Hematologic Diseases - Fleisher: Anesthesia and Uncommon Diseases

Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

CHAPTER 11 – Hematologic Diseases

Gregory Fischer, MD,
Linda Shore-Lesserson, MD

Anemias

		Iron Deficiency Anemia
		Thalassemia
		Megaloblastic Anemia
		Hemolytic Anemias

Acute Blood Loss/Hemorrhagic Shock

Diseases of Leukocytes

		Lymphomas
		Leukemias
		Chronic Myeloproliferative Disease
		Myelodysplastic Syndrome

Diseases of Thrombocytes (Platelets)

		Thrombocytopenia
		Thrombasthenic Syndromes
		Diseases or Disorders of Impaired Coagulation
		Thrombotic Disorders
		Monitoring Platelet Function

The hematologic system plays a central role in maintaining homeostasis, although its importance is often overlooked by many clinicians. It is important to understand and appreciate its many different functions, ranging from oxygen transport and hemostasis to immunity and thermoregulation.

It is beyond the scope of this chapter to give an in-depth description of all hematologic diseases. The material presented here includes the pertinent aspects of hematologic diseases that can be recognized perioperatively and may be amenable to diagnosis and selective treatment by the anesthesiologist.

ANEMIAS

Anemia is a common finding among patients presenting for surgery. It is defined as a hemoglobin concentration less than normal for age and gender. Anemia can have many different causes, making it imperative that the clinician not be content with the diagnosis of anemia alone but to initiate a search for the underlying cause. Therapeutic interventions are then tailored to treat the cause of the diagnosed anemia.

Except for severe anemia, which can be diagnosed clinically by pallor and lethargy, the diagnosis of anemia is a laboratory diagnosis. In adults, hemoglobin concentrations less than 11.5 g/dL in females and 12.5 g/dL in males are considered to be anemia. To aid in the differential diagnosis, erythrocyte indices are used to help categorize anemias and pinpoint probable causes of anemia ( Table 11-1 ). Erythrocyte indices are defined as follows:

		MCH: mean corpuscular hemoglobin (Hb × 10/RBC)
		MCV: mean corpuscular volume (Hct × 10/RBC)
		MCHC: mean corpuscular hemoglobin concentration (Hb/Hct)

TABLE 11-1 -- Anemia by Erythrocyte Indices

Anemia	RBC Size	Chromatic	MCH/MCV	Reticulocytes	Serum Iron
Thalassemia	Microcytic	Hypo-	↓	↓	↑
Myelodysplastic syndrome	Microcytic	Hypo-	↓	↓	↑
Iron deficiency	Microcytic	Hypo-	↓	↓	↓
Inflammation-infection	Micro/normocytic	Hypo/normo-	↓/↑	↓	↓
Tumor	Micro/normocytic	Hypo/normo-	↓/↑	↓	↓
Hemolytic anemia	Normocytic	Normo-	Normal	↑	Normal
Hemorrhage	Normocytic	Normo-	Normal	↑	Normal
Aplastic anemia	Normocytic	Normo-	Normal	↓	Normal
Renal failure	Normocytic	Normo-	Normal	↓	Normal
Megaloblastic	Macrocytic	Hyper-	↑	Normal	Normal
Hypochromatic Microcytic Anemia		Normochromatic Normocytic Anemia		Hyperchromatic Macrocytic Anemia
MCH + MCV reduced		MCH + MCV normal		MCH + MCV increased
Serum iron increased: thalassemia, myelodysplastic syndrome		Reticulocytes increased: hemolytic anemia, hemorrhage		Normal reticulocytes: megaloblastic anemia
Serum iron decreased: iron deficiency anemia		Reticulocytes decreased: aplastic anemia, renal anemia

Iron decrease and ferritin increase: inflammatory, infection, and tumor anemia.

MCH, mean corpuscular hemoglobin; MCV, mean corpuscular volume.

Anemia complicates the management of patients by reducing the oxygen content in circulating blood, which in turn can reduce oxygen delivery to peripheral tissues. To avoid hypoxia the cardiovascular system must compensate by increasing cardiac output.

When interpreting the formula in Box 11-1 , one sees that physically dissolved oxygen (Pao₂ × 0.003) results in only a fraction of the total oxygen content (Cao₂) found in blood. The vast majority of oxygen is bound chemically to hemoglobin. This makes it easy to understand why in states of hypoxemia one should treat the anemic patient, providing a normal Pao₂ exists, with the administration of erythrocytes, most commonly given in form of packed RBCs. Increasing FIo₂ and thus increasing Pao₂ only leads to slight increases in Cao₂.^[1]

BOX 11-1

Formula for Calculation of Oxygen Delivery

Do₂ = CO × Hb × SaO₂ × 1.34 + PaO₂ × 0.003)

where DO₂ = oxygen delivery; CO = cardiac output; Hb = hemoglobin concentration; SaO₂ = percent of oxygenated hemoglobin; 1.34 = Hüfner number (constant 1.34-1.36); and 0.003 = dissolved oxygen (mL/mm Hg/dL).

One of the controversial topics in recent years has been determining the threshold at which anesthesiologists should transfuse patients in the perioperative setting.^{[2] [3] [4]} The best hematocrit at which the oxygen-carrying capacity is ideally matched with the rheologic properties of blood is approximately 27%. However, the “10/30 rule” (10 g/dL hemoglobin or 30% hematocrit), once thought to be the gold standard by many clinicians, has been challenged by recent studies. There is no evidence in the literature suggesting that patients presenting to the operating room with mild anemia have increased adverse advents such as poorer wound healing, increased stroke, or myocardial infarction rates.^[5] In fact, patients who receive transfusion are at high risk for perioperative infection due to the immunomodulating effects of transfusion. Thus, transfusing red cells solely on the basis of hemoglobin concentration or hematocrit is no longer considered proper care. Indications for transfusion of red cells should be based on the oxygen supply/demand ratio in the individual patient. Decreased mixed venous oxygen saturations (SVo₂), serial measurements of lactate showing progressively increasing concentrations, and electrocardiographic changes suggestive of myocardial ischemia are all appropriate indications for transfusion of RBCs.^{[6] [7] [8] [9] [10]} For example, Nelson and colleagues found that a hematocrit less than 27% was associated with an increased incidence of myocardial ischemia and infarction in patients undergoing infrainguinal bypass surgery.^[11]

Despite great advancements in transfusion medicine, life-threatening complications still do occur. Transfusion reactions can be divided into three major pathophysiologic groups. The most common complication is the transfusion of immunologic incorrectly matched blood resulting in hemolysis. The ABO and Rhesus antigens are responsible for this reaction. Patients under general anesthesia will present with hypotension, tachycardia, and hemoglobinuria, possibly progressing to acute renal failure. Second, febrile nonhemolytic reactions are seen in 0.5% to 5% after transfusion of blood products.^[12]These reactions are caused by leukocyte and thrombocyte antigens.^{[12] [13]} Third, transmission of infectious diseases (hepatitis B and C viruses and human immunodeficiency virus [HIV]) is a rare phenomenon but has serious and long-lasting consequences for the patient.^{[14] [15] [16] [17] [18]}

The complications of blood product transfusion should always make the clinician weigh benefits against potential risks. Strict indications for the transfusion of blood products should be employed. Transfusion solely to achieve volume expansion or to raise the hematocrit to a certain value cannot be recommended. Finally, in a society becoming more and more conscious of the financial burden brought on by its health care system, avoiding unnecessary transfusions poses a major source of potential savings.

