Chapter 3 Hemostasis
Principles of Surgery Companion Handbook
|Biology of Hemostasis|
|Tests of Hemostasis and Blood Coagulation|
|Evaluation of the Surgical Patient as a Hemostatic Risk|
|Preoperative Evaluation of Hemostasis|
|Congenital Defects in Hemostasis|
|Classical Hemophilia (Factor VIII Deficiency)|
|Christmas Disease (Factor IX Deficiency)|
|von Willebrand Disease|
|Acquired Hemostatic Defects|
|Acquired Hypofibrinogenemia-Defibrination Syndrome (Fibrinogen Deficiency)|
|Anticoagulation and Bleeding|
|Indications for Replacements of Blood or its Elements|
BIOLOGY OF HEMOSTASIS
Hemostasis is a complex process that prevents or terminates blood loss from the intravascular space, provides a fibrin network for tissue repair, and ultimately, removes the fibrin when it is no longer needed. Four major physiologic events participate in this process (Fig. 3-1).
FIGURE 3-1 Simplified view of the process involved in hemostasis.
This is the initial response to injury, even at the capillary level. Vasoconstriction begins prior to platelet adherence as a reflex response to various stimuli. It is subsequently linked to platelet plug and fibrin formation. The vasoconstrictors thromboxane A2 (TXA2) and serotonin are released during platelet aggregation. Local physical factors, including the extent and orientation of injury to the blood vessel, also may influence the degree of bleeding.
Platelets normally number 150,000400,000/mm3, with an average life span of 10 days. They contribute to hemostasis by two processes. Primary hemostasis is a reversible process that is not affected by heparin administration. Platelets adhere to the subendothelial collagen of disrupted vascular tissue. This process requires von Willebrand factor (vWF), a protein congenitally absent in von Willebrand disease. The platelets expand and initiate a release reaction, recruiting additional platelets. The resulting aggregate forms a plug, sealing the disrupted vessel. ADP, TXA2, and serotonin are the prominent mediators in this process. Opposing these mediators are prostacyclin, endothelium-derived relaxing factor (EDRF), and prostaglandin E2 (PGE2), which are vasodilators and inhibit aggregation. The second process by which platelets act, which is irreversible, involves fibrinogen-dependent degranulation. Platelet factor 3 is released, acting at several points in the coagulation cascade. Platelet-derived mediators also influence the subsequent fibrinolytic process.
Coagulation refers to a cascade of zymogen activation that ultimately results in the cleavage of fibrinogen to insoluble fibrin that stabilizes the platelet plug. The intrinsic pathway is initiated by exposure of coagulation factors to subendothelial collagen at the site of vascular damage. The extrinsic pathway is activated by tissue factors (glycoproteins). The two pathways converge at activated factor X (Xa), which, in turn, cleaves prothrombin to thrombin. All the coagulation factors except thromboplastin, factor VIII, and Ca2+ are synthesized in the liver. Factors II, VII, IX, and X are dependent on vitamin K (Fig. 3-2).
FIGURE 3-2 Outline of the intrinsic (A) and extrinsic (B) pathways of fibrin formation.
The patency of blood vessels is maintained by lysis of fibrin deposits and by antithrombin III (which neutralizes several of the proteases in the complement cascade). Fibrinolysis depends on plasmin, which is derived from the precursor plasma protein plasminogen. Plasmin lyses fibrin, the fragments of which interfere with platelet aggregation.
TESTS OF HEMOSTASIS AND BLOOD COAGULATION
The most valuable part of this assessment is a careful history and physical examination. Specific questions should be asked to determine if there was a prior history of transfusion, untoward bleeding during a major surgical procedure, any bleeding after a minor operation, any spontaneous bleeding, or any family history of bleeding difficulties.
The history should include a list of medications and underlying medical disorders (e.g., malignancy, liver or kidney disease) that may affect normal hemostasis. Laboratory studies also provide important clues of hemostatic ability.
Platelet Count Spontaneous bleeding rarely occurs with a platelet count of greater than 50,000/mm3. Platelet counts in this range are usually adequate to provide hemostasis following trauma or surgical procedures if other hemostatic factors are normal.
