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Chapter 25 discusses the evidence that normovolemic anemia or polycythemia increases perioperative morbidity. The results indicate that knowledge and pretreatment of polycythemia might decrease perioperative morbidity and mortality.
Except for patients with ischemic heart disease (see later), no such evidence exists for normovolemic anemia (this topic is also reviewed in Chapter 25 ).[431] [432] Thus, there are no specific preoperative routines for anemia itself, except regarding patients who have or are likely to have ischemic heart disease (as determined by risk factors).[864] [865] [866] [867] [868] [869] For these patients, hematocrits above or below 29% to 34% were found in two separate studies to be associated with increased episodes of myocardial ischemia after vascular surgery[431] [432] (see Fig. 27-18 ). For patients at risk for current ischemic heart disease, data indicate that transfusion to a hematocrit level of 29% to 34% may be appropriate (also, see the earlier section on cardiovascular diseases). It should be remembered that anemia is a reduction in circulatory erythrocyte mass below the range of values considered normal for persons of the same sex at the same location (age older than 6 months, race, and ethnic background do not explain anemia). Each erythrocyte lives for approximately 120 days; therefore, replacement of 15 to 20 mL of senescent cells needs to
Furthermore, because anemia can be a hallmark of many other diseases possibly affecting perioperative anesthetic management, the preoperative presence of anemia requires a search for and treatment of the underlying cause. For instance, anemia could indicate renal insufficiency or a drug reaction, both of which could alter anesthetic management. For this reason, the cause of anemia should be known preoperatively. Similarly, polycythemia can be a primary disease (e.g., polycythemia vera), or it can be secondary to smoking, the use of diuretic drugs, chronic use of androgens, hypoxia, or other forms of chronic lung/heart disease. Phlebotomies are quite effective for patients with mild polycythemia. Cerebral blood flow improves when the hematocrit is kept below 45%.[866] [867] No prospective controlled study has been performed on humans regarding a possible decrease in perioperative morbidity or wound healing[431] [432] [864] [865] [866] [867] [868] [869] from perioperative treatment of anemia or polycythemia. The time of most danger to the patient may be the early recovery room period, during which time oxygen delivery to the lungs is perhaps at its worst[431] [432] (also see Chapter 71 and Chapter 74 ). When religious convictions prohibit blood transfusion and the patient is anemic or may become anemic, therapeutic options include autotransfusion with the salvaged or removed blood always connected to (or in contact with) the patient and the use of blood substitutes. Although perfluorocarbons have fallen into disrepute because of effects on reticuloendothelial function, other substitutes, including hemoglobin-based substitutes, may become available, and synthetic erythropoietin will find greater use in preoperative prophylaxis and preoperative predeposit blood programs.[811] [870] This subject is discussed in greater detail in Chapter 47 and Chapter 48 .
Erythropoietin is one of the substances necessary for normal production of red blood cells. Production and secretion of erythropoietin from the peritubular cells of the kidney are stimulated by tissue hypoxia. Signal transduction of this hypoxic stimulus depends on a hemecontaining oxygen-sensing protein that mediates changes in the stability of messenger RNA from chromosome 7 in erythropoietin-producing cells. Erythropoietin triggers quiescent, early erythroid progenitor cells into cycle by acting like a mitogen and facilitating differentiation into late committed erythroid progenitor cells. In normoxic individuals, synthesis of erythropoietin is not stimulated until the concentration of hemoglobin falls below 10.5 g/dL. In severe anemia, erythropoietin levels can increase more than 1000-fold. Iron, folic acid, and vitamin B12 are also needed for normal maturation of erythrocytes. Several forms of anemia present special situations, such as sickle cell anemia, hereditary spherocytosis, and the autoimmune hemolytic anemias.