Iron Deficiency Anemia

Iron deficiency anemia is the most commonly diagnosed anemia in the industrialized world. Its cause is usually due to chronic blood loss (e.g., menstruation, chronic gastrointestinal bleeding) or to increased requirements seen in pregnancy or infancy. An adult male has 50 mg/kg of iron stored in his body and requires a daily intake of 12 mg to absorb 1 mg to compensate for losses. An adult female has 35 mg/kg of iron stored and requires 15 mg to absorb 2 mg. During pregnancy the iron intake must be doubled to compensated for approximately 3 mg of daily iron losses.

Iron deficiency anemia is a microcytic/hypochromatic anemia with increased serum transferrin, low serum ferritin, and low serum iron concentrations. Microscopic examination of bone marrow reveals low to missing iron depots. The differential diagnoses to iron deficiency anemia are shown in Table 11-2 . Clinically, these patients suffer from general anemia symptoms as well as from skin and mucous membrane problems. Koilonychia, hair loss, Plummer-Vinson syndrome and perlçche are all symptoms associated with iron deficiency.

TABLE 11-2 -- Anemia and Iron Metabolism

	Serum Iron	Transferrin	Serum Ferritin
Iron deficiency	↓	↑	↓
Myelodysplastic syndrome	↑	↓	↑
β-Thalassemia	Normal-↑	Normal-↓	Normal-↑
Inflammatory or tumor associated	↓	↓	↑

The treatment of iron deficiency consists of replacing the losses either orally or parenterally and in locating the source of chronic blood loss.^{[19] [20]}

Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Thalassemia

Thalassemia consists of a group of inherited disorders resulting in the inability to produce structurally normal globin chains. This results in an abnormal hemoglobin molecule with subsequent hemolysis. The disorder can affect both the α and β globin chain synthesis, and depending on whether the bearer is homozygous or heterozygous the disease is called major or minor. β-Thalassemia major (Cooley's anemia) is rare and carries a poor prognosis. Patients of Mediterranean descent present with this illness in early stages of life. Patients have prehepatic jaundice, hepatosplenomegaly, and an increased susceptibility to infection. Owing to multiple blood transfusions the patients also develop secondary hemochromatosis and die of complications related to cardiac hemochromatosis (e.g., arrhythmias, congestive heart failure). α-Thalassemia is not compatible with life.

Minor thalassemias show mild anemic states with microcytic/hypochromatic erythrocyte indexes. Iron stores are normal or increased. The diagnosis is confirmed by hemoglobin electrophoresis.

Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Megaloblastic Anemias

Megaloblastic anemias are anemias with macrocytic/ hyperchromatic erythrocyte indexes. The two most common forms are vitamin B₁₂ deficiency and folic acid deficiency.

Both vitamin B₁₂ and folic acid are important cofactors in the synthesis of DNA. A deficiency of either vitamin leads to an insufficient amount of DNA, resulting in the inability of bone marrow to produce an adequate amount of blood cells. This, in turn, results in very large blood cells, each packed with an abnormally high amount of hemoglobin.^{[21] [22]}

Vitamin B₁₂ deficiency is most commonly caused by an autoimmune disease and results in pernicious anemia.^[23] An autoantibody targeted toward the intrinsic factor leads to the inability to absorb vitamin B₁₂. Intrinsic factor is produced by gastric parietal cells and is required to absorb vitamin B₁₂ (extrinsic factor) in the terminal ileum. Other causes are rare and include strict vegetarian diet, malabsorption syndromes, blind loop syndromes, and tapeworm (Diphyllobothrium latum) infection ( Table 11-3 ).

TABLE 11-3 -- Differential Causes of Vitamin B12 Deficiency

Vegetarian diet

Reduction in intrinsic factor

		Pernicious anemia
		Subtotal or partial gastric resection

Malabsorption syndrome

Tapeworm (Diphyllobothrium latum)infection

Blind loop syndrome

Vitamin B₁₂ deficiency can also lead to neurologic and gastroenterologic symptoms. An atrophic tongue, known as Hunter's glossitis, is a typical sequela of vitamin B₁₂ deficiency. Neurologic symptoms resulting from degeneration of the lateral and posterior spinal cord columns lead to peripheral neuropathy and gait ataxia. Depression and psychotic symptoms are also seen. Clinically, the loss of sensation to vibration is an early warning sign. The diagnosis is obtained by measuring vitamin B₁₂ concentrations in plasma. At present, parenteral administration of vitamin B₁₂ is the only therapeutic option available to patients.

Folic acid deficiency is the third most common cause of anemia seen in pregnancy due to increased requirements. Other risk factors for folic acid deficiency are alcoholism, abnormal dietary habits, and certain medications (methotrexate, phenytoin). Folic acid deficiency does not present with neurologic sequelae in the adult. It has, however, been linked to neural tube defects in early stages of pregnancy. The diagnosis is confirmed, as in vitamin B₁₂ deficiency, by measuring plasma concentrations. Folic acid can, however, be supplemented orally.

Nitrous oxide has the ability to irreversibly oxidize the cobalt ion found in vitamin B₁₂. It would therefore seem prudent to avoid the use of nitrous oxide in patients already suffering from megaloblastic anemia to avoid a synergistic effect. Otherwise the same principles apply as in treating any other form of anemia.

Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Hemolytic Anemias

Hemolytic anemias can be caused by corpuscular defects of the erythrocyte or by extracorpuscular pathologic processes. Typical corpuscular hemolytic anemias are ones seen with cell membrane defects (e.g., spherocytosis), hemoglobinopathies (e.g., thalassemia, sickle cell disease) or enzyme defects within the erythrocyte (e.g., glucose-6-phosphate dehydrogenase deficiency or pyruvate kinase deficiency).

Extracorpuscular hemolytic anemias are immunologically mediated (Rh incompatibility, ABO transfusion reactions, autoimmune hemolytic anemias), the result of consumption of certain medications, caused by infectious diseases, metabolic derangements (Zieve syndrome), or the result of microangiopathic pathologic processes (hemolytic-uremic syndrome, thrombotic thrombocytopenic purpura).

Spherocytosis

Spherocytosis is one of the most common inherited hemolytic anemias. It is caused by a defect in the erythrocyte membrane, which leads to an increased permeability for sodium and water, giving the erythrocyte its typical spherical form. This renders the erythrocytes susceptible to phagocytosis in the spleen at an early age. Patients are prone to hemolytic crisis and gallstones formed primarily out of bilirubin. Normocytic anemia accompanied by signs of hemolysis (increased indirect bilirubin, increased lactate dehydrogenase, increased reticulocytes) are the typical laboratory findings. The diagnosis is confirmed by osmotic testing of the erythrocytes.

Patients with recurrent hemolytic crisis may have undergone a splenectomy. The anesthesiologist must be aware that these patients, if not properly vaccinated, are at increased risk for sepsis (overwhelming postsplenectomy sepsis).

Hemoglobinopathies

There are approximately 300 known abnormal hemoglobin molecules. Most of these pathologic globin molecules differ from the physiologic α and β chains through exchange of only one amino acid with another. It is beyond the scope of this chapter to list all hemoglobinopathies. We will concentrate on the illnesses seen most likely in daily practice.