Bleeding Time This assesses the interaction between platelets and a damaged blood vessel and the formation of a platelet plug. Deficiencies in platelet number, platelet function, or some coagulation factors will yield a prolonged bleeding time.
Prothrombin Time (PT) This test measures the extrinsic pathway of blood coagulation. Thromboplastin, a procoagulant, is added with calcium to an aliquot of citrated plasma, and the clotting time is determined. The test will detect deficiencies in factors II, V, VII, and X or fibrinogen.
Partial Thromboplastin Time (PTT) A screen of the intrinsic clotting pathway, the PPT will determine abnormalities in factors VIII, IX, XI, and XII. This test has a high sensitivity; only extremely mild deficiencies in factor VIII or IX will be missed. The PTT, used in conjunction with the PT, can help place a clotting defect in the first or second stage of the clotting process.
Thrombin Time (TT) This screen detects abnormalities in fibrinogen and will detect circulating anticoagulants and inhibitors of anticoagulation.
Tests of Fibrinolysis Fibrin degradation products (FDPs) can be measured immunologically. Falsely positive results (>10 mg/mL) may be seen in liver disease, kidney disease, thromboembolic disorders, and pregnancy.
EVALUATION OF THE SURGICAL PATIENT AS A HEMOSTATIC RISK
Preoperative Evaluation of Hemostasis
Rapaport has suggested four levels of concern (given the patient's history and the proposed operation) that should dictate the extent of preoperative testing.
Level I: The history is negative, and the procedure is relatively minor (e.g., breast biopsy or hernia repair). No screening tests are recommended.
Level II: The history is negative and a major operation is planned, but significant bleeding is not expected. A platelet count, blood smear, and PTT are recommended to detect thrombocytopenia, circulating anticoagulant, or intravascular coagulation.
Level III: The history is suggestive of defective hemostasis, and the patient is to undergo a procedure in which hemostasis may be impaired, such as operations using pump oxygenation or cell savers. This level also applies to situations where minimal postoperative bleeding could be detrimental, such as intracranial operations. A platelet count and bleeding time should be done to assess platelet function. A PT and PTT should be used to evaluate coagulation, and the fibrin clot should be checked to screen for abnormal fibrinolysis.
Level IV: These patients have a known hemostatic defect or a highly suggestive history. The same tests suggested for level III should be checked, and a hematologist should be consulted. In case of an emergency, assessment of platelet aggregation and a TT are indicated to detect dysfibrinogenemia or a circulating anticoagulant.
Patients with liver disease, obstructive jaundice, kidney failure, or malignancy should have the platelet count, PT, and PTT checked preoperatively.
CONGENITAL DEFECTS IN HEMOSTASIS
Classical Hemophilia (Factor VIII Deficiency)
Classical hemophilia (hemophilia A) is a sex-linked recessive disorder in which there is a failure to synthesize normal factor VIII. The incidence is approximately 1 in 10,000 to 1 in 15,000 persons. Spontaneous mutations account for almost 20 percent of cases. Clinical expression of the disease is highly variable.
The severity of the clinical manifestations is related to the degree of factor deficiency. Spontaneous bleeding and severe complications are the rule when virtually no factor VIII activity can be detected. Concentrations of approximately 5 percent of normal may produce no spontaneous bleeding, yet there may be severe bleeding with trauma or surgical therapy.
Significant bleeding is usually first noted when the subject is a toddler. At that time the child may be subject to bleeding into joints, epistaxis, and hematuria. Intracranial bleeding, associated with trauma in half the cases, accounts for 25 percent of deaths. Hemarthrosis is the most characteristic orthopedic problem. Retroperitoneal bleeding or intramural intestinal hematoma also may occur, causing nausea, vomiting, or crampy abdominal pain. Upper gastrointestinal examination may demonstrate uniform thickening of mucosal folds (picket fence or stack of coins appearance).