The sickle cell syndromes constitute a family of hemoglobinopathies caused by abnormal genetic transformation of amino acids in the heme portion of the hemoglobin molecule.[871] The sickle cell syndromes arise from a mutation in the β-globin gene that changes the sixth amino acid from valine to glutamic acid. A major pathologic feature of sickle cell disease is the aggregation of irreversibly sickled cells in blood vessels. The molecular basis of sickling is the aggregation of deoxygenated hemoglobin B molecules along their longitudinal axis.[871] This abnormal aggregation distorts the cell membrane and thereby produces a sickle shape. Irreversibly sickled cells become dehydrated and rigid and can cause tissue infarcts by impeding blood flow and oxygen to tissues.[871] [872] [873] [874] [875] Some have challenged this hypothesis, with several studies showing enhanced adhesion of sickled erythrocytes to vascular endothelium.[876] Some other abnormal hemoglobins interact with hemoglobin S to various degrees and give rise to symptomatic disease in patients heterozygous for hemoglobin S and one of the other hemoglobins such as the hemoglobin of thalassemia (hemoglobin C).
Three tenths of 1% of the African American population in the United States has sickle cell-thalassemia disease (hemoglobin SC); these patients also have end-organ disease and symptoms suggestive of organ infarction. For these patients, perioperative considerations should be similar to those for patients with sickle cell disease (hemoglobin SS), discussed later.
Whereas 8% to 10% of African Americans have the sickle cell trait (hemoglobin AS), 0.2% are homozygous for sickle cell hemoglobin and have sickle cell anemia. Sickle cell trait is a heterozygous condition in which the individual has one βS globin gene and one βA globin gene, which results in the production of both hemoglobin S and hemoglobin A, with a predominance of hemoglobin A. Sickle cell trait should not be considered a disease because hemoglobin AS cells begin to sickle only when the oxygen saturation of hemoglobin is below 20%. No difference has been found between normal persons (those with hemoglobin AA) and those with hemoglobin AS regarding survival rates or the incidence of severe disease, with one exception: patients with hemoglobin AS have a 50% increase in pulmonary infarction. However, single case reports of a perioperative death and a perioperative brain infarct in two patients with hemoglobin AS disease do exist,[875] [877] and a report of death believed to be due to aortocaval compression during general anesthesia that resulted in a sickling crisis does exist.[878] Frequent measurement of oxygen saturation (pulse oximetry) in multiple areas of the body is recommended, including the ear and toe in pregnant patients.[878] A retrospective review of exercise in military recruits showed that soldiers with sickle cell trait had a higher risk of sudden death after extreme exertion during basic training than did black soldiers with only hemoglobin A—32 per 100,000 versus 1 per 1,000,000. [879] Although this magnitude of increase may not seem great, the vasoactive responses of the perioperative period can be similar to those of moderate to extreme exertion.
The pathologic end-organ damage that occurs in sickle cell states is attributable to three processes: the sickling or adhesion (or both) of cells in blood vessels, which causes infarcts and subsequent tissue destruction secondary to tissue ischemia; hemolytic crisis secondary to hemolysis;
Because sickling is increased with lowered oxygen tensions, acidosis, hypothermia, and the presence of more desaturated hemoglobin S, current therapy includes keeping the patient warm and well hydrated, giving supplemental oxygen, maintaining high cardiac output, and not creating areas of stasis with pressure or tourniquets. Meticulous attention to these practices in periods when we do not usually pay most careful attention (i.e., waiting in the preinduction area) or when gas exchange may be most unmatched to the cardiovascular-metabolic demands (early postoperative period) may be important in lessening morbidity. Even following these measures routinely, with no special emphasis placed on the periods described, succeeded in reducing mortality to 1% in several series of patients with sickle cell syndromes.[877] [878] [879] [880] [881] Retrospective review of patient charts led the authors of those studies to conclude that at most, a 0.5% mortality rate could be attributed to the interaction between sickle cell anemia and anesthetics.
Can this rate be decreased?[872] [881] [882] [883] Several investigators have advocated using partial exchange transfusions perioperatively. In children with sickle cell anemia and acute lung syndromes, partial exchange transfusion improved clinical symptoms and blood oxygenation. In addition, serum bilirubin levels decreased in patients with acute liver injury. Clinical improvement of pneumococcal meningitis and cessation of hematuria in papillary necrosis also accompanied exchange transfusion.[872] [884] The goal of exchange transfusion is to increase the concentration of hemoglobin A to 40% and the hematocrit to 35%. The 40% figure is an arbitrary one because no controlled studies have established the threshold ratio of hemoglobin A to S that would render blood unable to sickle in vivo. To achieve the 40% ratio in a 70-kg adult, about 4 U of washed erythrocytes would have to be exchanged; the system is inexpensive but efficient.