Sickle Cell Anemia.

Sickle cell anemia is the most common form of inherited hemoglobinopathy found in humans. Five to 10 percent of the African-American population are heterozygotic carriers. The mutation is in the sixth amino acid in the β chain of the hemoglobin molecule. Glutamic acid is replaced by valine.^[24]

In its deoxygenated form hemoglobin S (HbS) has the tendency to precipitate, causing the erythrocytes to lose their normal biconcaval form and to take on a sickle-like structure. This leads to sludging and eventually to occlusion of the microvasculature, resulting in end organ infarction.

Heterozygotic carriers are generally asymptomatic, expressing only a sickle cell trait found in laboratory testing (HbS < 50%). However, homozygotic carriers can display sickle cell crisis as early as infancy, with signs of hemolysis and painful vaso-occlusive infarctions (spleen, kidney, bones). Due to an atrophic spleen caused by recurrent microinfarctions, patients are prone to Streptococcus pneumoniae and Hemophilus influenzae infections of the respiratory tract and osteomyelitis. The diagnosis of sickle cell anemia is made either through a microscopic sickle cell test or by hemoglobin electrophoresis.

Conventional anesthetic management is geared toward avoiding a sickle cell crisis during the perioperative period.^[25] Patients should be kept well hydrated, warm, and well oxygenated. Acidosis should be avoided at all costs.^[26] Sickle cell patients presenting for cardiac surgery can be appropriately managed by maintaining temperature and hemoglobin concentration. Fast-track or early extubation protocols have been utilized with success.^[27] Many of the practices geared toward avoiding a sickle cell crisis are still followed in modern-day management, but some of the classic “dogmas” have been challenged during the past decade. For example, the use of tourniquets for orthopedic procedures is no longer considered an absolute contraindication.^{[28] [29] [30]} Exchange transfusion solely with the intent to improve a laboratory value (HbS fraction < 30%) can no longer be considered proper standard of care.^[31] Griffin and colleagues suggest that transfusion before elective surgery in children may not be necessary at all. The authors successfully provided anesthesia for 54 children with sickle cell disease without a transfusion. They found that smaller surgical procedures could be easily performed without complication but that pulmonary complications arose after laparotomy, thoracotomy, and tonsillectomy.^{[32] [33]} Although there are benefits for pain management and rheology that accompany the use of neuraxial anesthesia, it is still believed by many investigators that the patient with more complex sickle cell anemia is better managed using general anesthesia.^[25]

The anesthesiologist is sometimes asked to assist as a pain consultant in managing an acute sickle cell crisis.^[32] Adequate oxygenation, normothermia, and euvolemia are the cornerstones of management. Analgesia is achieved with opiates. Caution must be used when utilizing analgesics (e.g., nonsteroidal anti-inflammatory agents), which can potentially impair renal function, because these patients frequently suffer from renal microinfarctions with reduced baseline renal function. Vaso-occlusive crisis of the lower extremities can be managed with continuous neuraxial blocks. Occasionally a partial exchange transfusion with packed red blood cells is performed to increase the fraction of HbA greater than 50%. For rheologic reasons, the hematocrit should not exceed 35%.

In parturients with sickle cell disease, transfusion therapy is recommended to treat the complications of the disease, especially those associated with chest pain syndromes, preeclampsia, and multiple gestations.^{[34] [35]} Antibiotic prophylaxis for both mother and newborn should be actively practiced. The avoidance of adverse events during labor does not seem to be associated with the type of analgesia provided (regional vs. systemic) but appears more related to careful monitoring for the known consequences of the disease.^[36]

Newer therapies are being investigated for the anesthetic management of patients with sickle cell disease. Cytotoxic agents such as hydroxyurea stimulate the production of fetal hemoglobin and are being studied in the prevention of vaso-occlusive crises. Inhaled nitric oxide and other new investigational drugs have shown promise in being able to reduce the sickling process and even to unsickle cells.

Enzyme Deficiency Anemias

Enzyme defects within erythrocytes can lead to hemolysis. The two most commonly seen defects are glucose-6- phosphate dehydrogenase deficiency and pyruvate kinase deficiency.

Glucose-6-Phosphate Dehydrogenase Deficiency.

This disease is most commonly seen in individuals of African, Asian, or Mediterranean descent. The illness is inherited recessively on the X chromosome. Patients with this defect have erythrocytes containing a reduced amount of glutathione, leading to oxygenation injury of the cell membrane. A hemolytic crisis can be induced through infections or ingestion of beans and certain medications (e.g., sulfonamides, aspirin, quinidine). No specific therapy exists. Avoiding trigger substances is the only recommendation available at the present time.

Pyruvate Kinase Deficiency.

This deficiency is the most common defect of the glycolysis pathway. It has an autosomal recessive pattern of inheritance. The normal erythrocyte does not have mitochondria and relies on glycolysis to produce adenosine triphosphate to maintain cellular integrity. Homozygous carriers present with hemolytic anemia, splenomegaly, and acanthocytes.

Antibody-Induced Hemolysis

Antibodies can result in two major reactions: hemolysis and agglutination. Antibodies directed against erythrocytes are either IgM or IgG in structure. IgM antibodies are larger (molecular weight 900,000 daltons) and can act like a bridge between two erythrocytes. The term complete antibodies is sometimes used. Examples of IgM antibodies are ABO isoagglutinins and cold agglutinins. IgG antibodies are smaller in size (150,000 daltons) and cannot form a bridge between two erythrocytes (incomplete antibodies). Examples of IgG antibodies are Rhesus (Rh) agglutinins and warm antibodies. The Coombs test is used to diagnose the presence of incomplete antibodies either already attached to the surface of erythrocytes (direct Coombs test) or in the patient's serum (indirect Coombs test).

Autoimmune Hemolytic Anemia.

Autoimmune hemolytic anemias can be caused by either warm (IgG) or cold (IgM) antibodies. Seventy percent of all autoimmune hemolytic anemias are caused by warm antibodies. Warm autoimmune hemolytic anemias are seen in patients with non-Hodgkin's lymphoma, systemic lupus erythematosus, viral infection, and after ingestion of certain drugs (penicillin, α-methyldopa). These antibodies bind to the surface of erythrocytes at body temperature without causing hemolysis. The erythrocytes undergo phagocytosis in the spleen. The erythrocyte survival time can be diminished to only a few days, with erythropoiesis increased by tenfold. Fifteen percent of all patients with autoimmune hemolytic anemia present with cold antibodies. These antibodies are seen in patients after Mycoplasma pneumonias or mononucleosis. These antibodies lead to acrocyanosis and hemolysis as soon as intravascular temperature decreases below 25° to 30°C.

Traumatic Hemolysis

Traumatic injury to erythrocytes leading to hemolysis can be seen in patients with mechanical heart valves, intra-aortic balloon pumps, or after severe physical exertion (e.g., extreme hiking, runner's anemia).

