PERIOPERATIVE ANTICOAGULATION AND THROMBOLYSIS IN CONGENITAL AND ACQUIRED COAGULOPATHIES

PERIOPERATIVE USE OF ANTICOAGULANTS AND THROMBOLYTICS

0889-8537/99 $8.00

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PERIOPERATIVE ANTICOAGULATION AND THROMBOLYSIS IN CONGENITAL AND ACQUIRED COAGULOPATHIES Leonard0 Kapural, MD, PhD, and Juraj Sprung, MD, PhD

Patients with congenital or acquired coagulopathies are undergoing increasingly complex operations that may require anticoagulation. Using large doses of heparin in patients with hemophilia during coronary artery bypass surgery without first correcting the underlying coagulation deficit may have catastrophic consequences. Before 1965, mortality for hemophiliacs undergoing general surgical procedures ranged from 13% to 67%. Over the last 30 years, operations on patients with hemophilia and other coagulopathies have been performed with low morbidity and mortality results, primarily because of improved laboratory testing, perioperative administration of coagulation factors to bring the missing factor activity to normal, and close perioperative follow-up to evaluate and further correct hemostatic protein activityzo0To prepare these patients properly for surgery, complex diagnostic tests and specific therapies are required preoperatively because diagnosis and treatment during the surgery may be difficult or impossible, with severe consequences for the patient. As the perioperative use of anticoagulants in patients with congenital coagulopathies is becoming safe and routine, physicians are becoming aware of other acquired coagulation disorders such as heparin-induced From the Division of Anesthesiology and Critical Care Medicine (LK) and the Department of General Anesthesiology US), The Cleveland Clinic Foundation, Cleveland, Ohio

ANESTHESIOLOGY CLINICS OF NORTH AMERICA

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thrombocytopenia. Heparin-induced thrombocytopenia has special clinical significance because heparin is still the first-choice treatment for the systemic anticoagulation required for certain cardiac and vascular surgeries. Finding that it was contraindicated in some patients stimulated intense research for alternatives, which produced heparin substitutes such as heparinoids, low molecular weight heparins (LMWHs), direct thrombin inhibitors, and glycoprotein IIb / IIIa receptor inhibitors. The expansion of knowledge about the coagulation and anticoagulation mechanisms over the last several decades has also brought a better understanding of some of the thrombotic phenomena that anesthesiologists and surgeons encounter in their daily practice. The increased incidence of thrombosis in some segments of the population is now known not to be simple “bad luck,” but rather to be the result of underlying pathologies of the coagulation cascade, most commonly protein C, protein s, and antithrombin I11 deficiencies. In 1993, investigators in Sweden38and the Netherlands”’ described a new defect in the hemostatic pathway, called resistance to activated protein C. This disorder occurs in 4% to 6% of the US population, making them especially prone to thromboembolic events during the perioperative period, pregnancy, or oral contraceptive use. Antiphospholipid antibodies may also cause a hypercoagulable state. Taylor et allg4demonstrated that antiphospholipid antibodies are present in 25.6% of patients undergoing peripheral vascular surgery. This patient population may require not only short-term perioperative thrombotic prophylaxis but also long-term prophylaxis. However, dosage and duration of anticoagulant therapy for some of the hypercoagulable states is still not fully defined. In this article, we describe the pathophysiology of the most common hyper- and hypocoagulable disorders and discuss the impact of perioperative use of anticoagulants and thrombolytics in patients with these conditions. CONGENITAL HYPOCOAGULABLE DISORDERS Patients who present with histories suggestive of extensive or prolonged bleeding should be screened and treated for hypocoagulable disorders before surgery, particularly surgeries that require anticoagulation, because treatment of excessive bleeding during the surgery may be difficult and postoperative care complicated. In this section, we discuss the three most common congenital hypercoagulable disorders: hemophilia A (representing 68% of all congenital hypocoagulable disorders); hemophilia B (20%); and von Willebrand disease (vWD) (6%).*0° Hemophilias Hemophilia A (Factor Vlll Deficiency) Hemophilia A (classic hemophilia) is a sex-linked recessive bleeding disorder caused by deficiency of coagulation factor VIII (Table 1). Factor

vWF

=

von Willebrand factor; APC

AT-I11 deficiency

Activated protein C resistance

Protein S deficiency

activated protein C; BT =

bleeding time; AT-111 = antithrombin111;

vWF (synthesized in endothelial cells and megakaryocytes and stored in endothelial cells and platelets) has receptors for factor VIII, platelets, and some adhesive proteins such as collagen. Decreased or absent plasma levels of vWF will decrease factor VIII half-life, impair platelet adhesion, and fibrin formation. Protein C is activated when thrombin binds to its cofactor thrombomodulin. APC has anticoagulant properties, inactivating the coagulation factors Va and VIIIa. Protein S is a cofactor that accelerates the inactivation of factors Va and VIIIa. Free protein S promotes binding of APC to the membranes of platelets and endothelial cells and subsequent degradation of the coagulation factors Va and VIIIa (Fig. 1). A single point mutation encodes glutamine instead of arginine. This position on factor V is one of the three cleavage sites for inactivation by APC. The mutation makes factor V resistant to physiologic inactivation by APC. AT-111 is a naturally occurring serine protease inhibitor synthesized by the liver and endothelial cells. Thrombin and other serine proteases can be irreversibly inhibited by AT-111. AT-I11 is also a heparin cofactor necessary for the anticoagulant action of heparin, and heparin also enhances AT-I11 activity against factor Xa.

von Willebrands disease

=

Deficiency of factor IX

Hemophilia B

Protein C deficiency

Deficiency of factor VIII

Deficiencyhlechanism of Disease

Hemophilia A

Disease

t

=

prolonged or increased;

1 = decreased or low level; nl

=

normal.

History of thrombosis / thromboembolism J plasma AT-111 level by functional assay of AT-I11 (heparincofactor assay)

History of thrombosis/ thromboembolism 1. Anticoagulant response to APC in an aPTT assay (APCresistance test); 2. Genetic (DNA) analysis

History of bleeding 1. t aPTT; 2. t BT; 3. vWF antigen electroimmunoassay: measures amount of circulating vWF antigen; 4.Factor VIII antigen or activity is often 1;5. Hypersensitivity to platelet aggregation by antibiotic ristocetin History of thrombosis / thromboembolism 1. J plasma protein C concentration (electroimmunoassay); or 2. Dysfunctional protein C (activity assay) History of thrombosis / thromboembolism 1 plasma protein S concentration (immunologic assays of total and free protein S) or functional assay of protein S

1)

History of bleeding 1. J plasma factor VIII activity; 2. T aPTT; 3. nl PT; 4. nl BT History of bleeding 1. J. plasma factor IX activity; 2. t aP'lT; 3. nl PT (rarely, slightly

History and Diagnostic Tests

Table 1. MECHANISMS AND PRESENTATIONS OF HEREDITARY HYPOCOAGULABLE AND HYPERCOAGULABLE COAGULOPATHIES

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Table 2. SEVERITY AND CLINICAL MANIFESTATION OF HEMOPHILIA A Severity

Factor Vlll Activity (“A)

Clinical Manifestation

Severe Moderate Mild

<1 14 535

Spontaneous hemarthroses, bleeding into soft tissues Bleeding after trauma or surgery Little risk for spontaneous hemorrhage

Data

Cohen AJ, Kessler CM: Treatment of inherited coagulation disorders. Am J Med 99:675,

1995

VIII acts as a cofactor for the cleavage of factor X by activated factor IX (factor IXa), accelerating this reaction by several thousandfold. The incidence of hemophilia A is 1 per 5000 male births, and the clinical presentation correlates with the level of factor VIII in plasma (Table 2).31, An important potential complication relevant to the anesthesiologist is life-threatening airway compromise from oropharyngeal bleeding: Of patients with hemophilia A admitted to the hospital, 13% had some form of airway compromise, and in 8% it was life threatening.19 Hemophilia B (Factor IX Deficiency)