The possible decrease in preoperative morbidity after partial exchange transfusion has not been compared with the risks of exchange, except in two studies[874] [885] in which the risks of exchange were found to exceed the benefits. In the first study, a retrospective review of 82 surgical procedures performed between 1978 and 1986 in 60 patients, no advantage was noted for preoperative exchange transfusion, as measured by a decrease in postoperative complications.[885] (However, only the sickest may have received exchange because patients were not randomly allocated to exchange or nonexchange groups.) A slight increase in postoperative atelectasis requiring treatment was seen in patients given preoperative transfusions. More than 50% of the patients given transfusions had a postoperative complication. Patients who began with a hematocrit of more than 36% had a lower rate of complications. [885] In the second study, a randomized comparison of aggressive versus conservative transfusion practices in 551 patients (604 operations), perioperative sickling complications were not different between groups, and transfusion-related complications were substantially less in the conservative group.[874] Therefore, our recommendation is to pay meticulous attention to preventing conditions that increase sickling or that cause infection and to limit exchange transfusion to crisis situations. Perhaps giving higher concentrations of enriched oxygen to patients undergoing laparoscopic procedures should also become routine. Induction of hyponatremia has been shown to abort acute sickle cell crisis; however, this treatment has not gained widespread acceptance. Other conditions are common in sickle cell syndromes: pulmonary dysfunction with increased shunting, renal insufficiency, gallstones, small MIs, priapism, stroke, aseptic necrosis of bones and joints, ischemic ulcers, retinal detachment from neovascularization, and complications of repeated transfusions.
Recently, bone marrow transplantation with low-risk regimens that produce hematopoietic chimerism seem promising.[886] This regimen may make all other older therapies irrelevant if it is as successful as it now seems to be.
In thalassemia, globin structures are normal, but because of gene deletion, the rate of synthesis of either the α- or β-chains of hemoglobin (α- and β-thalassemia, respectively) decreases.[887] [888] [889] Two copies of the gene that codes for the α-globin chain are located on chromosome 16. Deletion of all four of these genes causes cell death in utero, and three deletions cause severe chronic hemolysis and a shortened life span. "α-Thalassemia-1 (trait)" occurs when two genes have been deleted and mild anemia results; "α-thalassemia-2 (silent)" occurs when the two genes have been deleted but no mild anemia or microcytosis results. In α-thalassemia trait, the hemoglobin A2 level is normal. β-Thalassemia is associated with an excess of α-chains, which denature developing erythrocytes, thereby leading to their premature death in marrow or to shortened survival in the circulation. An elevated hemoglobin A2 level is the hallmark of β-thalassemia trait, a common cause of mild anemia and microcytosis. Bone marrow transplantation and pharmacologic manipulation of hemoglobin F synthesis are being tried in these hemoglobinopathies, as is direct gene replacement therapy. These therapies seem to be promising in even reversing liver failure from previous iron overload.[890] These syndromes are common in Southeast Asia, India, and the Middle East and in people of African descent.
In thalassemia, facial deformity from erythropoietin-stimulated ineffective erythropoiesis (ineffective because of a genetic inability to produce useful hemoglobin) has been reported to make endotracheal intubation difficult.[887] [888] This one case report[888] has not been amplified, and there are no reports of this complication in patients with sickle cell anemia. However, the anemia associated with these syndromes often produces a compensatory hyperplasia of the erythroid marrow, which in turn is associated with severe skeletal abnormalities.[887] [888] [889]
Congenital abnormalities of the erythrocyte membrane are becoming better understood. In elliptocytosis and hereditary spherocytosis, the membrane is more permeable to cations and more susceptible to lipid loss when cell energy
Glucose-6-phosphate dehydrogenase (G6PD) deficiency (a gender-linked recessive trait) is also reported to occur in approximately 8% of African-American men.[892] Young cells have normal activity, but older cells are grossly deficient when compared with normal cells. A deficiency in G6PD results in hemolysis of the erythrocyte and the formation of Heinz bodies. Red cell hemolysis can also occur with intercurrent infections or after the administration of drugs that produce substances requiring G6PD for detoxification (e.g., methemoglobin, glutathione, and hydrogen peroxide). Drugs to be avoided are sulfa drugs, quinidine, prilocaine, lidocaine, antimalarial drugs, antipyretic drugs, non-narcotic analgesics, vitamin K analogs, and perhaps sodium nitroprusside.