Renal Anemia

Patients presenting for surgery with chronic renal failure (glomerular filtration rate < 30 mL/min) frequently have a normochromic, normocytic anemia owing to inadequate production of erythropoietin.^{[37] [38]} Hemoglobin concentration is generally found to be around 9 g/dL. Transfusion of packed red blood cells is necessary should signs of ischemia develop. These patients are frequently treated with recombinant human erythropoietin to raise baseline hemoglobin values.^[39]

Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

ACUTE BLOOD LOSS/HEMORRHAGIC SHOCK

One of the most challenging situations an anesthesiologist can be confronted with is having to induce a patient in hemorrhagic/hypovolemic shock. Complicating matters is the fact that acute hemorrhage is often difficult to diagnose. Laboratory values for hemoglobin are normal in the immediate period after an acute blood loss. If one loses half of his or her circulating blood volume, there will be no change in the concentration of hemoglobin unless fluid with a different hemoglobin concentration is added. In clinical practice, fluids are administered parenterally after obtaining access to the circulatory system. Advanced Trauma Life Support protocols advise administering 2 L of crystalloid solution to patients in suspected hypovolemic shock. This will lead to dilution of the original hemoglobin concentration. Providing intravenous fluids are not administered, anemia will result within hours through movement of interstitial fluid into the intravascular space. Because of this time delay the hemoglobin and hematocrit are not ideal parameters for detecting acute blood loss.

In addition to the problems encountered in the laboratory diagnosis of acute blood loss, the volume state of a patient is also extremely difficult to assess clinically. Especially in young patients, the sympathetic nervous system is capable of masking even extreme states of hypovolemia, giving the clinician a false sense of security. Subtle signs such as orthostatic hypotension, tachycardia, narrowing pulse pressure, alterations of cerebral function, and low urine output must be sought before induction of anesthesia is indicative of hypovolemia.

In an attempt to maintain adequate perfusion to the brain and myocardium the vegetative nervous system compromises perfusion to the kidneys, skeletal muscular system, and gut. This redirection in blood flow is achieved by increasing the sympathic adrenergic tone of the vegetative nervous system, resulting in increased heart rate, systemic peripheral resistance (SVR), and narrowing pulse pressure. As a consequence of impaired tissue perfusion, lactate concentrations increase while urine output and mixed venous saturation decrease.

The treatment of acute blood loss is primarily aimed at replacing lost volume. This can be achieved by administering either crystalloid or colloid solutions. There is much debate on this subject regarding whether primarily crystalloid or colloid solutions should be employed to replace lost blood volume. The literature, however, does not clearly support the use of one over the other. Blood products need to be administered, owing to the rapid dilution of red cells and coagulation factors. The goal of therapy is aimed at restoring adequate perfusion and oxygen delivery to all organ systems. A successful course of treatment can be seen by normalization of vital signs, urine output, lactate concentrations, and SvO₂. Vasopressors should be used only as a temporary resort in maintaining perfusion pressure to the myocardium and cerebrum until adequate volume replacement can be achieved.

Inducing a hypovolemic patient is one of the most challenging situations confronting anesthesiologists. All induction agents can potentially reduce the adrenergic tone needed by the organism to maintain adequate perfusion pressure to the brain and myocardium. If not corrected quickly, a vicious cycle is started that will lead to further hemodynamic deterioration. Invasive monitoring and the use of induction agents with the least suppressive effect on hemodynamics such as ketamine and etomidate are good choices. If perfusion pressure declines, the use of a vasopressor might be indicated until adequate access is obtained and volume loading begins.

Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

DISEASES OF LEUKOCYTES

Leukocyte abnormalities rarely alter an anesthetic plan. There are, however, a few exceptions, which every anesthesiologist must know. It is the intent of this chapter to offer a brief overview of diseases associated with the leukocyte system, providing an in-depth view of the illnesses that can alter an anesthetic plan.

Lymphomas

Lymphomas are neoplasms of the lymphatic system. Clinically, they are divided into two groups: Hodgkin's disease and non-Hodgkin's lymphoma (NHL). The primary localization of these tumors is in the lymph nodes. As the disease progresses, metastatic lesions can be found in every organ. A major concern to the anesthesiologist are lesions that may obstruct the airway. Large tumor bulks can be found in the mediastinum, growing undetected until vital organs (blood vessels, heart, airway) are compressed. Mediastinal mass syndrome is the acute obstruction of the trachea or large vessels (superior vena cava, right atrium, right ventricle) by tumor mass after induction of general anesthesia. Patients frequently complain of dyspnea while in the supine position. The supine position in combination with muscle relaxation can lead to positional changes of the tumor mass and result in airway obstruction. Careful preoperative evaluation and review of the patient's computed tomographic scan can alert the anesthesiologist to this potential complication. Discussion with the patient and surgeon regarding these concerns can provoke a search for alternative means of analgesia (e.g., local anesthesia in monitored anesthesia care).

Should a general anesthestic be deemed necessary, then an inhalational induction with sevoflurane, keeping the patient breathing spontaneously and avoiding muscle relaxation, is a prudent plan. If airway compromise still occurs, then the anesthetic should be aborted and the patient awakened immediately. Awake fiberoptic intubation is another alternative, providing the bronchoscope can be passed distal to the lesion. A distal lesion, however, poses the same problems seen in conventional intubation because the end of the endotracheal tube will lie proximal to the lesion. In an urgent situation, a rigid ventilating bronchoscope must be passed immediately.

Hodgkin's Disease

Hodgkin‚ disease has an incidence of 3/100,000, showing a double peaked distribution in western countries during the third and sixth decades of life. Males are more frequently affected by the illness than females (3:2). Whether the Ebstein-Barr virus plays a similar role in the etiology as in the development of Burkitt's lymphoma remains unclear. Hodgkin's disease leads to immunosuppression, with increased susceptibility for tuberculosis and fungal and viral infections. Oncologists use the Ann Arbor Classification to describe the progression of disease ( Table 11-4 ).

TABLE 11-4 -- Ann Arbor Staging System for Hodgkin's Disease

Stage	Description
I	Involvement in single lymph node region or single extralymphatic site
II	Involvement in two or more lymph node regions on the same side of diaphragm
III	Involvement of lymph node regions on both sides of diaphragm; may include spleen
IV	Disseminated involvement of one or more extralymphatic organs with or without lymph node involvement

A Symptoms: without general symptoms of disease.

B Symptoms: fever, loss of weight, night sweats, pruritus.

This classification can also be used to assess patient prognosis. The higher the grading, the worse the prognosis. Stages I and II are primarily treated with radiation therapy. Stages III and IV are additionally treated with chemotherapy. As a result of improved medical management, the long-term survival rates have increased dramatically over the past decade. Unfortunately, the cure of Hodgkin's lymphoma comes with a price. An increasing number or “survivors” are presenting with long-term complications of the medical treatment (e.g., second neoplasms, cardiotoxicity induced by chemotherapy [doxorubicin], pulmonary toxicity through bleomycin). For patients with a history of doxorubicin therapy, assessment of cardiac function should be made, including cardiovascular testing if appropriate. Surgical patients who have been exposed to bleomycin therapy should have a complete set of PFTs if they exhibit pulmonary symptoms. This is especially helpful in patients presenting for pulmonary resection. The PFT profile of bleomycin toxicity will demonstrate a severe restrictive lung disease pattern with small lung volumes and a reduced carbon monoxide diffusion ratio.

Non-Hodgkin's Lymphomas

In contrast to Hodgkin's disease, NHL cannot be regarded as a single malignant entity but as a heterogeneous collective of neoplasia originating from T lymphocytes in lymphatic tissue. Thirty percent of cases of NHL present with a leukemic element. The incidence is reported between 5 and 10/100,000, increasing with age. As in Hodgkin's disease the male gender is more prone to acquiring the disease (1.5:1). HIV-positive patients are 1,000 times more susceptible to developing NHL than a control population.