Hemophilia B (Christmas disease) is a sex-linked recessive bleeding disorder caused by deficiency of coagulation factor IX (see Table 1).The incidence of hemophilia B is 1per 30,000 male births,31, and the clinical presentation is similar to that of hemophilia A. A number of inherited and spontaneous mutations of factor IX have been identified. The mutations decrease rates of activation of factor IX, alter binding of factor IX to phospholipid membranes, or reduce factor IX circulation times.31 Perioperative Management and Use of Anticoagulants in Patients with Hemophilia A or B

For moderate to severe cases of hemophilia A, factor VIII concentrates are administered as little as 30 minutes before surgery. There is no universally accepted consensus for perioperative adjustment of the dose of factor VIII, but most authors agree that the factor VIII level should be close to 100% of normal at the time of surgery as well as for the first 24 to 48 postoperative hours.182Factor VIII plasma concentration should be kept at 50% (0.5 U/mL) for 2 to 7 days after the surgery and then decreased to 30% (0.3 U/mL) for an additional 3 to 7 days until wound healing is complete and sutures are removed.21Formulas to guide replacement with factor VIII are based on factor VIII pharmacokinetics data. One unit of factor VIII per kilogram of body weight raises the plasma factor VIII concentration by 2?!0.’~~To achieve an 80% level (0.8 U/mL) in a 70-kg man with severe hemophilia, 40 U/kg of factor VIII must be given. Because the half-life of factor VIII is about 8 to 12 hours, and clearance in a patient weighing 70 kg is approximately 150 U/h,

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maintaining 50% factor VIII plasma activity requires continuous infusion (150 U/h) or bolus (1200-1800 U) every 8 to 12 hours. The patient must be closely monitored with either repeated factor VIII assays or activated partial thromboplastin time (aPTT) to ensure stable factor VIII levels during the perioperative period. Adequacy of treatment must be judged by the clinical effects; therefore, the dosage may vary with individual cases. Treatment with factor VIII concentrate is ineffective in patients who have high titers of the antibody that inhibits factor VIII activity (factor VIII inhibitor).146These patients should be treated preoperatively with porcine factor VIII, if there is no cross-reactivity.182 Alternative treatments include plasmapheresis followed by factor VIII infusion if surgery is urgent147or administration of activated prothrombin complex concentrate, called factor VIII bypassing activity (FEIBA).145 Mild hemophilia A may be treated with desmopressin (l-desamino-8-~-arginiinevasopressin, DDAVP), which increases factor VIII plasma levels. The intravenous infusion of DDAVP acetate at a dose of 0.3 pg/kg in 50 mL of normal saline over 20 minutes results in a median 62% increase in factor VIII levels.1s2Cryoprecipitate may also be used because it contains roughly 9.6 U/mL of factor VIII.142Fresh frozen plasma (FFP) is ineffective because it contains only 0.6% factor VIII and excessive volumes would be needed to restore the factor VIII activity. Patients with hemophilia B should be given factor IX. Each unit of factor IX infused per kilogram of body weight will yield a 1%increase in factor IX plasma concentration.ls2To achieve a preoperative level of 80% (0.8 U/mL) in a 70-kg man, 80 U/kg must be given. Because the half-life of factor IX is approximately 24 hours, it should be administered at intervals of 12 to 24 hours.182A factor IX plasma concentration higher than 30% of normal should be maintained until healing is complete and sutures are removed. However, prolonged infusion of factor IX has been associated with thromboembolic events, including disseminated intravascular coagulation (DIC), deep venous thrombosis (DVT), pulmonary embolism, and, rarely, nonatherosclerotic myocardial i n f a r ~ t i o n . ~ ~ After the primary coagulopathy is corrected with either factor VIII or factor IX and confirmed by appropriate tests (plasma levels of factors or normalized aPTT), systemic anticoagulants (heparin or LMWH) can be given perioperatively. Systemic anticoagulation, necessary for certain vascular and cardiac procedures, is a pharmacologically controllable state of anticoagulation that can be quickly reversed. Myocardial revascularization has been successful in hemophiliacs pretreated with factor VIII, factor IX, cryoprecipitate, and DDAVP.142, During open-heart surgeries, full systemic heparinization (300 U / kg body weight) was achieved after the patients were pretreated with factor VIII, factor IX, or ~ryoprecipitate.’~~, 2oo Similarly, with proper preparation patients with hemophilia A can safely undergo surgical treatment for abdominal aortic aneurysm (AAA). Three patients with hemophilia A underwent successful AAA surgery without excessive bleeding with purified recombinant factor VIII preoperatively, low-dose systemic hepa-

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rin (3000 U) before aortic cross-clamping, and protamine sulfate (30 mg) later to reverse the heparin effects.14,Io9 It is absolutely necessary in patients with AAA and hemophilia to evaluate and correct perioperative hemostatic activity. The first successful report of AAA repair in the patient with hemophilia B dates from the time when factor IX concentrate became available.83Since that time, numerous successful operations including orthopic liver transplantation in patients with hemophilia A and B were performed.71,75, 117, 137 Gordon et a175described long-term phenotypic cure of hemophilia in 24 patients who survived more than 12 days after transplantation. Patients with good liver allograft function do not require 137 further replacement therapy for hem~philia.~~, von Willebrand's Disease von Willebrand's disease is a group of disorders caused by qualitative or quantitative abnormalities of the vWF114(see Table 1). The vWD is the most common congenital (autosomal dominant) bleeding disorder, with a prevalence of 1%in the general population.168Acquired vWD is a separate entity usually associated with lymphoproliferative diseases, monoclonal gammopathies, other malignancies, drugs, cardiopulmonary bypass, and, rarely, autoimmune disease.166 The severe forms of vWD are rare and are usually diagnosed before surgery; however, heterozygotes may not be preoperatively diagnosed.18 A preoperative history of excessive bleeding after the ingestion of aspirin may be indicative of mild vWD or other qualitative platlet disorders. Perioperative Management and Use of Anticoagulants Patients with vWD should be given repeated perioperative doses of cryoprecipitate, FFP, or DDAVP; however, response to DDAVP depends on the type of vWD (Table 3).25Factor VIII concentrate is not useful in vWD because it does not contain a sufficient amount of multimeric von Willebrand factor ( v W F ) . ~Cryoprecipitate ~ is rich in high molecular weight vWF and effectively corrects prolonged bleeding time. Fresh frozen plasma is useful, but because of the large amount sometimes required, circulatory volume overload may be induced. Some types of acquired vWD may be complicated by the presence of antibodies directed against high molecular weight molecules of vWF, and for these patients intravenous immunoglobulins may be effective.166 It has been suggested that cardiopulmonary bypass (CPB) increases the release of vWF and high molecular weight multimers from store 208 which may lower plasma vWF concentrations after CPB and increase postoperative blood 175 Perrin et reported that administering DDAVP to patients undergoing open-heart surgery significantly decreased postoperative blood loss, and that these patients received usual doses of heparin and protamine intraoperatively without

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Table 3. TYPES OF VON WILLEBRANDS DISEASE AND RESPONSE TO DESMOPRESSIN (1-DESAMINO-8-D-ARGININEVASOPRESSIN) Classification

Defect

Type 1

Quantitative deficiency of vWF. Most common form (70%-90% of cases) Qualitative variants of vWF

Type 2

A

B M

N Type 3

Absence of high molecular weight vWF multimers Same as 2A and increased affinity for platelet glycoprotein r0 Abnormal functional vWF not caused by absence of high molecular weight multimers Qualitative variants with markedly decreased affinity for factor VIII Complete absence of vWF (most severe form)

DDAVP Therapy

Very effective Variable response: contraindicated in type 2B as may cause thrombocytopenia owing to increased binding of platelets to vWF

Ineffective because there is no vWF in tissue stores owing to genetic defect

vWF = von Willebrand factor; DDAVP = desmopressin Modified from Cohen AJ, Kessler CM: Treatment of inherited coagulation disorders. Am J Med 99:675-682, 1995; with permission.

excessive bleeding. Similarly, Blomback et all8 demonstrated that if the patient's history of vWD was known and if appropriate therapeutic measures were undertaken (administration of cryoprecipitate, FFP, DDAVP, and so forth), vWD did not carry an increased risk for intraoperative bleeding, even when intraoperative anticoagulants were Other Protein Coagulation Deficiencies