The autoimmune hemolytic anemias include cold antibody anemia, warm antibody anemia (idiopathic), and drug-induced anemia.[893] [894] [895] Cold antibody hemolytic anemias are mediated by IgM or IgG antibodies, which at room temperature and below cause red blood cells to clump. When these patients are given blood transfusions, the cells and all fluid infusions must be warm, and body temperature must be meticulously maintained at 37°C if hemolysis is to be prevented. Warm antibody (or "idiopathic") hemolytic anemia is a difficult management problem characterized by chronic anemia, the presence of antibodies active against red blood cells, a positive Coombs test, and difficulty in crossmatching blood. For patients undergoing elective surgery, autologous transfusions, predeposit of blood with or without erythropoietin stimulation, [870] and blood from rare Rh-negative red blood cell donors or the patient's first-degree relatives (or both) can be used. In emergency situations, the possibility of autotransfusion, splenectomy, or corticosteroid treatment should be discussed with a hematologist knowledgeable in this area.
Drug-induced anemias have three mechanisms. In receptor-type hemolysis, a drug (e.g., penicillin) binds to the membrane of the red blood cell, and the complex stimulates the formation of an antibody against the complex. In "innocent bystander" hemolysis, a drug (e.g., quinidine, sulfonamide) binds to a plasma protein, thereby stimulating an antibody (IgM) that cross-reacts with an erythrocyte. In autoimmune hemolysis, the drug stimulates the production of an antibody (IgG) that cross-reacts with the erythrocyte. Drug-induced hemolytic anemias generally cease when therapy with the drug ends. In emergency situations, the least incompatible cells available should be used for blood transfusion.
Granulocyte mechanisms have undergone experimental elaboration
in the last decade, partly because of the molecular biologic revolution: in addition
to erythropoietin (discussed earlier), more than 14 hemolymphopoietic growth factors
or cytokines have been characterized biochemically and cloned genetically. These
growth factors interact with cell-surface receptors to produce their major actions
[896]
( Table
27-49
). The use of the colony-stimulating factors has permitted more intense
oncologic treatment. The few reports related to their perioperative effects detail
| Cytokine | Other Names | Biologic Effects |
|---|---|---|
| Erythropoietin |
|
Erythrocyte production |
| Interleukin-3 (IL-3) | Multicolony-stimulating factor | Stimulates proliferation and differentiation of granulocyte, macrophage, eosinophil, mast cell, megakaryocyte, T- and B-cell lineages, and early myeloid stem cells. Interacts with erythropoietin to stimulate erythroid colony formation, stimulates proliferation of AML blasts, and stimulates histamine release by mast cells |
|
|
Stem cell activating factor |
|
|
|
Persisting cell-stimulating factor |
|
|
|
Hemopoietin-2 |
|
| Granulocyte colony-stimulating factor (G-CSF) | Differentiation factor MGI-2 | Stimulates granulocyte lineage proliferation and differentiation. Acts on early myeloid stem cells, especially in association with other factors; synergizes with IL-3 to stimulate megakaryocyte colony formation. Increases neutrophil phagocytes and antibody-dependent cell-mediated cytotoxicity. Releases neutrophils from bone marrow and is chemotactic for neutrophils and monocytes. Enhances phagocytosis and antibody-dependent cell-mediated cytotoxicity and oxidative metabolism of neutrophils. Stimulates monocyte killing of Mycobacterium avium-intracellulare and Candida species, tumoricidal activity of monocytes, antibody-dependent cell-mediated cytotoxicity, and expression of cell-surface proteins |
| Granulocytemacrophage colony-stimulating factor (GM-CSF) |
|
Stimulates granulocyte, macrophage, and megakaryocyte proliferation and differentiation, early myeloid stem cells, and—in the presence of erythropoietin—erythropoiesis. Enhances cytotoxic and phagocytic activity of neutrophils against bacteria, yeast, parasites, and antibody-coated tumor cells. Increases surface expression of neutrophil adhesion proteins and enhances eosinophil cytotoxicity, macrophage phagocytosis, and basophil histamine release. Amplifies IL-2-stimulated T-cell proliferation and stimulates B-cell lines to proliferate |