Multiple Myeloma and Macroglobulinemia

Multiple myeloma, also known as plasmacytoma or Kahler's disease, is a malignant disorder of plasmacytes. It is classified into the group of non-Hodgkin's lymphomas. The neoplastic plasmacytes produce either a monoclonal immunoglobulin (IgG, IgA, IgD) or isolated light chains (Bence Jones plasmacytoma). During this process bone marrow is displaced by infiltration of the tumor, resulting in a loss of functioning peripheral blood cells. The tumor also leads to osteolysis with a loss of normal bone architecture, resulting in an increased risk of pathologic fractures.

Patients present with high erythrocyte sedimentation rates, Bence Jones proteinuria, or a change in their protein or immunoglobulin electrophoresis. Patients will typically be anemic and have signs of coagulopathy due to thrombocytopenia, thrombocytopathy, and decreased functional plasmatic coagulation factors. Renal failure due to toxic deposition of immunoglobulin in the renal tubuli is the most common cause of mortality. Hypercalcemia resulting from increased osteoclastic activity supports the development of renal failure and can lead to hypercalcemic crisis. Ten percent of patients will develop amyloidosis. Treatment includes radiation therapy and/or chemotherapy. Prognosis is poor at present.

Macroglobulinemia or Waldenström's disease is generally seen in the aging population and caused by malignant plasmocytes producing IgM immunoglobulins. This illness is four times as seldom as multiple myeloma and is not as aggressive. Osteolysis and hypercalcemia are not seen; however, hemorrhagic diathesis caused by disorders of thrombocyte aggregation and binding of coagulation factors is observed. Hyperviscosity syndrome leading to Raynaud-like acral perfusion deficits and visual disturbances is also seen. Prognosis is better than for multiple myeloma.

Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Leukemias

Leukemia means “white blood” and refers to an increased amount of leukocytes seen in peripheral blood. Leukemias are divided into acute or chronic forms and myeloplastic or lymphatic forms, depending on the cell row from which the neoplasm originated.

All leukemias lead to impaired immune reactions, making patients more prone to infection. Because of the possibility of infiltration of leukemic cells into virtually all organs, a reduction in organ function can be associated with this illness.

Leukemia is treated classically with chemotherapy. The anesthesiologist should be aware of the agents employed during chemotherapy cycles. Doxorubicin is known to cause systolic dysfunction that can affect the anesthetic technique. Emerging techniques utilized to treat leukemia are allogenic bone marrow transplantation and stem cell transplantation. Treatment is generally more successful in children, with 5-year survival rate reaching 80%.

Acute Leukemia

The cornerstone for the diagnosis of an acute leukemia is the presence of immature hematopoietic cells in peripheral blood. The incidence is 4/100,000 per year. Eighty percent of acute leukemias in childhood originate from lymphatic cells; in adulthood, 80% are myelocytic. The etiology is multifactorial. Retroviruses, bone marrow damage caused by radiotherapy or chemical substances, and genetic composition of the patient (e.g., Down's syndrome, Klinefelter's syndrome) have all been linked to an increased risk for developing acute leukemia.

Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Chronic Myeloproliferative Disease

Chronic myeloproliferative disease incorporates four illnesses (chronic myelocytic leukemia, polycythemia vera, essential thrombocythemia, and osteomyelosclerosis). All of these diseases show a monoclonal proliferation from a myelocytic stem cell. Initially, all three cell rows are increased in number (leuko-, erythro- and thrombocytosis). Splenomegaly is common. Eventually, sclerosis of the patient's bone marrow occurs, leading to loss of its function. Extramedullary hematopoiesis is seen (liver, spleen). In the terminal phase a blast crisis is frequently seen.

Chronic leukemias develop over a prolonged period of time, sometimes taking a decade to manifest clinically. Chronic myelocytic leukemia presents as the highest concentration of leukocytes (<500,000/μL), resulting in organ infarction. Chronic lymphatic leukemia is the most common form of leukemia and increases in incidence with increasing age. Chronic myelocytic leukemia has a low degree of malignancy, allowing patients to survive for many years without impairing quality of life. Lymphadenopathy and splenomegaly are common manifestations in chronic leukemia.

Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Myelodysplastic Syndrome

This disease represents a heterogenic clonal stem cell pathology with qualitative and quantitative changes of hematopoiesis, peripheral cytopenia, and a high proportional amount of blast in bone marrow. It is primarily seen in the elderly (20 to 50/100,000/year in those older than age 70 years).

Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

DISEASES OF THROMBOCYTES (PLATELETS)

Circulating platelets are anucleate discoid cells that are formed from megakaryocytes. The normal platelet count is 140,000 to 450,000/μL. Platelets have many different roles in maintaining circulation and hemostasis. Platelets form the primary phase of hemostasis, the platelet plug. This initial adhesion of platelets to the injured endothelium is responsible for the physical “healing” of the wound and for the biochemical signaling that occurs when other cells and coagulation factors are summoned to the site of injury. The platelet surface phospholipid is a critical surface on which the coagulation cascade proteases become activated and form a fibrin clot. On physical examination, the absence of normal platelet number or function can be detected by the presence of petechiae. Conversely, an excessive number of platelets or excessively activated platelets will predispose to arterial occlusive disease. Patient and family history are the most important factors in assessing platelet-related disorders.

Routine screening for platelet abnormalities is not recommended in the absence of any of the signs or symptoms. In the presence of signs of symptoms of a bleeding diathesis, a platelet count is obtained. A minimal platelet count of 50,000 to 100,000/μL is recommended before elective surgery. Spontaneous bleeding can occur with platelet counts less than 30,000/μL. Further testing such as the bleeding time and other aggregation studies will be described as they relate to individual disease states.

Thrombocytopenia

Thrombocytopenia is due to either decreased production of platelets, excessive destruction of platelets, or splenic or other sequestration. A common cause of decreased production is the result of bone marrow hypoplasia or marrow toxic drugs. Increased destruction may be drug induced or autoimmune. Thrombocytopenia also occurs in the parturient and may represent risks to maternal or fetal well-being if not recognized early.^[40] A list of common causes of thrombocytopenia is found in Table 11-5 .

TABLE 11-5 -- Disease States Associated with Thrombocytopenia

Impaired Production	Increased Destruction	Sequestration
Megakaryocyte dysfunction	Autoimmune (immune thrombocytopenic purpura)	Hypersplenism
Aplastic anemia	Immune (post-transfusion)	Splenomegaly
Drug (ticlopidine)	Drug (chemotherapy)	Adhesion to synthetic surfaces
Vitamin B₁₂/folate deficiency	Disseminated intravascular coagulation	Platelet-platelet adhesion
Myelodysplastic disorders	Thrombotic thrombocytopenic purpura	Heparin-induced thrombocytopenia type 1
	Hemolytic-uremic syndrome
	Hemodilution
	Heparin-induced thrombocytopenia type 2

Immune (Idiopathic) Thrombocytopenic Purpura

Immune or idiopathic thrombocytopenic purpura (ITP) is a common abnormality causing a low platelet count. It affects 0.01% of the population and is the result of autoantibodies that bind to the platelet surfaces, thus decreasing their life span.^[41] It frequently affects young women and is thus encountered in the parturient.^[42] Cutaneous signs such as petechiae are often the presenting feature. Treatment is not usually recommended until the platelet count is less than 30,000/μL unless the patient is having uncontrolled bleeding or major surgery. Therapy begins with corticosteroid therapy at the lowest possible dose that will lead to a response. In the presence of catastrophic bleeding, platelet transfusion can be given in conjunction with corticosteroid therapy or immune globulin therapy to decrease the immunologically mediated destruction. Plasmapheresis has also been used in conjunction with other therapies with some success. Emergent splenectomy is reserved for the patient who fails the therapies and who has life-threatening bleeding.^[43]

Thrombotic Thrombocytopenic Purpura

The signs and symptoms of thrombotic thrombocytopenic purpura (TTP) consist of fever, hemolytic anemia, thrombocytopenia, renal disease, and central nervous system disease. The management of this disease consists of corticosteroids, plasmapheresis, and plasma transfusion. When TTP presents during pregnancy it can appear identical to toxemia of pregnancy. During the last trimester of pregnancy, treatment of this constellation of symptoms is delivery of the infant.