Treatment The plasma concentration of factor VIII necessary to provide hemostatic integrity is normally quite small (as little as 23 percent). Once serious bleeding begins, however, much higher levels (30 percent) of activity are required to achieve hemostasis. The half-life of factor VIII is 812 h; after an initial transfusion, its half-life is approximately 4 h. One unit of factor VIII is considered to be the amount present in 1 mL normal plasma. Cryoprecipitate concentrates of factor VIII contain 9.6 units/mL. The amount of activity suggested to be repleted varies according to the severity of the lesion. To calculate the amount of factor VIII needed: 1 unit/kg of body weight will yield approximately a 2 percent rise in activity. Half this amount is subsequently administered every 46 h to maintain a safe level.
Wet-frozen cryoprecipitate is preferred for replacement in patients with mild hemophilia, since it provides the lowest risk of viral hepatitis. Factor VIII concentrates are preferred in severe disease. In mild hemophilia A and mild von Willebrand disease, dDAVP, a synthetic derivative of vasopressin, has been used to produce a dose-dependent increase in all factor VIII activities and release plasminogen activator. Following major surgical treatment of a hemophiliac, transfusion replacement of factor VIII should be continued for at least 10 days. Even relatively minor procedures should be supplemented with factor VIII to achieve levels above 2530 percent.
Christmas Disease (Factor IX Deficiency)
Factor IX deficiency is clinically indistinguishable from factor VIII deficiency. It is also inherited as an X-linked recessive disease with variable expression. The clinically severe form of the disease has a level of less than 1 percent of normal activity. Half the patients belong to this group.
Treatment All patients require substitution therapy when major or minor surgery is performed. Current therapy involves the administration of factor IX concentrate. The initial half-life is shorter than that of factor VIII; its steady-state half-life is much longer (1840 h). A number of factor IX concentrates are available. Konyne contains 1060 units/mL of factor IX but has been associated with thromboembolic complications. Newer preparations have had additional clotting factors removed, and the incidence of thromboembolic events is lower. During severe hemorrhage, treatment should be directed to achieving levels of 2050 percent of normal for the first 35 days and then maintaining a plasma level of 20 percent for approximately 10 days. Plasma activity should be monitored during the course of therapy. The development of antibodies occurs in about 10 percent of patients.
von Willebrand Disease
von Willebrand disease occurs in approximately 1 in 1000 individuals. The clinically severe form of the disease occurs much less frequently. This disorder is usually transmitted as an autosomal dominant trait, but recessive inheritance may occur. The disease is characterized by abnormal vWF and a decrease in the level of factor VIII:C (procoagulant) activity, which corrects the clotting abnormality in hemophilia A. Characteristically, patients with this disease have a prolonged bleeding time, but this is less consistent than the factor VIII:C reduction. A given patient may have an abnormal bleeding time on one occasion and a normal bleeding time on another. Ristocetin fails to cause platelet aggregation in about 70 percent of patients with this disease.
Clinical Manifestations Clinical manifestations are usually minimal until trauma or surgery makes them apparent. Spontaneous bleeding is often limited to the skin or mucous membranes. Epistaxis and menorrhagia are relatively common. Serious bleeding following minor surgery is not uncommon.
Treatment Treatment is directed at correcting the bleeding time and factor VIII R:vWF (the von Willebrand factor). Only cryoprecipitate is effective (1040 units/kg q12h). Replacement therapy should start 1 day before surgery, and the duration of therapy should be the same as that described for classic hemophilia.
ACQUIRED HEMOSTATIC DEFECTS
Thrombocytopenia, the most common abnormality of hemostasis in the surgical patient, may be due to massive blood loss, medications, or a variety of disease processes. Heparin-induced thrombocytopenia is notable for being reported in 0.6 percent of patients receiving heparin and is thought to be immune mediated. The lowest platelet counts occur after 415 days of initial therapy and after 29 days in patients receiving subsequent courses.
Abnormalities in platelet number also may be accompanied by abnormalities in function. Uremia affects bleeding time and platelet aggregation. Defects in platelet aggregation and secretion occur in patients with thrombocytopenia, polycythemia, or myelofibrosis.
