1 How can you identify a patient at risk for bleeding?

Preoperative evaluation includes history, physical examination, and performance of appropriate laboratory tests. Questions about bleeding disorders and problems (e.g., tendency to form large hematomas after minor trauma, severe bleeding while brushing teeth) and bleeding after previous surgical procedures (e.g., dental extractions, tonsillectomy) are important. Prior surgery without transfusion suggests the absence of an inherited coagulation disorder. Review of medications is necessary to identify medications with anticoagulant potential (e.g., nonsteroidal antiinflammatory drugs [NSAIDs], antiplatelet drugs, and anticoagulants). Coagulation studies may confirm a clinical suspicion that the patient has a bleeding disorder. No evidence supports the value of preoperative coagulation studies in asymptomatic patients.

2 What processes form the normal hemostatic mechanism?

Three intertwined processes ensure that blood remains in a liquid state until vascular injury occurs: primary hemostasis, secondary hemostasis, and fibrinolysis.

3 Describe primary hemostasis

Within seconds of vascular injury, platelets become activated and adhere to the subendothelial collagen layer of the denuded vessel via glycoprotein receptors; this interaction is stabilized by von Willebrand’s factor (vWF). Collagen and epinephrine activate phospholipases A and C in the platelet plasma membrane, resulting in formation of thromboxane A2 (TXA2) and degranulation, respectively. TXA2 is a potent vasoconstrictor that promotes platelet aggregation. Platelet granules contain adenosine diphosphate (ADP), TXA2, vWF, factor V, fibrinogen, and fibronectin. ADP alters the membrane glycoprotein IIb/IIIa, facilitating the binding of fibrinogen to activated platelets. Thus a platelet plug is constructed and reinforced.

4 Review secondary hemostasis

Secondary hemostasis involves the formation of a fibrin clot. The fibrin network binds and strengthens the platelet plug. Fibrin can be formed via two pathways (intrinsic and extrinsic) and involves activation of circulating coagulation precursors. Regardless of which pathway is triggered, the coagulation cascade results in the conversion of fibrinogen to fibrin.

5 What are the intrinsic and extrinsic coagulation pathways?

Traditionally these two pathways have been viewed as separate mechanisms that merge after the formation of activated factor X (Figure 7-1). This rigid division has lost absolute validity because of the crossover of many factors. For instance, factor VIIa can activate factor IX; but factors IXa, Xa, thrombin, and XIIa can activate factor VII. However the classic two-pathway model is still useful for the interpretation of in vitro coagulation studies.

Figure 7-1 The clotting cascade, including intrinsic and extrinsic pathways. The roman numerals indicate the different clotting factors. The letter “a” indicates the activated form. HMWK, high-molecular-weight heparin; TF, tissue factor; wVF, von Willebrand’s factor.

(From Griffin J, Arif S, Mufti A: Crash course: immunology and hematology, ed 2, St. Louis, 2004, Mosby.)

The intrinsic pathway occurs within the blood vessel and is triggered by the interaction between subendothelial collagen with circulating factor XII, high-molecular-weight kininogen, and prekallikrein. Platelet phospholipid (PF3) serves as a catalyst to this pathway. The extrinsic pathway begins with the release of tissue thromboplastin (factor III) from the membranes of injured cells.

6 Explain fibrinolysis

The fibrinolytic system is activated simultaneously with the coagulation cascade and functions to maintain the fluidity of blood during coagulation. It also serves in clot lysis once tissue repair begins. When a clot is formed, plasminogen is incorporated and then converted to plasmin by tissue plasminogen activator (tPA) and fragments of factor XII. Endothelial cells release tPA in response to thrombin. Plasmin degrades fibrin and fibrinogen into small fragments. These fibrin degradation products possess anticoagulant properties because they compete with fibrinogen for thrombin; they are normally cleared by the monocyte-macrophage system.