Platelet Sequestration

Platelet count will be reduced due to sequestration of platelets in the spleen. This clinical condition is almost akin to a pseudo-thrombocytopenia because the platelets are present in the body but they are not circulating in the bloodstream. Platelets adhere to extracorporeal surfaces such as a cardiopulmonary bypass circuit. This plus hemodilution accounts for most of the thrombocytopenia seen after cardiac surgery.^[44]

Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Thrombasthenic Syndromes

In contrast to thrombocytopenia, clinical conditions in which the platelet count often falls to levels less than 30,000/μL before treatment is initiated, patients with thrombasthenic syndromes ( Table 11-6 ) require treatment with platelet transfusion at much higher levels of platelet count because platelet function is so compromised.

TABLE 11-6 -- Platelet Disorders and Available Testing Modalities

Disorder	Pathophysiology	Testing
Bernard-Soulier syndrome	Absent GPIb	Flow cytometry, bleeding time, PFA-100
Glanzmann's thrombasthenia	Absent GPIIbIIIa	Flow cytometry, aggregation, Ultegra, TEG
Von Willebrand's disease	vWF	Bleeding time, PFA-100
Gray platelet syndrome	Alpha granule depletion	Flow cytometry, aggregation
Drug Therapy
Aspirin ingestion	Cyclooxygenase inhibition	Aggregation, bleeding time, PFA-100, modified TEG
Clopidogrel ingestion	ADP P2Y12 inhibition	Aggregation, bleeding time, modified TEG
Abciximab	GPIIbIIIa blockade	Aggregation, flow cytometry, Ultegra
Nitroglycerin	Increased nitric oxide	Aggregation, flow cytometry

GP, glycoprotein; vWF, von Willebrand factor; TEG, thromboelastography.

von Willebrand's Disease

von Willebrand factor (vWF) is synthesized in the endothelium and in the platelet and acts as a ligand for platelet adhesion via the GPIb receptor. von Willebrand's disease is a common disorder of the vWF that frequently manifests as a bleeding disorder. It is inherited via an autosomal dominant genetic trait. Laboratory analysis of von Willebrand's disease consists of the measurement of vWF activity, vWF antigen, factor VIII activity, vWF multimeric analysis, and the bleeding time. The vWF multimeric analysis is important for the classification of the subtype of von Willebrand's disease ( Table 11-7 ). If only factor VIII level is reduced, von Willebrand's disease can be confused with hemophilia A.^[45] If only the bleeding time is prolonged, it can be confused with a primary platelet disorder. There are different subtypes of the disease that respond differently to therapy; thus, it is important to know which subtype of the disease exists in a patient.

TABLE 11-7 -- von Willebrand's Disease: Laboratory Analysis and Therapy

Disease Type	vWF Activity	Antigen	Bleeding Time	Factor VIII	Treatment
Type 1	↓	↓	↑	↓	Desmopressin
Type 2A	↓	↓	↑	↓	Factor VIII concentrates
Type 2B	↓	↓	↑	↓	Factor VIII concentrates
Type 2N	Normal	Normal	↑	↓	Factor VIII concentrates
Type 3	↓↓	↓↓	↑	↓↓	Factor VIII concentrates plus desmopressin
Platelet (pseudo–von Willebrand's disease)	↓	↓	↑	↓	Platelets
Hemophilia A	Normal	Normal	Normal	↓	Factor VIII concentrates

Patients with von Willebrand's disease have a prolonged bleeding time. Clinically, they can have a range of abnormalities from mild bleeding to hemorrhagic symptoms. They often have increased mucocutaneous bleeding (during dental procedures), and women frequently present with menorrhagia.^[46]

Type I disease is marked by a reduced quantity of normal vWF. The large multimers of vWF that are so critical for platelet adhesion are normal in size but reduced in quantity. Treatment of type I includes desmopressin (D-arginine vasopressin [DDAVP]), which increases the release of vWF from the endothelium and the platelet.^{[47] [48]} Desmopressin is available in intranasal or intravenous forms, and the intravenous form is often given intranasally. In patients with type I disease, a doubling of vWF activity (and factor VIII) and shortening of the bleeding time occur within 15 to 30 minutes of administration of desmopressin. The dose is 0.3 μg/kg intravenously over 30 minutes. It must be infused slowly or it will cause hypotension.

In type IIA von Willebrand's disease there is a qualitative abnormality of vWF in which there are defective platelet-vWF interactions. This is due to the absence of high- and middle-molecular-weight vWF multimers. Patients may have normal levels of vWF protein, but the protein is dysfunctional. These variants account for 15% to 30% of cases.^{[49] [50] [51]} Type IIB von Willebrand's disease is caused by a qualitative abnormality of vWF in which there is increased platelet-vWF interaction due to an increased affinity of vWF for its platelet receptor, GPIb. The hallmark of type IIB von Willebrand's disease is an enhanced aggregation of the patient's platelets in the presence of reduced concentrations of ristocetin. In type IIB disease, a low concentration of ristocetin stimulates a full aggregation response. This form of the disease can be marked by thrombocytopenia, but there may also be increased adhesiveness and thrombosis. Thus, the administration of desmopressin as therapy is not recommended. In type IIN, there may be qualitative variants with markedly decreased affinity for factor VIII. The measured vWF activity and antigen may be normal. Type III is a severe form, with nearly complete deficiency of vWF. Usually, vWF activity and antigen are undetectable and factor VIII levels are markedly reduced. The bleeding time is prolonged, usually to more than 20 minutes. Patients with type III disease have essentially no vWF multimers. This severe form of von Willebrand's disease may be the result of a homozygous defect or a complex heterozygous defect. Desmopressin is not of benefit in patients with type III disease because they have almost no endogenous production of vWF. Platelet-type or pseudo-von Willebrand's disease is a primary platelet disorder involving the platelet receptor for vWF, GPIb. Although this is primarily a platelet disorder, patients with platelet-type, pseudo-von Willebrand's disease have absent high-molecular-weight multimers, reduced factor VIII, reduced vWF activity, and a prolonged bleeding time. The laboratory analysis is similar to patients with type IIB disease. Aggregation is enhanced in response to low concentrations of ristocetin (0.3 to 0.5mg/mL), and mild thrombocytopenia is commonly present. Von Willebrand's disease can also be acquired. This is thought to occur by antibodies to vWF that neutralize vWF activity.