Often, inherited coagulation protein deficiencies, as described below, are rare but require the same degree of detailed planning and implementation as the more common inherited coagulopathies. Congenital factor XI deficiency, even when severe, may remain clinically occult until the patient is challenged by surgical trauma. Hemorrhage may also occur in heterozygous patients who have normal aPTT and only a mild deficiency of factor XI. Patients with this deficiency may bleed regardless of the degree of deficiency and may require FFP prophylactically (10-20 mL/ kg/ d). Therapy should be monitored with aPTT and factor XI assays.200Cryoprecipitate is used in patients with deficiencies of fibrinogen or factor XII.200When the primary deficiency is corrected, the patient may receive anticoagulation therapy during

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surgery, if required. However, the primary coagulation deficit must be monitored perioperatively and treated until the wound has healed. Deficiencies of coagulation factors 11, V, VII, X, and XIII, and of fibrinogen may require treatment with blood products before surgery. Deficiency of factor I1 (prothrombin) is suspected if the PT and aPTT are prolonged and the thrombin time is normal. Deficiency of factor V (proaccelerin) is suspected if the PT and aPTT are prolonged and if the patient’s plasma does not correct the deficiency of plasma from a patient known to lack factor V activity.I4OA diagnosis of factor VII (stable factor) deficiency should be considered if the PT is prolonged and the aPTT is normal. The diagnosis of factor X (Stuart-Power factor) deficiency is established by demonstrating that plasma from a patient suspected of having this inherited coagulopathy does not correct known factor X-deficient plasma. Deficiency of factor XI11 (fibrin-stabilizing factor) is characterized by normal PT, aPTT, and platelet function but with prolonged bleeding after surgery or trauma. The laboratory diagnosis consists of demonstrating that a fibrin clot, made by recalcification of the patient’s plasma, dissolves overnight at room temperature in 6M urea and 1%monochloroacetic acid.140All these conditions present with unusual bruising and mucosal hemorrhage. Clinical characteristics and treatment of these rare coagulopathies, which generally include FFP, are summarized in Table 4. When comtemplating surgery for patients with inherited coagulopathies, the physician must consider the advantages and disadvantages of each form of replacement therapy as well as the clinical severity of the coagulopathy. Vander Woude et aPo0 demonstrated that elective cardiovascular procedures using systemic heparinization can be carried out reasonably safely with minimal hemorrhagic complications, provided that (a) the preoperative recommendations of the hematologist are followed; and (b) antiplatelet medications are avoided for at least 10 days before surgery. Closely monitoring the coagulation variables during surgery and ensuring a ready supply of blood components for at least 2 postoperative weeks guarantee a complication-free perioperative course in patients with congenital coagulopathies. INHERITED HYPERCOAGULATION ABNORMALITIES

Inherited hypercoagulable abnormalities (thrombophilias) are caused by abnormalities in the production of plasma clotting prot e i n ~ .185~ ~ Some , of the most frequently encountered thrombophilias are listed in Table 5. Alterations in proteins C and S, endothelial thrombomodulin, factor V, and factor VIII are the most common causes of inherited hypercoagulable disorders (Fig. l).39, Ia5, 191) Thrombophilias are a frequent cause of thromboembolic events, especially during precipitating conditions such as surgery, injury, or pregnancy. Therefore, perioperative thromboprophylaxis is of paramount importance in certain patient populations.

$ CI

10%-25% of normal 20%40% of normal 5% of normal

1 per 500,000 births

- 4% of Ashkenazi Jews 1 per several million births

Severe type Ill disease usually recessive X-linked recessive

Autosomal recessive

VWF (type 3 )

25% of normal 80%100% of normal for lifethreatening bleeding, 50% of normal for significant bleeding, 30% of normal for minor bleeding Total or partial correction of activity to 50% bleeding time and raising vWF of normal

‘Minimum dcsired level to treat active bleeding or prevent surgical bleeding. vWD = von Willebrand’s disease; vWF = von Wtllebrand factor; FFP = fresh frozen plasma Am J Med 99:675482, 1995; with permission.

Froin Cohen AJ, Kessler CM: Treatment of inherited coagulation disorders.

Factor Xlll

Factor XI

Autosomal dominant; severe type homozygous Autosomal recessive

25%-50% of normal, depending on extent of surgery or bleeding

1 per 1 million births 1 per 30,000 male births

Usually autosomal dominant

vWF

Factor IX Hemophilia B Christmas disease Factor X

-1 per 1000 births

Autosomal recessive X-linked recessive

Factor VII Factor Vlll (antihemophilic factor) Hemophilia A

25% of normal

Autosomal recessive

Factor V (labile factor)

30% of normal

Autosomal dominant or recessive

100 mg/dL

Minimum Desired Level*

Factor I1 (prothrombin)

Rare (<300 families reported) Extremely rare Rare (>200 types described) Extremely rare (25 kindreds) 1 per 1 million births 1 per 500,000 births 1 per 10,000 births (1 per 5000 male births)

Prevalence

Autosomal dominant or recessive Autosomal dominant or recessive

Autosomal recessive

Inheritance Pattern

Hypofibrinogenemia Dysfibrinogenemia

Factor I (fibrinogen) Afibrinogenemia

Coagulation Protein Deficiency

Table 4. GENETICS. EPIDEMIOLOGY. AND THERAPY OF INHERITED COAGULATION PROTEIN DEFICIENCIES

FFP or cryoprecipitate

FFP, factor IX complex concentrates, or factor IX (human) concentrates FFP or factor IX complex concentrates FFP

Desmopressin for mild-to-moderate vWD (except 28) (variable responses in 2A); cryoprecipitate; FFP; intermediate-purity factor concentrates containing a full complement of vWF multimers

FFP/factor IX complex concentrates Cryoprecipitate; factor VIII concentrate; desmopressin for mild-to-moderate disease

FFP

FFPifactor IX complex concentrates

Cryoprecipitate/ FFP

Replacement Sources

N

W

W

XI1

ACTIVATION OF COAGULATION

INHIBITION OF COAGULATION

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Pabinger et found that the risk of thromboembolism associated with inherited thrombophilias was significant only after age 14; before 14 years of age only 1 of 80 surgical procedures and 0 of 21 leg injuries were followed by thrombosis. After 14 years of age, thromboembolic events occurred after abdominal surgery or leg injury in one third of patients. They recommended that thromboprophylaxis should be used in all patients with inherited thrombophilias over the age of 13 for any high-risk situation, including pregnancy and the postpartum period.

Protein C Deficiency Vascular endothelium plays an active role in preventing blood clot formation in vivo, through a cell-surface thrombin-binding protein, thrombomodulin, which converts thrombin into a protein C activator.61 Interaction between thrombin and thrombomodulin alters macromolecular specificity of thrombin and increases by greater than a thousandfold activation of protein C. Activated protein C, a vitamin K-dependent protein, then acts as an anticoagulant by inactivating two regulatory proteins of the coagulation system, factors Va and VIIIa (see Fig. 1, Table 1).61Two types of protein C deficiency (PCD) have been described (Table 5).140,ls5 Protein C deficiency is associated with both venous and arterial thromboses in extremitie~,~~, heart (myocardial infar~tion),~~ and brain (childhood and adult stroke).49, 94 Acquired PCDs are found in patients with chronic liver disease, DIC, adult respiratory distress syndrome, and malignancie~.'~~ The most likely mechanism of PCD after DIC is increased thrombin formation and accelerated clearance of protein C from the circulation. Protein C concentrations decrease immediately postoperatively, even after minor surgeries, with the lowest values found on the third postoperative day.127In vascular surgery patients, PCD may

Figure 1. Interaction between activation and inhibition of coagulation and schematic presentation of the pathways that participate in the inactivation of factors Va and Vllla. At a site of endothelial injury, coagulation cascade is initiated, resulting in platelet adherence and fibrin formation (clot). At the same time, vascular endothelium plays an active role in preventing excessive blood clot formation. A cell-surface thrombin-binding protein, thrombomodulin, converts thrombin into a protein C (PC) activator. Activated protein C (APC), inhibitor of explosive coagulation, requires plasma cofactor, free protein S, as well as platelets and/or endothelial cells to inactivate two regulatory proteins of the coagulation system, factors Va and Vllla. Protein S exists free in plasma, in complex with C4b protein (C4bP) or in complex with protein S-binding protein and is in reversible equilibrium with C4bP Only the free form of protein S functions in the anticoagulant pathway. Hypercoagulability can result from the absence, low levels, or functionally inactive proteins C and S, or from congenital resistance to APC (the factor V Leiden mutation). PCD = protein C deficiency; PSD = protein S deficiency; APC-R = activated protein C resistance; Va = factor V activated; Vi = factor V inactivated; Vllla = factor Vlll activated; Vllli = factor Vlll inactivated; Th. = thrombin; TM = thrombomodulin. (Data from Esmon CT The regulation of natural anticoagulant pathways. Science 2351348, 1987; with permission.)