7 Why doesn’t blood coagulate in normal tissues?

Coagulation is limited to injured tissue by localization of platelets to the site of injury and maintenance of normal blood flow in noninjured areas. The monocyte-macrophage system scavenges activated coagulation factors in regions of normal blood flow. Normal vascular endothelium produces prostacyclin (prostaglandin I₂); it is a potent vasodilator that inhibits platelet activation and helps confine primary hemostasis to the injured area. In addition, antithrombin III, proteins C and S, and tissue factor pathway inhibitor are coagulation inhibitors that are normally present in plasma. Antithrombin III complexes with and deactivates circulating coagulation factors (except factor VIIa). Protein C inactivates factors Va and VIIIa; protein S augments the activity of protein C. Finally tissue factor pathway inhibitor antagonizes factor VIIa.

8 What is an acceptable preoperative platelet count?

A normal platelet count is 150,000 to 440,000/mm³. Thrombocytopenia is defined as a count of <150,000/mm³. Intraoperative bleeding can be severe with counts of 40,000– to 70,000/mm³, and spontaneous bleeding usually occurs at counts <20,000/mm³. The minimal recommended platelet count before surgery is 75,000/mm³. However, qualitative differences in platelet function make it unwise to rely solely on platelet count. Thrombocytopenic patients with accelerated destruction but active production of platelets have relatively less bleeding than patients with hypoplastic disorders at a given platelet count.

Assessment of preoperative platelet function is further complicated by lack of correlation between bleeding time or any other test of platelet function and a tendency for increased intraoperative bleeding. However, normal bleeding times range from 4 to 9 minutes, and a bleeding time >1.5 times normal (>15 minutes) is considered significantly abnormal.

9 List the causes of platelet abnormalities

Thrombocytopenia

Dilution after massive blood transfusion

Decreased platelet production caused by malignant infiltration (e.g., aplastic anemia, multiple myeloma), drugs (e.g., chemotherapy, cytotoxic drugs, ethanol, hydrochlorothiazide), radiation exposure, or bone-marrow depression after viral infection

Increased peripheral destruction caused by hypersplenism, disseminated intravascular coagulation (DIC), extensive tissue and vascular damage after extensive burns, or immune mechanisms (e.g., idiopathic thrombocytopenic purpura, drugs such as heparin, autoimmune diseases)

Qualitative platelet disorders

Inherited (e.g., von Willebrand’s disease)

Acquired (uremia, cirrhosis, medications [e.g., aspirin, NSAIDs])

10 How does aspirin act as an anticoagulant?

Primary hemostasis is controlled by the balance between the opposing actions of two prostaglandins, TXA2 and prostacyclin. Depending on the dose, salicylates produce a differential effect on prostaglandin synthesis in platelets and vascular endothelial cells. Lower doses preferentially inhibit platelet cyclooxygenase, impeding production of TXA2 and inhibiting platelet aggregation. The effect begins within 2 hours of ingestion. Because platelets lack a cell nucleus and cannot produce protein, the effect lasts for the entire life of the platelet (7 to 10 days). NSAIDs have a similar but more transient effect than aspirin, lasting for only 1 to 3 days after cessation of use.

11 Review the properties of factor VIII

Factor VIII is a large protein complex of two noncovalently bound factors, vWF (factor VIII:vWF) and factor VIII antigen. Factor VIII:vWF is necessary for both platelet adhesion and formation of the hemostatic plug through regulation and release of factor VIII antigen. In von Willebrand’s disease there is a decrease of both factor VIII antigen and factor VIII:vWF.

12 How does vitamin K deficiency affect coagulation?

Four clotting factors (II, VII, IX, and X) are synthesized by the liver. Each factor undergoes vitamin K–dependent carboxylation to bind to the phospholipid surface. Without vitamin K the factors are produced but are not functional. The extrinsic pathway is affected first by vitamin K deficiency because the factor with the shortest half-life is factor VII, found only in the extrinsic pathway. With further deficiency both extrinsic and intrinsic pathways are affected.

The warfarin-like drugs compete with vitamin K for binding sites on the hepatocyte. Administration of subcutaneous vitamin K reverses the functional deficiency in 6 to 24 hours. With active bleeding or in emergency surgery, fresh frozen plasma (FFP) can be administered for immediate hemostasis.

