothelial cells. In those deficient in PAI-1 significant bleeding can develop when the normal mechanisms are overwhelmed by things such as trauma. It is aggressively released by activated platelets and probably accounts for the fact that platelet-rich clots seen in arterial thrombus are much harder to lyse than the cell-poor thrombus noted in venous clots.

Many patients at risk for perioperative bleeding complications can be identified through the performance of a complete personal and family history and physical examination. Basic screening and confirmatory testing may be performed as indicated by findings on this initial evaluation. Appropriate perioperative management of patients with bleeding disorders depends on identifying those patients at risk and defining the defect in coagulation pathways that may be present.

Initial discussion with the patient centers on the occurrence of prior serious bleeding problems related to injuries, dental procedures, surgical procedures, or menstruation and childbirth in women. Of particular concern are episodes of spontaneous, excessive, or delayed in onset. A family history of bleeding episodes should be elicited, although a negative family history does not entirely exclude an inherited coagulation disorder due to the occurrence of spontaneous mutations and incomplete penetrance of certain conditions. Prior history of iron-responsive anemia or need for transfusions as well as history of thyroid, liver, or kidney disease may suggest a bleeding diathesis. Review of prescription and over-the-counter medications may also reveal patients at risk for perioperative bleeding. While prescription anticoagulants such as aspirin, clopidogrel, and Warfarin are well known to increase bleeding risk, many frequently used nonprescription medications, vitamins, and dietary supplements can also interfere with hemostatic mechanisms. Nonsteroidal anti-inflammatory agents, vitamin E, ginkgo biloba, ginseng, garlic, and echinacea have all been associated with an increased risk of bleeding. In addition, use of antibiotics may alter the gut flora metabolism of vitamin K while malnutrition or malabsorption may decrease the synthesis of vitamin K-dependent coagulation factors.

Physical examination help distinguish between disorders of platelet number and function versus a coagulation factor deficiency. Petechiae, superficial ecchymoses, mucocutaneous bleeding, and purpura are suggestive of platelet or blood vessel abnormalities, while deep tissue hematomas and hemarthroses implicate inherited defects in coagulation factors.

In the absence of identified risk factors, patients may proceed to minor procedures without formal laboratory evaluation of hemostatic parameters. General screening tests are recommended for more invasive procedures or in the setting of concerns raised on history and physical examination. Initial testing of platelet count, prothrombin time (PT), and activated partial thromboplastin time (aPTT) may identify some patients at risk for perioperative bleeding and distinguish between defects of platelets and coagulation factors. Peripheral blood smear will provide insight into platelet number and morphology. Bleeding time has long been recommended as a comprehensive test of platelet and blood vessel hemostatic functions, although it is not uniformly offered at all centers due to the resources involved in performing the test as well as variation in technical factors in performance of the test. The Platelet Function Analyzer (PFA-100) is a more standardized test of platelet function and is increasingly available. Prothrombin time tests for integrity of the extrinsic pathway and is used to monitor the effects of Warfarin. Due to variability in assays, the PT is usually reported as an international normalized ratio (INR). aPTT tests the intrinsic pathway of coagulation and is used to monitor heparin effects. An elevated aPTT may suggest heparin effect or deficiency of any factor, except VII and XIII. Concern for deficiency of specific coagulation factors may be assessed by testing for specific factors or factor inhibitors. Fibrinogen activity may be measured while testing for abnormal fibrinolysis and is assessed by measuring fibrin and fibrinogen degradation products (FDP). Measurement of D-dimers reflects presence of clot as breakdown of previously cross-linked fibrin is required. Findings of the various tests of coagulation are described with the disorders described below.

Acquired bleeding disorders are much more common than congenital deficiencies in coagulation. A review of common bleeding disorders serves to outline the use of preoperative screening and diagnostic testing as well as appropriate management to minimize morbidity and mortality following surgical procedures. Management of these uncommon conditions should be undertaken in a multidisciplinary approach including hematologists and blood bank physicians for optimal outcomes.