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Table 5. INHERITED HYPERCOAGULATION DISORDERS Disorder (with Subtype)

AT-111 deficiency Type 1 Type 2

Prevalence

("/.I 1-2

Normal AT-I11 synthesized at low rate AT-111 at normal concentration but functionally abnormal AT-111 both abnormal and at low concentrations

Type 3 Protein C deficiency Type 1

Type 2 Activated protein C resistance Protein S deficiency Type 1 Type 2 Type 3

Protein Defect

2-5

20-50

Too little protein C Heterozygote has 50% normal protein C concentration Homozygote has no protein C Impaired protein C function Factor V is resistant to physiologic inactivation by activated protein C

2-5 Low level of functionally normal protein Protein binds abnormally to C4-binding protein and enters a bound, inactive state Protein functionally abnormal

Data from Hathaway WE: Clinical aspects of antithrombin 111 deficiency. Semin Hematol 2819, 1991; and Mosher DF Disorders of blood coagulation. In Bennet JC, Plum F (eds): Cecil Textbook of Medicine, ed 20. Philadelphia, WB Saunders, 1996, p 987

contribute to early postoperative thrombosis especially of infrainguinal 55 After arterial infrapopliteal revascularization, about 40% of patients with normal preoperative protein C will become protein Cdeficient, possibly because of increased consumption of protein C in low-grade DIC induced by tissue damage.161 Perioperative Management and Use of Anticoagulants and Fibrinolytics All patients with unexplained episodes of venous thromboembolism should undergo perioperative testing for PCD, especially if they are younger than 45 years old and have a family history of such events. Because acute thrombotic events and warfarin both lower plasma concentrations of proteins C and s, testing for PCD should be performed well after the acute event, and when the patient is no longer taking anticoagulants and anticoagulant effects have worn off.160 Although there is no evidence to support long-term anticoagulation in asymptomatic patients with PCD, they need prophylactic anticoagulants perioperativelys9 especially for the major orthopedic surgeries, which are known to promote thrombosis. Pregnant women with PCD require perioperative antithrombotic prophylaxis with heparin49because warfarin has teratogenic effects. Perioperative anticoagulants are mandatory for patients with PCD undergoing vascular re~onstruction.5~ They

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may also benefit from perioperative transfusions of FFP to replace missing Protein C concentrate is available as a replacement therapy, and is especially recommended for children with homozygous PCD.lZ9 As a rule of thumb, 2 units of protein C per kilogram of body weight Normal will result in a 2% increase in the plasma protein C range of protein C activity is between 70 and 130 U/dL. Subsequent infusions of protein C concentrate must be based on the average halflife which, in young homozygous PC-deficient children, is 7.6 However, anticoagulant therapy still remains the treatment of choice because of complications related to protein C concentrates, such as DIC, indwelling catheter-tip thrombosis, large-vessel thrombosis, bloodtransmitted diseases, and development of antibodies against protein C. Fresh frozen plasma is a source of protein C, but the amount of FFP required to maintain even modest levels of protein C is excessive, causing both high levels of plasma proteins and circulatory fluid overload.l24,205 Thrombolytic therapy with urokinase at 4000 IU/ min appears to be safe and efficient in the treatment of acute lower limb ischemia in patients with PCD, and survival rates are comparable to those of more complex surgical procedure^.'^^ Gruber et alS2demonstrated that administering streptokinase to patients with acute myocardial infarction increased the level of plasma-activated protein C on average elevenfold, even when the pretreatment protein C plasma concentrations were low. The proposed mechanisms of this increase are activation of protein C by plasmin, by thrombin-thrombomodulin complex, or by both. Therefore, streptokinase generates at least two potent antithrombotic factors in the circulation, plasmin and the natural anticoagulant enzyme, activated protein C, which may help prevent reocclusion during or immediately after thrombolysis.82 Activated Protein C Resistance

A new defect in the anticoagulation pathway, resistance to activated 40, protein C (APC), has been recently discovered (see Table l).38, The defect is caused by a mutant gene, inherited in an autosomal dominant pattern, which codes for coagulation factor V. This adenine-to-guanine mutation, known as factor V Leiden mutation, makes factor V resistant to physiologic inactivation by APC. This mutation is the cause of most cases of functional resistance to APC.lS,188, Activated protein C resistance (APC-R) is the most prevalent hypercoagulable state associated 164 and it with increased risk for recurrent venous thromboembolism,24~ has been detected in 20% of the women with obstetric complication^.^^^ The carrier frequency of the factor V Leiden mutation in the healthy population is between 2% and lo%.”’, 162, 164 Heterozygous patients have a sevenfold increase in risk for DVT, and homozygous patients have an 80-fold increase.171It is less frequently associated with arterial thromboembolism, such as myocardial infarction and cerebrovascular disease.163 Activated protein C resistance appears to be a risk factor for failure of

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infrainguinal bypass grafts, and screening for APC-R may be useful in patients with peripheral vascular disease so that normal thrombogenic balance can be restored with anticoagulant therapy.151 Perioperative Management and Use of Anticoagulants and Fibrinolytics Standard perioperative antithrombotic regimens (using heparin, warfarin, or LMWH) were used to correct hemostatic imbalance leading to thrombotic events in APC-R patients undergoing microvascular surgerys coronary artery bypass surgery60or peripheral vascular surgery.52 Patients with factor V Leiden mutation after hip surgery had a significantly lower incidence of venous thrombosis if prophylaxis was continued for several weeks after hospital discharge compared to patients who had prophylaxis stopped when discharged from the hospital.190Other thrombotic events attributed to APC-R are indwelling catheter thrombosis in pediatric patients149and early graft loss in renal transplant pat i e n t ~ In . ~ pediatric ~ APC-R patients with Broviac catheters, low-dose unfractionated heparin did not prevent catheter thromb~ses,'~~ although in a previous study in children without APC-R, the therapy was successfu1.201 Aprotinin, an antiprotease enzyme from bovine lungs that competitively inhibits APC, reduces blood transfusion requirements during cardiac surgery.17, However, it should not be used during cardiac surgery on patients with factor V Leiden mutation, who have an inherited resistance to APC proteolysis, because it may precipitate thrombosis.37, 174, 189, 192 The prevalence of APC-R among patients with peripheral vascular disease is very high (24%).66Because early graft thrombosis may be associated with APC-R,120all patients who experienced acute thromboembolism should be'giiren long-term thrombopr~phylaxis.~~ In patients who have-an uneventful recovery, chronic anticoagulation may not be needed. However, Foley et aP6 demonstrated that APC-R did not affect long-term graft patency after arterial reconstructive surgery. Protein S Deficiency

The way in which protein S deficiency (PSD) affects coagulation is shown in Figure 1 and Table 1. Protein S deficiency is inherited in an autosomal dominant fashion,59and it has been associated with venous185 and arterial thromboembolism.3~ 59 The prevalence of heterozygous PSD in patients with venous thrombotic disease is between 5% and 8%87with similar rates among those with arterial thromb~sis.~ Whereas venous thromboembolic manifestations include DVT of lower extremities and mesenteric vein thrombosis, arterial manifestations are ischemic stroke, myocardial infarction, and arterial thrombosis of the lower extremitie~.~~, 73, la7 Three types of PSD have been described (see Table 5).35, 81 Acquired PSD may be associated with systemic lupus erythemato-

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sus, oral anticoagulation therapy, oral contraception, pregnancy, liver 77 During CPB, the complement cascade is disease, or ~hemotherapy.~~, activated via the classic pathway,@ increasing plasma concentrations of the C4-binding protein-which binds free protein S, leading to its depletion-and to reduced anticoagulant activitya7,148 (see Fig. l ) . 1 4 0 Perioperative Management and Use of Anticoagulants