13 How does heparin act as an anticoagulant?

Heparin is a polyanionic mucopolysaccharide that accelerates the interaction between antithrombin III and the activated forms of factors II, X, XI, XII, and XIII, effectively neutralizing each. The half-life of heparin’s anticoagulant effect is about 90 minutes in a normothermic patient. Patients with reduced levels of antithrombin III are resistant to the effect of heparin. Heparin may also affect platelet function and number through an immunologically mediated mechanism.

14 Give a general description of the different coagulation tests

The basic difference between the intrinsic and extrinsic pathways is the phospholipid surface on which the clotting factors interact before merging at the common pathway. Either platelet phospholipid (intrinsic pathway) or tissue thromboplastin (extrinsic pathway) can be added to the patient’s plasma, and the time taken for clot formation is measured. Less than 30% of normal factor activity is required for the tests to be affected. The tests are also prolonged in the setting of decreased fibrinogen concentration (<100 mg/dl) and dysfibrinogenemias. The partial thromboplastin time (PTT), activated partial thromboplastin time (aPTT), and activated clotting time (ACT) measure intrinsic and common pathways.

15 What does the partial thromboplastin time measure?

PTT measures the clotting ability of all factors in the intrinsic and common pathways except factor XIII. Partial thromboplastin is substituted for platelet phospholipid and eliminates platelet variability. Normal PTT is about 40 to 100 seconds; >120 seconds is abnormal.

16 Describe the activated partial thromboplastin time

Maximal activation of the contact factors (XII and XI) eliminates the lengthy natural contact activation phase and results in more consistent and reproducible results. An activator is added to the test tube before addition of partial thromboplastin. Normal aPTT is 25 to 35 seconds.

17 How is the activated clotting time measured?

Fresh whole blood (providing platelet phospholipid) is added to a test tube already containing an activator. The automated ACT is widely used to monitor heparin therapy in the operating room. The normal range is 90 to 120 seconds.

18 What is the prothrombin time?

Prothrombin time (PT) measures the extrinsic and common pathways. Tissue thromboplastin is added to the patient’s plasma. The test varies in sensitivity and response to oral anticoagulant therapy whether measured as PT in seconds or simple PT ratio (PT_patient/PT_normal), where “normal” is the mean normal PT value of the laboratory test system. Normal PT is 10 to 12 seconds.

19 Explain the international normalized ratio

The international normalized ratio (INR) was introduced to improve the consistency of oral anticoagulant therapy. INR is calculated as (PT_patient/PT_normal-ISI), where ISI is the international sensitivity index assigned to the test system. The recommended therapeutic ranges for standard oral anticoagulant therapy and high-dose therapy, respectively, are INR values of 2 to 3 and 2.5 to 3.5.

20 What are the indications for administering fresh frozen plasma?

When microvascular bleeding is noted and PT or PTT exceeds 1.5 the control value, FFP should be considered. The usual dose is 10 to 15 ml/kg. FFP will also reverse the anticoagulant effects of warfarin (5 to 8 ml/kg). (Administration of vitamin K will have the same result but will take 6 to 12 hours to become effective.) Volume expansion is not an indication for FFP.

21 What is cryoprecipitate? When should it be administered?

Cryoprecipitate is the cold-insoluble white precipitate formed when FFP is thawed. It is removed by centrifugation, refrozen, and thawed immediately before use. Cryoprecipitate contains factor VIII, vWF, fibrinogen, and factor XIII. It is used to replace fibrinogen, factor VIII deficiencies, and factor XIII deficiencies. It has been used to treat von Willebrand’s disease (unresponsive to desmopressin) and hemophilia. There is now a purified factor VIII concentrate more appropriate for use in these selected problems. One unit of cryoprecipitate per 10 kg of body weight will increase fibrinogen levels by 50 mg/dl. Since cryoprecipitate lacks factor V, for the treatment of disseminated intravascular coagulation, FFP is also necessary.