In preparation of the patient with von Willebrand's disease for surgery, baseline factor VIII and bleeding time should be obtained within 1 week of surgery. One to 2 hours before surgery, treatment with desmopressin at a dose 0.3 μg/kg should be infused. If baseline factor VIII and bleeding time were abnormal, these measures should be confirmed normal after desmopressin treatment and before surgery is begun. After surgery, these measures should be repeated once a day until wound healing is complete. Desmopressin may need to be given once daily after surgery. For more extensive surgery, factor VIII concentrates may be necessary so that desmopressin can enhance vWF activity of the administered product. Patients with type II or III disease should receive factor VIII concentrates along the same timeline as described for the treatment of type I disease. Desmopressin may cause thrombocytopenia or increased aggregation^[52] in these patients, but some still suggest that it may be effective therapy in addition to replacement therapy for patients with type II and III disease. After surgery, treatment is continued every 12 hours until wound healing is complete.

Other Thrombasthenic Syndromes

Bernard-Soulier syndrome is marked by deficiency of the GPIb receptor, the major receptor responsible for platelet adhesion to collagen, vWF, and other ligands.^[53] Patients with this disorder have hemorrhagic tendencies.

Glanzmann's thrombasthenia is inherited as an autosomal recessive disorder. Patients with this disorder have severe impairments in platelet aggregation, a prolonged bleeding time, and a normal platelet count. The disease is marked by the absence of the GPIIbIIIa receptor (α_2bβ₃ integrin).^[53] Either component of this receptor, the α or the β component, may be absent or abnormal for the disease to be expressed. Fibrinogen binding to GPIIbIIIa induces a conformational change in the receptor, making it more likely to bind fibrinogen and further enhancing the aggregation process. GPIIbIIIa is the major receptor whereby fibrinogen bridges adjacent platelets. Thus, patients with Glanzmann's thrombasthenia have lifelong bleeding histories and require platelet transfusions to achieve normal platelet aggregation. In certain clinical scenarios such as percutaneous cardiologic intervention, pharmacologic agents are prescribed that competitively or permanently block the GPIIbIIIa receptor. The effect achieved is one of extreme platelet “paresis.” If large enough doses are administered, nearly 100% of GPIIbIIIa receptors can be blocked and platelet aggregation to raw atherogenic surfaces (coronary arteries) will not occur. During drug infusion, patients are very susceptible to bleeding, but careful monitoring and drug dosing has minimized this risk. Examples of these drugs include abciximab, tirofiban, and eptifibatide. Anesthetic management of the patient with absent GPIIbIIIa function includes the transfusion of allogeneic platelets. In patients who have received GPIIbIIIa antagonist drugs, additional fibrinogen in the form of cryoprecipitate may be transfused to compete with the drug for the platelet receptor. However, this is often not done because the drugs have a higher affinity for the receptor than does the fibrinogen ligand. In emergency surgery, antifibrinolytic drugs have been used to minimize the amount of bleeding seen in these patients, but the data supporting this practice come from animal and in-vitro studies. The degree of platelet inhibition can be measured using laboratory and point-of-care tests so that an approximation of the patient's transfusion needs can be made. Laboratory testing of platelet function is discussed in a different section of this chapter.

Concomitant Drugs

In patients with thrombocytopenia and/or platelet dysfunction it is often suggested that other drugs that impair platelet function be avoided. However, many drugs and drug classes have been shown to impair platelet function in vitro.^[54] The most common class of drugs would be the nitric oxide donors.^{[55] [56]} This class of drugs includes nitrates (sodium nitroprusside, nitroglycerin),^[57]phosphodiesterase inhibitors (milrinone),^[58] and nitric oxide itself. Nitric oxide has such a short half-life that its effects on platelet function would be short lived.^{[59] [60]} However, nitric oxide donors such as nitroprusside may clinically impair platelet function to a measurable degree in a patient whose platelet activity is already compromised.^[61] Despite the fact that nitric oxide donors impair platelet function in the laboratory, this does not translate into a clinical problem.^{[56] [62] [63]} In fact, when nitric oxide was compared with control inhalation after cardiopulmonary bypass, nitric oxide patients had preserved platelet counts and lower expression of GPIb. Aggregation was not different between nitric oxide and control groups.^[64] The acute effects of milrinone on platelet function in vivo was also not measurable by standard laboratory or clinical tests.^[65]

Antithrombotic Drug Therapy

The glycoprotein IIbIIIa (GPIIbIIIa) receptor is responsible for mediating platelet-platelet aggregation via fibrinogen bridging. Drugs that inhibit this receptor in a reversible or an irreversible fashion are potent inhibitors of platelet aggregation and include abciximab (Reopro), eptifibatide (Integrilin), and tirofiban (Aggrastat). They are frequently infused to prevent thrombus formation in patients who have undergone a high-risk coronary interventional procedure. Large-scale multicenter studies have shown that re-thrombosis and infarction rates after percutaneous angioplasty and after stent procedures have been reduced with the use of these drugs.^[66] Reductions in mortality and re-infarction rates have been shown in such patient groups as diabetics and patients with prior cardiac surgery.^[67]

Of the three intravenous GPIIbIIIa inhibitors, abciximab is a large monoclonal antibody that binds and causes permanent dysfunction of the GPIIbIIIa receptor, while also blocking other receptors owing to its large size. Comparative studies and head-to-head comparisons have shown that abciximab is superior to the other agents in preventing ischemic complications, which explains its prevalence of use.^[68]However, its potent platelet-inhibiting properties also render it likely to cause increased episodes of major bleeding. Patients who present for surgery after having received abciximab often require a prolonged operative time to achieve hemostasis and an increased incidence of platelet transfusions.^[69] By contrast, the small molecule agents eptifibatide and tirofiban are competitive blockers whose small size and half-life of approximately 2 hours make it possible to conduct cardiac surgery without an increased risk of bleeding. Studies have documented lower myocardial infarction rates^[70] and similar bleeding rates in emergency coronary bypass patients who received eptifibatide compared with those that received placebo before surgery.^[71]

Antiplatelet therapy has been rapidly advancing owing to the introduction of the thienopyridine derivatives ticlopidine and clopidogrel (Plavix, Sanofi). Clopidogrel has almost completely replaced ticlopidine for this use because it has a wider therapeutic index and a lesser side effect profile and is more efficacious at doses used clinically. Clopidogrel is a prodrug and requires metabolism by cytochrome P450 subtype 3A4 to form the active drug.^{[72] [73] [74]} These drugs act by noncompetitive antagonism at one of the platelet adenosine diphosphate (ADP) receptors, the P2Y12 receptor.^[75]There are three known ADP receptor subtypes: the P2X receptor is a calcium ion channel; the P2Y1 receptor is the major receptor responsible for regulating calcium influx and subsequent aggregation^{[76] [77] [78]}; and the P2Y12 receptor inhibits cyclic adenosine monophosphate production and potentiates platelet aggregation ( Fig. 11-1 ).



FIGURE 11-1 Role of clopidogrel in antiplatelet therapy.