No clear association has been demonstrated between thrombotic episodes and surgery in patients with PSD, although one author postulated that surgical trauma was the triggering event for thrombosis in 21% of protein %deficient patients.45In patients with PSD, short-term antithrombotic prophylaxis should be used whenever the risk of thrombosis is raised by immobility, pregnancy, or surgery. If the patient develops symptomatic thrombosis (DVT or pulmonary embolism), long-term anticoagulation should be implemented. In heterozygous PSD patients, a thrombotic state may be induced by extracorporeal circulation or by trauma to the endothelium of arterial or vein grafts, which may occur during coronary artery surgery.@De Paulis et a1@suggested that proteins C and S should be checked in all patients undergoing repeated surgery for early graft closure. They also suggested that after coronary artery bypass surgery, protein C-deficient or protein S-deficient patients should be treated with lifelong warfarin therapy because of the increased risk of early coronary artery bypass graft thrombosis. These patients should be given heparin in the immediate postoperative period because warfarin can cause transient hypercoagulability by further decreasing levels of proteins C and S.4 This paradoxical, warfarin-induced hypercoagulability with subsequent thrombosis may manifest with skin necrosis.159The problem can be prevented by initiating anticoagulation with heparin and switching to warfarin once a therapeutic PT is achieved. Recently, concentrates of human protein C and protein S have been used to protect patients with severe antithrombotic deficiencies from thromboembolic events.205 Alternatively, FFP, which contains proteins C and S, may be used; however, morbidity may be increased because of volume overload.26In cardiac surgery patients with PCD, antifibrinolytic agents such as epsilon aminocaproic acid (frequently used during these procedures) may be at least theoretically contraindicated because these patients are already deficient in endogenous antifibrinolytic activity. However, the effects of these drugs in vivo are unknown.81 Several general perioperative preventive measures should be implemented in all patients with PSD: preventing hypothermia; decreases in cardiac output; deliberate hypotension; hypovolemia; or excessive blood loss. Pregnancy is a high-risk period for thromboembolic disease, and recurrent thromboembolism may occur in pregnant patients with PSD if they are not anti~oagu1ated.l~~ Therefore, these patients should receive perioperative antithrombotic prophylaxis with heparin.63

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Deficiency of Antithrombin 111

Deficiency of antithrombin I11 (AT-111) can be inherited or acquired. The frequency of inherited AT-I11 deficiency is 1 per 2000 to 20,000 people.88The mechanism of disease is described in Table 1, and types of deficiency are described in Table 5. It is an autosomal dominant disorder56that may present with recurrent DVT and pulmonary embolisms.47, 56, Iol This deficiency may cause arterial thrombotic events, such as cornonary artery thrombosis, peripheral arterial thromboses,34,97 and cerebral thromboembolism in children.204Clinical features of AT-I11 deficiency also include a first thrombotic episode at an early age, recurrent venous thromboembolism, thrombotic episodes during pregnancy, and resistance to heparin therapy.88 Acquired AT-I11 deficiency has been observed in liver disease, DIC, pregnancy, oral contraceptive use, and menopause.79Surgery such as total hip replacement may produce significant decreases in AT-I11 plasma concentrations, but low AT-I11 concentrations do not predict postoperative thromboembolism and may be attributed to h e m ~ d i l u t i o nor ~ ~to the stress of surgery.178In elective hip replacement, levels of AT-I11 return to normal more rapidly after epidural anesthesia than after general anesthesia, which may explain why epidural anesthesia is associated with lower rates of thromboembolic complication^.^^ Perioperative Management and Use of Anticoagulants and Fibrinolytics

Thromboembolisms caused by AT-I11 deficiency should be perioperatively treated with anticoagulation therapy, AT-I11 concentrate, and fibrin01ytics.l~~ Lifelong treatment with anticoagulants in asymptomatic patients with AT-I11 deficiency is not justified because usually there are no thrombotic sequelae and survival is not improved after discontinuation of anticoag~lation.~~~ However, all asymptomatic pregnant patients with AT-I11 deficiency and patients with previous thromboembolism should be treated with heparin perioperatively.88,154 Intravenously administered heparin decreases the plasma concentration of AT-I11 and facilitates its clearance by increasing uptake by the liver.lo8Therefore, perioperative administration of heparin may actually reduce plasma AT-I11 concentrations and worsen the hypercoagulable state. Although some studies suggested that heparin administration alone is safe and sufficient treatment for acute thrombotic events,86others suggest that AT-I11 should be replaced simultane~usly~~ because AT111-deficient patients undergoing surgery who are given other forms of prophylaxis may still develop DVT.195The plan for perioperative anticoagulation for vascular surgery may include discontinuing warfarin 3 days before surgery and then reinstituting the warfarin at 10 mg daily beginning the evening before surgery along with subcutaneous heparin at 10,000 U twice daily.96AT-I11 replacement should be given just before the surgery at a dose calculated to increase AT-I11 activity to at least

PERIOPERATIVE ANTICOAGULATION AND THROMBOLYSIS

939

120%.96Usually, two AT-I11 doses are sufficient. The loading dose is calculated with the following equation, which is based on expected incremental in vivo recovery above baseline level for an AT-I11 of 1.4%/ IU per kilogram adrninistered:In

Units required (IU) = [desired-baseline AT-I11 level*)] x weight (kg)/1.4 +expressed as % normal level based on functional AT-I11 assay The goal of this perioperative replacement therapy is to maintain levels of AT-I11 above 80% at all times because values above this level are considered protective. Based on the pharmacokinetics of AT-I11 (initial 50% disappearance time for AT-I11 is between 8-20 hours), the second dose (50% reduced) may be given 10 to 12 hours later.96Typically, prophylactic heparin anticoagulation is started the evening before surgery, and further AT-I11 administrations may be discontinued after the second AT-I11 dose. Long-term AT-I11 therapy is suggested only for patients undergoing multiple arterial reconstructions or prolonged imm~bilization.~~ During arterial reconstructive surgeries when therapeutic heparin anticoagulation is necessary, even higher doses or more frequent administration of AT-I11 are suggested because heparin causes AT-I11 levels to decrease.128 Continuous infusion of heparin in patients with unstable angina can contribute to a preoperative decrease in AT-I11 plasma concentration. If these patients undergo cardiac surgery, CPB will cause further decreases (50%-60%) in AT-I11 concentrations, which persist over 24 to 48 postoperative hours.l18 These patients may benefit from preoperative administration of AT-I11 concentrate to keep AT-I11 levels above 80%.IIs Thrombolytic therapy is successful in patients with thrombotic events caused by AT-I11 deficiency.5O.70, 93 Direct endovascular thrombolysis with 850,000 IU of urokinase followed by heparinization has been used for isolated deep cerebral thrombo~is.~~ Similar therapies with urokinase, heparin, AT-I11 concentrate, or all three, have been successful in treating neonatal aortic t h r o m b o s i ~and ~ ~ dural sinus thrombo~is.~~ ACQUIRED ABNORMALITIES OF BLOOD COAGULATION Heparin-Induced Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is caused by platelet activation and aggregation secondary to the development of heparin-induced antibodies, usually IgG.Is0The IgG antibodies form immune complexes with platelet factor 4 and heparin.6,203 There are two types of HIT.27Type 1 is associated with mild thrombocytopenia seen in virtually all patients 'receiving heparin. Type 2 is associated with paradoxical thromboembolic complications and usually occurs 6 to 14 days after heparin treatment or earlier in patients who have had prior exposure to

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heparin.27Although HIT type 2 is usually associated with thrombocytopenia, severe thrombotic complications may develop without decrease in platelet counts.84 The risk of thrombosis in HIT is approximately 10% to 20%.207 Approximately 20% of patients with HIT may develop white clot syndrome in which the thrombus consists mainly of platelets and is pale.2o7 If the patient has familial thrombophilia, such as PCD, and simultaneously develops HIT, there is a much higher likelihood of severe thrombotic events.lZ5HIT has been shown to be a risk factor for early graft thrombosis in vascular Actually, all types of thrombotic events can be found in patients with HIT, including myocardial infarction and stroke.84 Preventing Heparin-Induced Thrombocytopenia