22 What is disseminated intravascular coagulation?

DIC is usually seen in clinical situations in which clotting pathways are activated by circulating phospholipid, leading to thrombin generation, but the usual mechanisms preventing unbalanced thrombus formation are impaired. The fibrinolytic system is activated, and plasmin begins to cleave fibrinogen and fibrin into fibrin degradation products (FDPs). DIC is not a disease entity but rather a clinical complication of other problems:

Obstetric conditions (e.g., amniotic fluid embolism, placental abruption, retained fetus syndrome, eclampsia, saline-induced abortion)

Septicemia and viremia (e.g., bacterial infections, cytomegalovirus, hepatitis, varicella, human immunodeficiency virus)

Disseminated malignancy and leukemia

Transfusion reactions, crush injury, tissue necrosis, and burns

Liver disease (e.g., obstructive jaundice, acute hepatic failure)

23 What tests are used for the diagnosis of disseminated intravascular coagulation?

There is no one diagnostic test. More often than not, both PT and PTT are elevated, and platelet count is reduced. Hypofibrinogenemia is common. In 85% to 100% of patients FDPs are elevated. One measured form of FDP is the D-dimer. D-dimer is a neoantigen formed by the action of thrombin in converting fibrinogen to cross-linked fibrin. It is specific for FDPs formed from the digestion of cross-linked fibrin by plasmin.

24 Describe the treatment of disseminated intravascular coagulation

The most important measure is to treat the underlying disease process. Often specific blood components are depleted and require repletion based on tests of coagulation. Occasionally, if bleeding persists despite conventional treatment, antifibrinolytic therapy with ε-aminocaproic acid should be considered, but only if the intravascular coagulation process is under control and residual fibrinolysis continues.

25 What is recombinant factor VIIa (NovoSeven)?

Factor VIIa complexes with tissue factor to activate factors IX and X. Factor Xa subsequently aids in the conversion of prothrombin to thrombin, which leads to the activation of fibrinogen to fibrin. The beneficial effects of recombinant factor VIIa have been demonstrated in the settings of hemophilia, liver transplantation, major trauma, intracerebral hemorrhage, gastrointestinal bleeding, cardiac surgery, and warfarin-induced bleeding when traditional approaches to the bleeding patient have proved to be marginally effective or noneffective.

26 Discuss the basic principles of thrombelastography

The thromboelastography (TEG) measures the viscoelastic properties of blood as it is induced to clot in a low shear environment resembling venous flow, providing some measure of clot strength and stability, including the time to initial clot formation, the acceleration phase, strengthening, retraction, and clot lysis. A sample of celite-activated whole blood is placed into a prewarmed cuvette. A suspended piston is then lowered into the cuvette that rotates back and forth. The forming clot transmits its movement on to the suspended piston. A weak clot stretches and delays the arc movement of the piston and is graphically expressed as a narrow TEG. Conversely, a strong clot will move the piston simultaneously in proportion to the movements of the cuvette, creating a thick TEG.

27 Discuss the parameters measured by thromboelastography

There are five parameters of the TEG tracing: R, k, alpha angle, MA, and MA60 (Figure 7-2).

R: Period of time from the initiation of the test to initial fibrin formation

k: Time from the beginning of clot formation until the amplitude of TEG reaches 20 mm, representing the dynamics of clot formation

Alpha angle: Angle between the line in the middle of the TEG tracing and the line tangential to the developing body of the tracing, representing the kinetics of fibrin cross-linking

MA (maximum amplitude): Reflects the strength of the clot, which depends on the number and function of platelets and their interaction with fibrin

MA60: Measures the rate of amplitude reduction 60 minutes after MA, representing the stability of the clot (Figure 7-2)

Figure 7-2 Typical thromboelastography pattern and variables measured as normal values and examples of some abnormal tracings.

(From DeCastro M: Evaluation of the coagulation system. In Faust RJ, editor: Anesthesiology reviews, ed 3, New York, 2002, Churchill Livingstone, p 352.)