Treatment A count greater than 50,000/mm3 requires no specific therapy. Thrombocytopenia due to acute alcoholism, drug effect, or viral infection generally will correct within 13 weeks. Severe thrombocytopenia may be due to vitamin B12 or folate deficiency. This condition is usually responsive to the appropriate nutrient therapy. In patients with idiopathic thrombocytopenia or lupus erythematosus, a platelet count of less than 50,000/mm3 may respond to steroid therapy or plasmapheresis. Splenectomy alone should not be performed to correct thrombocytopenia associated with splenomegaly due to portal hypertension.
Prophylactic platelet administration is not routinely required following massive blood transfusions. One unit of platelets contains approximately 5.5 × 105 platelets and would be expected to increase the circulating platelet count by 10,000/mm3 in a 70-kg man. In patients refractory to standard platelet transfusion, the use of human leukocyte antigen (HLA)compatible platelets has proved effective.
Acquired Hypofibrinogenemia-Defibrination Syndrome (Fibrinogen Deficiency)
This is rarely an isolated defect because deficiencies in factors II, VI, and VIII and platelets usually accompany this state. Most patients with acquired hypofibrinogenemia suffer from disseminated intravascular coagulation (DIC). DIC is caused by the introduction of thromboplastic material into the circulation. This syndrome has been seen with a retained dead fetus, separation of the placenta, and amniotic fluid embolism. Defibrination has been observed in association with extracorporeal circulation, disseminated carcinoma, lymphoma, and a variety of infections (including both gram-negative and gram-positive sepsis).
It is difficult to distinguish DIC from secondary fibrinolysis because both show prolongation in the TT, PTT, and PT. The combination of a low platelet count, a positive plasma protamine test, reduced fibrinogen, and increased FDPs (taken in the context of the patient's underlying disease) is highly suggestive of the syndrome.
The prime consideration in treatment is relieving the underlying medical problem. The use of intravenous fluids is indicated to maintain volume. If there is active bleeding, hemostatic factors should be replaced with fresh frozen plasma, cryoprecipitate, and platelet concentrates as needed. Most studies show that heparin is not indicated in acute forms of DIC but is indicated for purpura fulminans or venous thromboembolism. Fibrinolytic inhibitors may be used to block the accumulation of FDPs. They should not be used without prior effective antithrombotic treatment with heparin.
The acquired hypofibrinogenemic state in the surgical patient also may be due to pathologic fibrinolysis. This can be seen in patients with metastatic prostatic carcinoma, shock, sepsis, hypoxia, neoplasia, cirrhosis, and portal hypertension. A reduction in fibrinogen and factors V and VIII is seen, since they all are substrates for the enzyme plasmin. Thrombocytopenia is not an accompaniment of the purely fibrinolytic state. Treatment of the underlying disorder (if identified) is warranted. e-Aminocaproic acid (EACA), an inhibitor of fibrinolysis, also may be useful.
Thrombocytopenia can be treated by standard therapy for the underlying disease. Ideally, the hematocrit should be kept below 48 percent and the platelet count less than 400,000/mm3. In a study with polycythemic patients undergoing major surgical procedures, 46 percent had complications perioperatively, including a 16 percent mortality (in 80 percent of whom the disease was not under control). Hemorrhage is the most common complication in this group, followed by thrombosis and infection. Preoperative use of antiplatelet agents (e.g., aspirin, dipyridamole) and anticoagulants has been suggested in these patients.
Advanced liver disease may result in decreased synthesis of the coagulation factors II, V, VII, X, and XIII. Also, there may be increased fibrinolysis due to the failure of the liver to clear plasminogen activators.
ANTICOAGULATION AND BLEEDING
Spontaneous bleeding may be a complication of anticoagulant therapy, with an incidence proportional to the degree of anticoagulation. Surgical therapy may be necessary in patients receiving anticoagulant therapy. The risk of thrombotic complications is increased when anticoagulant therapy is suddenly discontinued and may be due to a rebound phenomenon. When the clotting time is less than 25 min in the heparinized patient or when the PT is less than 1.5 times control, reversal of anticoagulant therapy may not be necessary. If an emergent surgical procedure is necessary, anticoagulation can be reversed. Heparin can be reversed with protamine sulfate (1 mg protamine per 1000 units heparin). Bleeding is infrequently related to hypoprothrombinemia if the prothrombin concentration is greater than 15 percent. Warfarin can be discontinued several days before surgery. If emergency surgery is required, parenteral vitamin K1 can be used. Reversal may take up to 6 h, so fresh frozen plasma may be needed.