| Colony-stimulating factor-1 | Macrophage colony-stimulating factor | Stimulates predominantly macrophage-monocyte proliferation and differentiation with lesser effects on granulocytes. Acts synergistically with other factors on earlier myeloid stem cells. Stimulates macrophage phagocytosis, killing, migration, antitumor activity, and metabolism. Stimulates secretion of plasminogen activator, G-CSF, interferon, IL-3, or tumor necrosis factor by peritoneal macrophages |
| Interleukin-1 (α and β) | Endogenous pyrogen | Induces synthesis of acute-phase proteins by hepatocytes. Activates resting T cells, cofactor for T- and B-cell proliferation. Chemotactic for monocytes and neutrophils. Induces production of growth factors, including G-CSF, GM-CSF, IL-6, CSF-1, IL-3, and interferon by many cells. Radioprotective in mice |
|
|
Hemopoietin-1 |
|
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|
Osteoclast-activating factor |
|
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|
Lymphocyte-activating factor |
|
| Interleukin-2 | T-cell growth factor | Growth factor for T cells, activates cytotoxic T lymphocytes, promotes synthesis of other cytokines, enhances natural killer cell function |
| Interleukin-4 | B-cell stimulating factor-1 | Enhances antibody production (IgG and IgE) and upregulates class II MHC molecules and Fc receptors on B cells. Costimulant with anti-IgM antibodies for induction of DNA synthesis in resting B cells. Stimulates growth of activated T cells. In the presence of IL-3, enhances mast cell growth, with G-CSF enhances granulocytes of GM colony formation, and with erythropoietin and/or IL-1 stimulates erythroid and megakaryocyte colony formation |
|
|
B-cell differentiation factor (BCDF) |
|
|
|
IgG induction factor |
|
| Interleukin-5 | Eosinophil differentiation factor (EDF) | Enhances antibody production (IgA). Promotes proliferation and IgG secretion by B-cell lines and induces hapten-specific IgG secretion in vitro by in vivo primed B cells. Promotes differentiation by normal B cells. Stimulates eosinophil production and differentiation (GM-CSF and IL-3 act synergistically with IL-5 to stimulate eosinophil proliferation and differentiation). Enhances synthesis of IL-2 receptors |
|
|
T-cell replacing factor (TRF) |
|
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|
B-cell growth factor-II (BCGF-II) |
|
|
|
B-cell differentiation factor (BCDF) |
|
| Interleukin-6 | B-cell stimulating factor-2 (BSF-2) | B-cell differentiation and IgG secretion. T cells activated to cytotoxicity. Synergizes with IL-3 on early marrow myeloid stem cells and stimulates proliferation and differentiation of granulocytes, macrophages, eosinophils, mast cells, and megakaryocytes, as well as platelet production (may be a thrombopoietin) |
|
|
Interferon-B2 |
|
|
|
T-cell activation factor |
|
|
|
Hybridoma growth factor |
|
| Interleukin-7 | Lymphopoietin-1 | Stimulates pre-B-cell production. Stimulates T-cell proliferation |
| Interleukin-8 * | Neutrophil-activating factor | Inflammatory mediator; stimulates activation of neutrophils |
|
|
T-cell chemotactic factor |
|
| Interleukin-9 |
|
Stimulates erythroid colony formation and proliferation of a megakaryocyte cell line |
| Interleukin-10 | Cytokine synthesis-inhibiting factor | Inhibits cytokine production by TH 1 cells |
| Interleukin-11 |
|
Stimulates B-cell, megakaryocyte, and mast cell lineages |
| C-Kit ligand | Mast cell factor | Acts on relatively early stem cells synergistically with other cytokines. Stimulates pre-B cells |
|
|
Stem cell factor |
|
|
|
Hemolymphopoietic growth factor-1 |
|
| AML, acute myeloblastic leukemia; MHC, major histocompatibility complex; TH 1, first of the thymus-derived cells. | ||
| Modified from Quesenberg PJ, Schafer AI, Schreiber AD, et al: Hematology. In American College of Physicians: Medical Knowledge Self-Assessment. Philadelphia, American College of Physicians, 1991, p 374. | ||
In patients who have fewer than 500 granulocytes per milliliter of blood and established sepsis, the use of growth factor and granulocyte transfusion has been shown to prolong life.[898] [899] [900] Although bone marrow transplantation is being used increasingly, complications usually occur after transplantation, not on harvesting of cells (at which time the anesthesiologist who is not involved in critical care is most frequently involved). Abnormal results on pulmonary function testing before bone marrow transplantation seem to predict complications after transplantation, but not so strongly as to preclude transplantation.[901]