Generally, to reduce the incidence of HIT, oral anticoagulants should be used instead of heparin whenever the indication for anticoagulation is purely prophylactic, as it is frequently in orthopedic patients.92Initiation of LMWH thromboprophylaxis in patients with a history of HIT should overlap with warfarin for a minimum of 4 to 5 days. It is important to follow the same principle postoperatively; therefore, in addition to the 2 to 5 days of overlapping heparin-warfarin therapy, the international normalized ratio (INR) should ideally be kept at 2.0 or higher for 2 consecutive days. Perioperative Management and Use of Anticoagulants and Fibrinolytics

Perioperatively, all patients who have thrombotic complications during heparin treatment with or without thrombocytopenia should be screened for HIT. In patients with HIT and related thrombotic events, thrombin4pecific inhibitors are the agents of choice for anticoagulation. Hirudin (a direct thrombin inhibitor which, in contrast to heparin, does not require antithrombin for its anticoagulant activity) and argatroban (a synthetic derivative of L-arginine and a reversible, direct thrombin inhibitor) can replace heparin in patients with HIT.130,lM Ancrod is another direct thrombin inhibitor that may be used, because it apparently does not cause bleeding and preserves mature cross-linked fibrin.33 Another alternative is heparinoid, a heparin-like agent with a very low degree of sulfation and lower molecular weight than unfractionated heparin which, therefore, is less likely to bind to platelets or to be immunogenic. Because heparinoid contains a small amount of heparinlike substance, it has the potential to cause HIT, and plasma should be tested for antibody cross-reactivity with heparin, which occurs in about 10% of cases.95Low molecular weight heparins are possible third-line therapy, but in up to 90% of cases they cross-react with antibodies of patients with HIT.206Fibrinolytic agents, such as streptokinase and urokinase, may be used as a thrombolytic therapy in HIT with thrombo-

PERIOPERATIVE ANTICOAGULATION AND THROMBOLYSIS

941

s ~ s , ~ O but they cannot be used immediately after surgery in patients with HIT because of potential wound breakdown. Patients who undergo CPB usually have been exposed to heparin on several occasions before surgery. Receiving high doses of heparin during CPB and continuing exposure to heparin in the postoperative period may predispose them to HIT. Interestingly, Bauer et all1 found that 20% of patients had detectable heparin-induced antibodies before CPB and an astonishing 75% did after the procedure. However, only 0.95% developed serious complications related to HIT, which suggests that heparin-induced antibodies are common but do not always cause clinically manifested thrombosis." If CPB can be delayed and the patient does not require heparin therapy, discontinuing heparin for several weeks before cardiac surgery will decrease heparin-dependent antiplatelet antibodies (in vitro tests of heparin-induced platelet aggregation and activation will become negative after several weeks). Three patients in whom surgeries were delayed until platelet aggregation studies were negative underwent CPB with standard heparinization, and no perioperative thrombocytopenia or thrombosis occurred.150A recent study provided evidence that r-hirudin (a recombinant gene product) may be a safe and effective alternative for systemic anticoagulation in patients with documented or suspected HIT type 2 in whom cardiac surgery is needed urgently. This agent is a highly specific thrombin inhibitor with little effect on other serine proteases. This product is not used widely for CPB because it requires a monitoring test that is not readily available, ecarin clotting time, instead of aPTT or activated clotting time (ACT). The elimination half-life of rhirudin is 30 to 60 minutes, and its effects can be reversed with rmeizothrombin. More detailed instructions for treating patients with HIT undergoing CPB can be found in the review by Shorten and Comunale.184For HIT patients undergoing carotid endarterectomy, LMWH may be considered instead of unfractionated heparin, if the patient tested negative for LMWH-induced platelet antibodies. The empiric doses of LMWH in three patients who underwent uneventful carotid endarterectomy in one case series were between 0.8 and 1.4 mg/kg body Protamine sulfate may be used to reverse the effects of LMWH (1 mg of protamine sulfate for each 1 mg of LMWH administered); however, reversal is not as predictable as reversal after unfractionated heparin."O

Disseminated lntravascular Coagulation

Disseminated intravascular coagulation is the most frequent coagulopathy encountered by anesthesiologists and intensivists. This syndrome, which may occur in a variety of disorders, results when the coagulation cascade is activated, generating thrombin followed by fibrin01ysis.'~Disseminated intravascular coagulation is initially a thrombotic process with secondary hemorrhage occurring when platelets and clotting factors are sufficiently de~1eted.l~~ Underlying clinical conditions

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include those that cause release of procoagulant materials, such as incompatible transfusion, malignancies, endotoxemia, penetrating head injuries, malaria, burns, crush injuries, retained placenta or dead fetus, abruption, missed abortion, amniotic fluid embolus, and eclampsia. Other disorders that may cause DIC are endothelial injury (aortic crossclamping), antigen-antibody reaction, vasculitis, thrombotic thrombocytopenic purpura, or pulmonary embolism. Disseminated intravascular coagulation associated with ischemic liver injury during aortic reconstructive surgery may have high m~rtality."~ The cause of DIC during aortic reconstruction is presumably multifactorial. It may involve endothelial injury with release of prothrombin activator^'^^ or be caused by prolonged intestinal ischemia, hepatic ischemia, or both.32 Patients usually present with diffuse bleeding from venipuncture, surgical sites, or mucous membranes. A diagnosis of DIC can be made with assays for fibrin split products (FSP), fibrin degradation products (FDP), or the D-dimer fragment of fibrin. Other suggestive findings are decreased platelet count, decreased fibrinogen concentration, and prolonged prothrombin time (PT) and aPTT. Usually, at the time of diagnosis, all patients have platelet counts and fibrinogen levels no more than 50% An important group of patients with DIC in the everyday anesthesiologist's practice are those with chronic, compensated DIC who usually present with normal PT and aPTT and with the platelet count and fibrinogen either slightly decreased or normal, such as in patients with aortic aneurysms.' These patients may have increased FDPs, FSPs, or Ddimers. In these patients, even minor procedures may cause significant bleeding secondary to the activation of the clotting Perioperative Management and Use of Anticoagulants

Disseminated intravascular coagulation treatment should begin with correction of the precipitating event, such as infection or sepsis. Treatment options to correct the hemostatic defect and to dampen the intravascular clotting and fibrinolytic process include transfusion of blood products, heparin, AT-111, and fibrinolytic agents. Heparin may be beneficial in chronic DIC,l6,91 but some studies have found that heparin in acute DIC either brings benefit,36no benefit,lo7or causes damage.lZ1So far, heparin has not been proven to reduce morbidity and mortality in DIC, although some patients with malignancy-induced DIC benefit from heparin therapy used cautiously and at low Heparin is not required to prevent distal thrombosis when the aorta is cross-clamped. It does not contribute to perioperative blood loss, and it may protect against myocardial infar~ti0n.l~~ In a recent randomized, double-blind trial in 35 patients with septic shock and DIC, patients pretreated with AT-I11 concentrate had 44% lower mortality compared to untreated patients.67In patients with DIC and AT-I11 deficiency, raising AT-I11 levels to about 80% of normal has been proposed in order to correct the hemostatic disorder, but no large study has been done to

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943

establish a definite beneficial role of AT-I11 in the treatment of DIC. In postoperative treatment of the patients with DIC after liver resection, gabexate mesilate (an inhibitor of several coagulation and fibrinolytic proteases, including thrombin, plasmin, and factor Xa) may be used. However, its clinical use is not yet e~tab1ished.l~~ Coagulation Abnormalities Associated with Liver Disease