The goal of local hemostasis is to prevent the flow of blood from incised or transected blood vessels. The techniques may be classified as mechanical, thermal, or chemical.
The oldest mechanical device to effect closure of a bleeding point or to prevent blood from entering an area of disruption is digital pressure. The finger has the advantage of being the least traumatic means of hemostasis. Diffuse bleeding from multiple transected vessels may be controlled by mechanical techniques, including direct pressure over the bleeding area, pressure at a distance, or generalized pressure. Direct pressure is preferable and is not attended by the danger of tissue necrosis associated with a tourniquet. Gravitational suits have been used to create generalized pressure.
The hemostat represents a temporary mechanical device to stem bleeding. Ligature replaces a hemostat as a permanent method of hemostasis of a single vessel.
Cautery effects hemostasis by denaturation of proteins, which results in coagulation of large areas of tissue. Cooling also has been applied to control bleeding and acts by increasing the local intravascular hematocrit and decreasing the blood flow by vasoconstriction. Cryogenic surgery uses temperatures between 20 and 180°C.
Some chemicals act as vasoconstrictors, others are procoagulants, and others have hygroscopic properties that aid in plugging disrupted blood vessels. Epinephrine is a vasoconstrictor, but because of its considerable absorption and systemic effects, it is generally used only on areas of mucosal oozing. Local hemostatic materials include gelatin foam, cellulose, and micronized collagen.
Approximately 14 percent of all inpatient operations include blood transfusions. Blood provides transportation of oxygen to meet the body's metabolic demands and removes carbon dioxide.
Banked whole blood is stored at 4°C and has a storage life of up to 35 days. Up to 70 percent of transfused erythrocytes remain in the circulation 24 h after transfusion; 60 days after transfusion, approximately 50 percent of the cells will survive. Banked blood is rarely indicated.
Banked blood is a poor source of platelets. Factors II, VII, IX, and XI are stable in banked blood. Factor VIII rapidly deteriorates during storage. During the storage of whole blood, red cell metabolism and plasma protein degradation result in chemical changes in the plasma, including increases in lactate, potassium, and ammonia and a decrease in pH.
Typing and Crossmatching Serologic compatibility is routinely established for donor and recipient A, B, O, and Rh groups. As a rule, Rh-negative recipients should be transfused only with Rh-negative blood. In the patient receiving repeated transfusions, serum drawn less than 48 h before cross-matching should be used. Emergency transfusion can be performed with group O blood. If it is known that the prospective recipient is group AB, group A blood is preferable.
Fresh Whole Blood This term refers to blood given within 24 h of its collection.
Packed Red Cells and Frozen Red Cells Packed cells have approximately 70 percent of the volume of whole blood. Use of frozen cells markedly reduces the risk of infusing antigens to which the patients have previously been sensitized. The red cell viability is improved, and the ATP and 2,3-diphosphoglycerate (2,3-DPG) concentrations are maintained.
Platelet Concentrates Platelet transfusions should be used for thrombocytopenia due to massive blood loss replaced with stored blood, thrombocytopenia due to inadequate production, and qualitative platelet disorders. Isoantibodies are demonstrated in about 5 percent of patients after 110 transfusions, 20 percent after 1020 transfusions, and 80 percent after more than 100 transfusions. HLA-compatible platelets minimize this problem.
Fresh Frozen Plasma and Volume Expanders Factors V and VIII require plasma to be fresh or freshly frozen to maintain activity. The risk of hepatitis is the same as that of whole blood or packed red cells. In emergency situations, lactated Ringer's solution can be administered in amounts two to three times the estimated blood loss. Dextran or lactated Ringer's solution with albumin can be used for rapid plasma expansion.
Concentrates Antihemophilic concentrates are prepared from plasma with a potency of 2030 times that of fresh frozen plasma. The simplest factor VIII concentrate is plasma cryoprecipitate. Albumin also may be used as a concentrate (25 g has the osmotic equivalent of 500 mL), with the advantage of being hepatitis-free.