Although inherited platelet disorders are rare, acquired disorders are quite common and affect at least 20% of all patients in medical and surgical ICUs, with infections and drug therapies being the leading causes.[902] Both acquired and inherited platelet conditions cause skin and mucosal bleeding, whereas defects in plasma coagulation produce deep tissue bleeding or delayed bleeding. [903] Perioperative treatment of inherited platelet disorders (e.g., Glanzmann's thrombasthenia, Bernard-Soulier syndrome, Hermansky-Pudlak syndrome) consists of platelet transfusions. EACA has recently been used successfully (experimentally, 1 g/70 kg four times daily) to decrease perioperative bleeding in thrombocytopenic patients. The much more common acquired disorders may respond to one of several therapies. Immune thrombocytopenias, such as those associated with lupus erythematosus, idiopathic thrombocytopenic purpura, uremia, hemolytic-uremic syndrome, platelet transfusions, heparin, and thrombocytosis, may respond to steroids, splenectomy, platelet pheresis, eradication of Helicobacter pylori, or alkylating agents or may require platelet transfusions, plasma exchange, whole blood exchange, or transfusion; sometimes these disorders do not respond to anything.[470] [903] [904] [905] [906] Traditionally, splenectomy is performed when steroid therapy fails or reaches a dosage that poses unacceptable risks of toxicity. Newer agents such as anti-D immune globulin and rituximab may induce desirable remissions in idiopathic thrombocytopenic purpura without splenectomy.
Thrombotic thrombocytopenic purpura is a rare disorder of unknown cause. Despite various therapies, this disorder carries a very high mortality rate. However, the introduction of plasmapheresis has improved response rates dramatically in patients with this disease. One uncontrolled study implies that the benefit lies not only in improvement of the hematologic picture but also in prevention of adult respiratory distress syndrome, a leading cause of death in these patients.[906] In that study, early institution of plasmapheresis improved oxygenation.
By far the largest number of platelet abnormalities consists of drug-related defects in the aggregation and release of platelets. Aspirin irreversibly acetylates platelet cyclooxygenase, the enzyme that converts arachidonic acid to prostaglandin endoperoxidases. Because cyclooxygenase is not regenerated in the circulation within the life span of the platelet and because this enzyme is essential for the aggregation of platelets, one aspirin may affect platelet function for a week. All other drugs that inhibit platelet function (e.g., vitamin E, indomethacin, sulfinpyrazone, dipyridamole, tricyclic antidepressant drugs, phenothiazines, furosemide, steroids) do not inhibit cyclooxygenase function irreversibly; these drugs disturb platelet function for only 24 to 48 hours. If emergency surgery is needed before the customary 8-day period for platelet regeneration after aspirin therapy or if the 2-day period for other drugs has not elapsed, administration of 2 to 5 U of platelet concentrates will return platelet function in a 70-kg adult to an adequate level and platelet-induced clotting dysfunction to normal.[903] [907] Only 30,000 to 50,000 normally functioning platelets/mL are needed for normal clotting. Because low-dose aspirin therapy (<650 mg/day) allows aspirin to be gone from the body 24 hours after the last dose and because the body makes 70,000 platelets/mL blood per day, a 48-hour period after the last aspirin in minidose therapy should be sufficient time for platelet aggregation to become normal. This may be the time period that must pass to avoid platelet transfusions and their associated risks. One platelet transfusion will increase the platelet count from 4000 to 20,000/mL blood; the platelet half-life is about 8 hours.[903] [907] Although designer aspirin that affects only one part of the cyclooxygenase tree may soon be available, the form that is most likely to be used may cause clotting disturbances (without the GI effects, however) that are equal to those caused by the currently available form of aspirin.