Liver synthesizes vitamin K-dependent procoagulant proteins, fibrinogen, plasminogen, AT-111, and other proteins affecting coagulation.28 It appears that liver works near its maximum capacity in synthesizing vitamin K-dependent proteins. These protein levels are the first to decrease in liver disease, especially factor VII.lZ6As procoagulant factors decrease, plasma concentrations of AT-I11 and proteins C and S will also decline. The decline of factor VII parallels the decrease in the protein C level.80As cirrhosis progresses, plasma protein C and AT-I11 concentration decrease faster than protein S c~ncentration.~~ Protein C inhibitor levels also decrease in cirrhotic patients.68Patients with congenital metabolic disorders, such as Dubin-Johnson, Rotor, or Gilbert’s syndromes, may have low titers of factor VII and may require perioperative FFP. Perioperative coagulopathy related to hepatectomy is frequentlsl,193 and is attributed to significant decreases of plasma protein C activity and thrombomodulin.181Coagulopathy during orthotopic liver transplantation (OLT) is related to either primary liver disease or to the release of exogenous heparin and endogenous heparinoids from the donor hepatocytes.lo5In addition, exogenous heparin, administered to the donor during harvesting of the organ, may be released during reperfusion of the donor liver. Endogenous heparinoids are normally cleared by the liver, but cirrhosis decreases elimination, which increases the risk of intraoperative b1eedi11g.l~~ Also, donor liver releases very high levels of tissue plasminogen activators causing severe fibrinolysis in the presence of very low levels of plasminogen activator inhibitor.158 Significant changes in coagulation are seen during the anhepatic stage as well as during the cross-clamping of the hepatic vasculature, which completely stops hepatic production and clearance of the elements involved in coagulation. This produces intravascular coagulation, increases fibrinolysis, and decreases levels of coagulation factors.99 Perioperative Management and Use of Anticoagulants and Fibrinolytics

Perioperative management of patients with chronic liver disease may include administration of platelets for thrombocytopenia, either FFP or vitamin K to correct deficiencies in vitamin K-dependent coagulation factor, and cryoprecipitate to correct hypofibrinogenemia. Therapy with vitamin K may normalize PT after approximately 6 to 8 hours. In

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patients with hemophilia A or B undergoing OLT, it is necessary to increase levels of specific coagulation factors during the preanhepatic and anhepatic stages. When new grafted liver begins to function, no additional treatment is necessary.71,75, 114, 137 Patients with PCD who undergo OLT have a tendency to develop thromboembolisms, so heparin should be given until the transplanted liver starts to produce protein C. Patients with AT-I11 deficiency who undergo OLT are prone to develop thromboembolism; however, because they are resistant to heparin, they should receive AT-I11 concentrate until the transplanted liver starts to produce it.99Patients with hepatic neoplasms or Budd-Chiari syndrome who undergo OLT may manifest a hypercoagulable state and may require heparin (1000-2000 U intravenously) during and after Postoperatively, these patients may require a longer period of anticoagulation. Oral anticoagulant therapy may be started simultaneously with heparin, which should not be discontinued until the PT, expressed as INR, is in the therapeutic INR range of 3 to 5 (target INR, 4) for 2 days. After this intensity of anticoagulation has been maintained for 3 weeks, the INR range may be lowered to 2.5 to 4 (target INR, 3). Oral anticoagulation should be continued for as long as thrombophilia persists. Coagulation Abnormalities Associated with Renal Disease

Patients with nephrotic syndrome tend to have venous and arterial thromboses. This hypercoagulable state is caused by multiple factors including hemoconcentration and increased fibrinogen levels secondary to the use of diuretics,131and increased factor VIII activity with shortened PT and aPTT secondary to steroid use.153,199 In addition, increased protein elimination through the glomerular basement membrane in patients with nephrotic syndrome results in loss of AT-I11 and protein S in urine.'02,202 Surgery in patients with nephrotic syndrome may carry a high risk of perioperative thromboembolic complications and even arterial bypass graft occulsions.186Thrombophilias have also been postulated to contribute to the failure of renal transplants." Perioperative Management and Use of Anticoagulants and Fibrinolytics

Treatment of thrombosis secondary to the hypercoagulable state in nephrotic syndrome may include anticoagulants, thrombolytics, and AT111. If arterial thrombosis is present, heparin must be used in high doses. Antithrombin I11 potentiates the effects of heparin, and replacement with AT-I11 concentrates or FFP may be necessary to ensure proper systemic lol, IR6 antic~agulation.~~, Thrombolytic therapy has been used for renovascular thrombosis associated with nephrosis, and urokinase or streptokinase infused directly into the renal artery or vein restores kidney perfusion.'", 139 These

PERIOPERATIVE ANTICOAGULATION AND THROMBOLYSIS

945

patients must be monitored appropriately and kept in an intensive care unit when urokinase or streptokinase is given. After successful completion of the thrombolytic course and after venogram demonstrates resolution of the clot, patients will require systemic heparini~ati0n.I~~ Because of the fear of possible epidural hematoma, regional anesthesia in these patients should be avoided.

Coagulation Abnormalities Associated with Malignancy Malignancies may produce hyper- or hypocoagulable states that significantly alter the hemostatic system. Neoplasms may be associated with acquired deficiencies in AT-111, protein C, and protein S. In addition, increased levels of factors I, V, VIII:c, IX, and XI may also contribute to hypercoagulability in patients with malignancies. Mucinous adenocarcinomas frequently produce thrombotic states by generating sialic acid which in turn initiates coagulation by activating factors X and Xa. Pancreatic carcinoma also triggers thrombogenesis by secreting trypsin systemically and causing intravascular c ~ a g u l a t i o nDisseminated .~~ intravascular coagulation may be present in patients with myeloproliferative diseases or cancers of the biliary system, breast, colon, lung, or Intravenous injection of tumor cells may cause DIC,173so it has been proposed that in addition to producing thrombogenic products, tumor cells themselves may directly cause DIC. Patients with lupus anticoagulants and without clinical lupus erythematosus may have associated underlying malignancies,112and lupus anticoagulants may be present in Hodgkin’s and non-Hodgkin’s lymphomas.74 Malignancies are also associated with hypocoagulable states. Multiple myeloma, Waldenstrom’s macroglobulinemia, monoclonal gammopathies, hairy cell leukemia, chronic lymphocytic leukemia, and malignant lymphomas have all been reported to diminish the function of vWF and produce acquired VWD.~O~ Perioperative Management and Use of Anticoagulants and Fibrinolytics When evaluating cancer patients for surgery, it should be remembered that up to 15% of them may have clinical DIC,143and even more may have some other abnormality of blood ~oagulation.’~~ Patients in hypercoagulable states are usually treated preoperatively with warfarin, but those who have already developed thromboses require immediate heparinization. Warfarin is ineffective in patients with tumor-associated thromboses, probably because warfarin cannot inhibit the protease activity of thrombin or of thromboplastic substances.12Because thrombotic complications may be fatal, therapy with heparin is of paramount import a n ~ e .Prophylactic ’~~ treatment of malignancy-induced DIC with heparin has also been recommended, especially in patients who have DIC associ-

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ated with acute promyelocytic leukemia who always have some degree of bleeding.loOPerioperative treatment of patients with subclinical DIC is a gray area. Nand and M e ~ s m o r e 'suggest ~~ instituting therapy only in patients with clinical bleeding. The bleeding in cases of severe DIC may be managed with replacement of platelets or fibrinogen by means of cryoprecipitate and FFP (see previous section on DIC). Antiphospholipid Antibody Syndrome

Antiphospholipid antibody (APL) syndrome is caused by a heterogeneous group of antibodies that markedly increase thrombotic events. The hallmark of this syndrome is the presence of either lupus anticoagulant (LAC), anticardiolipin antibody (ACA), or both. Anticardiolipin antibodies are directed against protein-phospholipid complexes in the plasma membranes of platelets and e n d ~ t h e l i u m and ' ~ ~ against plasma proteins.179 Lupus anticoagulant and ACA are found in up to 60% of lupus erythematosus patients,179but they may also be found in other individua l ~ . Both ' ~ ~ antibodies are strongly associated with the risk of arterial and venous thromb~sis,~ thromb~cytopenia,'~~ hemolytic cardiac and neurologic complications, and fetal loss.122Approximately 30% to 60% of patients with either antibody will have thromboses,22, 85 mostly DVT of the leg. About 10% of patients will have arterial thromboses of the lower extremitie~,~~ or more rarely, coronary thrombosis causing myocardial infarcti~n.'~~ Increased thrombotic complications in patients with APL syndrome have been noted in other cardiovascular surgeries, including cardiac valve replacements, coronary artery bypass procedures, upper and lower extremity bypasses, aortic reconstruction, and carotid endarterectomie~.~~ Lupus anticoagulant immunoglobulins interfere in vitro with all phospholipid coagulation tests, including PT, aPTT, and Russell's viper venom time, by competing with coagulation factors to bind to pliospho1 i ~ i d s .Therefore, I~~ tests for LAC must use limited amounts of phospholipid reagent (tests include dilute aPTT and dilute Russell's viper venom time) or none (kaolin clotting time or thrombin time). Tests that use no phospholipid are not prolonged in the presence of LAC.179Anticardiolipin antibodies are identified by immunoreactivity on ELISA plates coated with cardiolipin and then blocked with bovine or human serum.179 Perioperative Management and Use of Anticoagulants and Fibrinolytics