INDICATIONS FOR REPLACEMENTS OF BLOOD OR ITS ELEMENTS
Volume Replacement The most common indication for blood transfusion in the surgical patient is the restoration of circulating blood volume. The hematocrit can be used to estimate blood loss, but up to 72 h is required to establish a new equilibrium after a significant blood loss.
In the normal person, reflex mechanisms allow the body to accommodate up to moderate-size blood losses. Significant hypotension develops only after about a 40 percent loss of blood volume.
Loss of blood during operation may be estimated by weighing the sponges (representing about 70 percent of the true loss). In patients who have normal preoperative blood values, replacement recommendations are shown in Table 3-1.
TABLE 3-1. BLOOD REPACEMENT RECOMMENDATIONS
Improvement in Oxygen-Carrying Capacity Transfusion should be performed only if treatment of the underlying anemia does not provide adequate blood counts for the patient's clinical condition. In general, raising hemoglobin levels above 78 g/dL provides little additional benefit. A whole blood substitute, Fluosol-DA, provides oxygen-carrying capacity in the absence of blood products.
Replacement of Clotting Factors Supplemental platelets or clotting factors may be required in the treatment of certain hemorrhagic conditions. Fresh frozen plasma is used in the treatment of a coagulopathy in patients with liver disease, but its efficacy is very low. The rigid use of PT and PTT to anticipate the effect of fresh frozen plasma is not justified. If fibrinogen is required, a plasma level greater than 100 mg/dL should be maintained.
Massive Transfusion This term refers to a single transfusion of greater than 2500 or 5000 mL over a 24-h period. A number of problems may accompany the use of massive transfusion, including thrombocytopenia, impaired platelet function, deficiency in factors V, VIII, and XI, and the increased acid load of stored blood products.
With large transfusions, a heater may be used to warm the blood, since hypothermia may result in decreased cardiac output and an acidosis.
Complications (Table 3-2)
TABLE 3-2. COMPLICATIONS OF TRANSFUSION
Hemolytic reactions from blood group incompatibilities are usually manifest by a sensation of warmth and pain along the site of transfusion, flushing in the face, pain in the lumbar region, and constricting pain in the chest. The patient additionally may experience chills, fever, and respiratory distress. In anesthetized patients, two signs of reaction are abnormal bleeding and continued hypotension in the face of adequate replacement. The morbidity and mortality of hemolytic reactions are high and include oliguria, hemoglobinuria, hypotension, jaundice, nausea, and vomiting. The transfusion should be stopped immediately if a transfusion reaction is suspected. Samples of the recipient and donor blood should be sent for comparison with pretransfusion samples. Renal function should be monitored following a suspected transfusion reaction. Renal toxicity is affected by the rate of urinary excretion and the pH. Alkalinization of the urine prevents precipitation of hemoglobin.
Febrile and Allergic Reactions These occur in approximately 1 percent of transfusions. They appear as urticaria and fever occurring within 6090 min of the start of the transfusion. Occasionally, the allergic reaction is severe enough to cause anaphylactic shock. Treatment consists of antihistamines, epinephrine, and steroids, depending on the severity of the reaction.
Transmission of Disease Posttransfusion viral hepatitis is the most common fatal complication of blood transfusion. Other viral illnesses may be transmitted (e.g., cytomegalovirus, human immunodeficiency virus, etc.), as well as several bacterial species.
Additional, less frequent complications include
Embolism: Intravenous volumes of less than 200 mL are generally well tolerated by normal adults.
Volume overload: The patient's risk is related to underlying cardiac reserve.
Bacterial sepsis: Gram-negative organisms and Pseudomonas predominate. Thrombophlebitis: More commonly seen with prolonged infusions.
For a more detailed discussion, see Schwartz SI: Hemostasis, Surgical Bleeding, and Transfusion, chap. 3 in Principles of Surgery, 7th ed.
Copyright © 1998 McGraw-Hill
Seymour I. Schwartz
Principles of Surgery Companion Handbook