Heparin-induced thrombocytopenia can develop within hours on re-exposure to heparin in a previously sensitized patient. Lepirudin and argatroban are new direct thrombin inhibitors effective in therapy for heparin-induced thrombocytopenia. [908]
Major risk factors for thrombosis include factor V Leiden and prothrombin 20210A mutations, elevated plasma homocysteine, and the antiphosphoid antibody syndrome.[909] [910] Clinicians facing these challenging patients might seek expert local consultation for help with management.
Abnormalities in blood coagulation as a result of defects in plasma coagulation factor are either inherited or acquired. Inherited disorders include X-linked hemophilia A (a defect in factor VIII activity), von Willebrand's diseases (defect in the von Willebrand component of factor VIII), hemophilia B (a sex-linked deficiency of factor IX activity), and other less common disorders. The sex-linked origin of some of these disorders means that hemophilia occurs almost exclusively in the male offspring of female carriers; men do not transmit the disease to their male offspring.
In elective surgery, levels of the deficient coagulation factor should be assayed 48 hours before surgery and the level restored to 40% of normal before surgery. One unit of factor concentrate per kilogram of body weight normally increases the factor concentration by 2%. Thus, in an individual essentially devoid of activity, administration of 20 U/kg body weight would be required as an initial dose. Because the half-life is 6 to 10 hours for factor VIII and 8 to 16 hours for factor IX, approximately 1.5 U/hr/kg of factor VIII or 1.5 U/2 hr/kg of factor IX should be given. Additional administration of factors VIII and IX should
These factors are available in various preparations: the newer genetically engineered von Willebrand factor, cryoprecipitate, which contains 20 U/mL, is obtained from regular donors (the risk of hepatitis being 1:200 for 5-mL lots) or from fresh frozen plasma (which contains 1 U/mL). Some risk of transmitting hepatitis and AIDS accompanies transfusion but, with better testing, much less than formerly.[914] [915] [916] [917] [918] Current screening of blood for AST or ALT levels is believed to result in a much lower risk of hepatitis C and even AIDS from transfusion. Theoretically, antigenic testing for HIV should further decrease the risk of transmission by blood products. Heat treatment is also reported to reduce the risk substantially. Factor IX, but not factor VIII is contained in prothrombin complex concentrates; however, these concentrates may contain activated clotting factors, which can lead to disseminated intravascular coagulation (DIC) and a high risk of hepatitis. In addition, although EACA or tranexamic acid (0.5 mg/kg) is sometimes administered as a fibrinolytic inhibitor, these substances carry with them a significant risk of DIC. Additional hazards of modern therapy include acute and chronic hepatitis, AIDS, hypersensitivity reactions, psychic trauma, chronic pain with narcotic addition, and inhibition of factors, especially VIII.
An antibody that inactivates factor VIII or IX (fresh frozen plasma fails to increase clotting factor activity after incubation with the patient's plasma) develops in approximately 10% of patients with either hemophilia A or B. These acquired anticoagulants are usually composed of IgG, are poorly removed by plasmapheresis, and are variably responsive to immunosuppressive drugs. The use of prothrombin complex concentrates can be lifesaving but carries the risk of DIC and hepatitis.