Treatment and prevention of LAC-related and ACA-related thromboses includes anticoagulants, aspirin, and, less frequently, intravenous gamma globulin^.^^ Lifelong treatment with warfarin is recommended for patients positive for either antibody who have previous multiple thrombotic episodes (Fig. 2).48,*06 In these patients, the INR should be

PERIOPERATIVE ANTICOAGULATION AND THROMBOLYSIS

Current thromboembolic event

947

Previous thromboernbdic events

No peviws thromboembolic events

Life-long warfarin INR>3

0bservation Antiplatelet therapy (aspirin)

I

Longterm self-administration heparin S.C. or LMWH - Corticosteroids? - Imrnunosupression?

I

I

I

I

Preoperatively

1

Heparin S.C. 5,000 U q8h

Continuous heparin infusion Heparin 25,000 U S.C. 2-3 divided doses, last one 2h before surgery

I

I

I

lntrroperstively

w

I

1

General Measures: Antithrombotic stockings Use of PRBC instead of whole blood (when necessary) Prevention of infection

H

Figure 2. Algorithm for perioperative thromboprophylaxis in patients with lupus anticoagulant (LAC) or anticardiolipin antibody (ACL). SC = subcutaneous; LMWH = low molecular weight heparin; PRBC = packed red blood cells; INR = international normalized ratio. (Data from Madan R, Khoursheed M, Kukla R, et al: The anaesthetist and the antiphospholipid syndrome. Anaesthesia 52:72, 1997; with permission.)

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kept above It is important to emphasize that many patients who have APL syndrome fail to respond to warfarin therapy. Thrombotic events in patients taking warfarin are suggestive of APL syndrome. These patients should be treated over the long term with self-administered subcutaneous heparin.2,29 Figure 2 delineates general and perioperative prophylaxis in patients with LAC or ACA. In these patients, an extensive laboratory work-up is recommended before any surgery, including a complete coagulation screen and platelet count because PT and aPTT may be elevated. This is true especially in patients with systemic lupus erythematosus because of antibodies to various coagulation factors. Factor deficiencies and thrombocytopenia heighten the risk of perioperative bleeding, which may preclude regional anesthesia. In contrast, regional anesthesia is not contraindicated in isolated elevation of aPTT secondary to LAC without thrombocytopenia or a history of bleeding diathe~is.~~, 90 Regional anesthesia reduces the incidence of thromboembolic events, such as DVT and pulmonary embolism,133, 138 but it is not known if this technique also has antithrombotic effects in patients with ACL syndrome. Other nonspecific intraoperative measures (see Fig. 2) to prevent thrombosis in patients with APL syndrome have included antithrombotic stockings, warming all intravenous fluids, preventing hypothermia, maintaining good hydration, using packed red blood cells rather than whole blood, and avoiding medications that may precipitate thrombosis, such as hydra1a~ine.I~~ Asymptomatic patients with LAC or ACA, no previous thrombotic events, and a normal coagulation screen should receive preoperative prophylactic subcutaneous unfractionated heparin. Patients who have a history of recurrent thromboses should receive a higher preoperative dose of heparin in 2 to 3 divided doses,'O with the final dose about 2 hours before surgery.123The aPTT should be checked before neuraxial block. For vascular surgery, intravenous heparin infusion will prevent clotting in the graft. ' If regional anesthesia is indicated, intravenous heparin may be stopped several hours before surgery, the aPTT should be checked, and, if normal, neuraxial block, with or without catheter insertion, may be initiated. Postoperatively, if heparin is used during surgery, aPTT should be checked and if not prolonged, the epidural catheter may be removed. One hour later, systemic heparinization may be resumed. In patients who require uninterrupted heparin infusion, general anesthesia is the only option. Even when receiving 40,000 U of heparin, patients with LAC or ACA may develop postoperative 136 In those patients, defibrinating enzyme such as Russell's viper venom may be administered intravenously.10 In asymptomatic patients, 5000 U of heparin can be given subcutaneously every 8 hours for several postoperative days.123In patients with a history of thromboses, subcutaneous heparin (25,000 U) in divided doses should be continued postoperatively. Warfarin should be administered at a dose that stabilizes the INR at 3 to 3.5, and should be continued for a prolonged period of time.9,58, 115, 141 Patients with APL antibody syndrome may have marked resistance to warfarin, and, occa-

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949

sionally, doses of 20 mg daily may be needed to achieve an INR of 3.1° No matter which type of heparin is used (unfractionated or LMWH), one universal principle must be followed in the transition from heparin anticoagulation to oral anticoagulation: Heparin anticoagulation should overlap with warfarin for at least 4 to 5 days, and the INR should be reconfirmed to be in desired range for 2 consecutive days before heparin is discontinued. In pregnant patients with the APL antibody and a history of recurrent fetal loss, aspirin may be used in conjunction with prednisone with relative success.'72 During CPB in patients with circulating lupus anticoagulants, the plasma heparin concentration should be determined directly rather than by using aPTT or activated clotting time (ACT).54Both ACT and aPTT are increased in patients with LAC, even before heparinization, but increased values do not necessarily indicate increased potential for bleeding.Io3Ducart et a154administered empiric doses of 300 U/kg heparin before CPB; however, for safe empiric administration, it is important to know that the AT-I11 levels are normal because heparin action depends on AT-I11 plasma concentration. Because of the heparin consumption during CPB and rewarming, heparin concentrations must be directly measured f r e q ~ e n t l y . ~ ~ Preoperative screening for LAC should be performed in all vascular surgery patients younger than 50 years old, patients with systemic lupus erythematosus, patients with a history of unexplained thrombotic events, and those who have prolonged aPTT without obvious cause.2 One third of all patients undergoing lower extremity bypass surgeries have APL antibodies, in most cases (87%)ACA.l16 Perioperative treatment in those patients may include steroids, antiplatelet agents, warfarin, and heparin, with variable success.2,65* lR3,194 Steroids and antiplatelet agents, although used, have not been proven benefi~ia1.l~~ Warfarin therapy is indicated in all patients with arterial or venous thromboses as long as they have detectable levels of APL antibodies, but there is no need for prophylactic treatment if the patient did not experience arterial or venous thrombo~es.'~~ Surprisingly, a large prospective study found that the presence of APL antibody made only a minimal difference in infrainguinal graft 4-year primary patency rates, and no difference in limb salvage and survival rates.l16All patients in this study received systemic heparin intraoperatively and aspirin after surgery. Some, but not all, received long-term warfarin treatment.Il6 CONCLUSION

With improved knowledge about coagulation disorders and with the availability of replacement therapy for deficient coagulation factors, surgeries that require intraoperative anticoagulation are becoming safer. At the same time, more patients undergoing peripheral vascular reconstructive surgeries are recognized to have hypercoagulable defects, and further studies are necessary to establish more precise criteria for periop-

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erative thromboprophylaxis in these patients. It is still not known how safe it is to interrupt thromboprophylaxis, or the risks of performing neuroaxial anesthesia in patients with thrombophilias who are receiving some form of thromboprophylaxis. Neuraxial block may increase the risk of intraspinal bleeding in patients who are receiving antiplatelet drugs or anticoagulants. The American Society for Regional Anesthesia has recently issued recommendations to minimize the potential for bleeding complications in these patient^.^ ACKNOWLEDGMENT We wish to thank Dr. Kenneth Ouriel, MD, Chief of vascular surgery at The Cleveland Clinic, for reviewing the manuscript; Ms. Jessica Ancher from the Department of Scientific Publications, The Cleveland Clinic Foundation, for editorial collaboration; and Ms. Diane Jordan, for typing the manuscript.

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