Vitamin K deficiency is discussed in the section on liver disease. To review, vitamin K-dependent clotting factors (II, VII, IX, and X) require vitamin K for the postsynthetic addition of γ-carboxyl groups to glutamate residues; administration of vitamin K or fresh frozen plasma can correct these deficiencies.
Patients who come to the operating room after having received many units of blood (as in massive GI bleeding) may have deficient clotting. This impaired clotting is initially caused by depletion of platelets, which occurs after approximately 10 to 15 U of blood has been given, and later, by depletion of coagulation factors[919] [920] (see Chapter 47 ). Treatment of these deficiencies can be corrected with platelet concentrates—each concentrate is normally suspended in 50 mL of fresh plasma; thus, coagulation factors are also replaced.
Urokinase, streptokinase, and tissue plasminogen activator (t-PA) have been used to treat pulmonary embolism, deep venous thrombosis, stroke, and arterial occlusive disease. These drugs accelerate the lysis of thrombi and emboli, in contrast to heparin, which may prevent, but not dissolve a thrombus. Bleeding complications associated with these fibrinolytic agents are the result of dissolution of hemostatic plugs and can be quickly reversed by discontinuing the medication and replenishing plasma fibrinogen with cryoprecipitate or plasma. However, cryoprecipitate and plasma are seldom needed preoperatively because the fibrinolytic activity of urokinase and streptokinase usually dissipates within 1 hour of discontinuing their administration. Nonetheless, insufficient data have accumulated to prescribe the ideal preoperative preparation and intraoperative management of hemostasis in patients recently treated with urokinase, streptokinase, or t-PA. Postponing surgery for three half-lives of the drug (increases in plasmin activity in blood can be assayed for ≥4 to 8 hours) may not be possible, and meticulous observation of the operative field for hemostasis may not suffice.[921] [922] The process may be even more complex in a vascular or cardiac patient who requires heparin administration intraoperatively. To correct fibrinogen deficiency in these patients, some clinicians administer fibrinogen before surgery and EACA at heparin administration. We usually delay or avoid giving EACA until heparin is administered in an effort to minimize the risk of thrombosis.
Desmopressin is now being tried in operations associated with high blood loss as a routine measure to decrease bleeding and transfusion requirements. Desmopressin therapy began as treatment of platelet dysfunction in von Willebrand's disease but has since expanded to routine use in patients undergoing cardiovascular surgery and frequent use in other high-blood loss operations. This increased use was prompted by the finding that desmopressin decreases bleeding and transfusion requirements.[923] Whether the side effects of desmopressin exceed the benefits remains to be determined and will probably influence how routine its administration becomes.
The problem of patients taking oral anticoagulants is discussed in the cardiovascular section of this chapter.[462] [463] [464] [465] [466] [467] [468] [469] [470] [471] [472] [473] [474] [475] [478] [479] [480] [481] Regional anesthetic techniques might be avoided in patients given anticoagulant drugs.[462] [463] [464] [465] [466] [467] [468] [469] [470] [471] [472] [473] [474] [475] [478] [479] [480] [481] Whether these regional techniques should also be avoided in patients treated prophylactically with low-dose subcutaneous heparin has not been studied. The effects of heparin sulfate can be reversed by titrating protamine with the activated clotting time used as a guide. Our group usually gives approximately 1 mg of protamine per 3 to 4 mg of heparin administered within the last 8 hours. Pharmacologic research is searching for specific molecular subtypes of heparin that have different anticoagulant potencies, binding affinities for antithrombin III, antithrombotic effects, and platelet aggregating effects (see the pulmonary section in this chapter on prophylaxis for deep venous thrombosis). The search is for a "new" heparin preparation that will block thrombosis without causing clinical bleeding (see earlier). Such a development might change our ways of monitoring clotting function. As of now, the new heparins appear to increase the risk of epidural hematoma. Determining the bleeding time, platelet count, partial thromboplastin time, and PT will identify almost all problems in patients with a suspected clotting or bleeding disorder (also see Chapter 47 ). As explained in Chapter 25 , these screening tests should probably not be obtained for asymptomatic patients.
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