The duration of antiplatelet activity is the life span of the platelet because the P2Y12 receptor is permanently altered. The effects of clopidogrel plus aspirin are additive and sometimes synergistic, depending on the model of platelet function studied. This may explain why cardiac surgical patients having received this combination of drugs seem to have excessive postoperative bleeding.^[79] Patients taking these medications at the time of cardiac surgery are at increased risk for bleeding complications and have a documented increase in transfusions and reoperations for bleeding.^{[73] [80] [85]} This increase in transfusion is seen despite the careful implementation of a transfusion algorithm^[82] or strict guidelines for transfusion therapy.^{[10] [86]}

The logical solution to an increased occurrence of bleeding would seem to be cessation of antithrombotic therapy in preparation for an elective surgical procedure. However, antithrombotic therapy is critical for at least 6 weeks when a bare metal stent is in situ.^[87] After this period, it is believed that the stent surface has sufficient surface of neo-endothelium and is not thrombogenic.^[88] The minimum period of time during which antithrombotic therapy is suggested in patients with drug-eluting stents is less well defined. The antiproliferative drugs embedded in these stents prolong the development of new endothelium and thus require longer periods (perhaps years) of antiplatelet medication.^[89] It has been suggested by retrospective and case reporting that cessation of antiplatelet therapy in patients whose stent has not developed endothelium leads to thrombosis and acute myocardial infarction.

Specific monitoring of the platelet defect induced by these antithrombotic drugs would be advantageous for a number of reasons. For therapeutic efficacy, the degree to which patients are protected from thrombotic events is related to the degree of platelet inhibition. Thus, platelet function monitoring can be used for titrating drug effect. Alternatively, patients taking these medications who present for surgery can be assayed for their degree of platelet dysfunction and their risk of bleeding and need for transfusion.

Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Diseases or Disorders of Impaired Coagulation

Hemophilia A is inherited as an X-linked disorder. Patients with hemophilia A have insufficient production of factor VIII and thus they have severe impairments in intrinsic coagulation. This can be detected by laboratory analysis by a prolonged partial thromboplastin time. Clinically, the disease manifests as hematuria, hemarthroses, and spontaneous hemorrhage when factor VIII levels are less than 3% of normal. It is important to measure the factor VIII level so that replacement therapy can be initiated before surgery.^[90] The goal of replacement therapy is to achieve 100% activity by transfusion of factor VIII concentrates. Assuming a plasma volume of 40 mL/kg, and the need for 100% functional factor VIII before surgery, the number of units of factor VIII needed can be calculated. Plasma contains 1 unit of procoagulant factor per milliliter; cryoprecipitate contains 5 to 10 units/mL, and factor VIII concentrates contain up to 40 units/mL. Factor VIII levels of greater than 30% are considered adequate for hemostasis after major surgery. Replacement therapy will have to be given twice daily in the perioperative period because the elimination half-life of factor VIII is 10 to 12 hours. Some forms of hemophilia are not easily treated with replacement factors because patients can have circulating inhibitors.

Hemophilia B is a disorder of the production of factor IX. The inheritance pattern for hemophilia B is similar to that for hemophilia A. The laboratory abnormalities are also similar in that activated partial thromboplastin time is prolonged. Replacement of factor IX is with specific procoagulant concentrates or complexes that contain high concentrations of factor IX.

Other isolated factor deficiencies are rare. Specific perioperative treatment for these disorders includes preoperative measurement of the deficient factor quantity. Replacement of that factor either in the form of factor concentrates or in a pooled plasma product should aim at bringing factor levels to 100% before surgery. Even the heat-treated factor concentrates that are manufactured carry a small risk of viral transmission because they are derived from human blood products that have been heat treated.

Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Thrombotic Disorders

Antithrombin III Deficiency

Antithrombin III deficiency can be inherited or acquired. The inherited form of the disease is usually marked by extremely low levels of this endogenous anticoagulant. AT3 inhibits thrombin, hence its name, but it also very effectively inhibits factors XI, X, and IX. Heparin works as an anticoagulant by enhancing the activity of AT3 by 1000-fold. Patients with congenital AT3 deficiency present with venous thromboses throughout life. They develop many complications owing to their hypercoagulable state and are unresponsive to heparin. Patients who “acquire” AT3 deficiency do so as a result of recent previous heparin administration. The continued dosing of heparin usually in intravenous form causes consumption of AT3. Thus, AT3 levels can be low and AT3 activity can also be impaired. When these patients present for cardiac surgery, they often have reduced dose-responsiveness to heparin.^[91] Treatment for AT3 deficiency is replacement of AT3.^[92] Specific AT3 concentrates are often available. If they are not, transfusion of plasma will replace AT3.^[93] Each unit of plasma contains one unit of AT3. Measurement of preoperative levels and attempted replacement to 100% before cardiac surgery is recommended in congenital AT3 deficiency. In the acquired form of the disease it is not clear that replacement therapy is actually indicated.^[94]

Protein C and S Deficiency

Proteins C and S are anticoagulant proteases that form a feedback mechanism to the coagulation cascade so that clotting does not occur unchecked. These two proteases are activated by the presence of thrombin and fibrin. It was once thought that protein C and S deficiencies were common in patients with hypercoagulable disorders. Now it is accepted that many of the patients previously classified as protein C deficient actually had the factor V Leiden mutation.

Factor V Leiden Mutation

Factor V Leiden mutation is now known to be a common familiar disorder in European and Western cultures. Once thought to be an abnormality of activated protein C, the factor V Leiden mutation confers activated protein C resistance by virtue of the factor V molecule, which is resistant. Factor V Leiden mutations, which occur in 3% to 5% of the population, yield a resistance to activated protein C, which impairs the signaling for anticoagulation and fibrinolysis. Using a clot-based assay, in-vitro analyses evaluating the response to activated protein C in cardiac surgical patients indicate that aprotinin induces a factor V Leiden-like defect in normal plasma. In-vitro analyses from factor V Leiden patients suggest that aprotinin further exacerbates this defect in the plasma. Corroborating clinical data demonstrate that patients with factor V Leiden mutation have lesser amounts of mediastinal tube drainage and allogeneic transfusions.^[95] One case report describes a patient with factor V Leiden mutation who experienced thrombosis of coronary artery revascularization grafts within a month of surgery, and other case series have described aortic thromboses after aortic replacement.^[96]

Heparin-Induced Thrombocytopenia

The syndrome known as heparin-induced thrombocytopenia (HIT) develops in 5% to 28% of patients receiving heparin. HIT is commonly categorized into two subtypes. Type I is characterized by a mild decrease in platelet count and is the result of the proaggregatory effects of heparin on platelets. Type II is considerably more severe, most often occurs after more than 5 days of heparin administration (average onset time, 9 days), and is mediated by antibody binding to the complex formed between heparin and platelet factor 4 (PF4).^{[97] [98]} Associated immune-mediated endothelial injury and complement activation cause platelets to adhere, aggregate, and form platelet clots, or “white clots.” Among patients developing HIT type II, the incidence of thrombotic complications approximates 20%, which in turn may carry a mortality rate as high as 40%. Demonstration of heparin-induced proaggregation of platelets confirms the diagnosis of HIT type II. This can be accomplished with a heparin-induced serotonin release assay or a specific heparin-induced platelet activation assay. A highly specific enzyme-linked immunosorbent assay for the heparin/PF4 complex has been developed and has been used to delineate the course of IgG and IgM antibody responses in patients exposed to unfractionated heparin during cardiac surgery.^[99] The options for treating these patients are few.^[100] If one has the luxury of being able to discontinue the heparin for 90 days, often the antibody will disappear and allow a brief period of heparinization for cardiopulmonary bypass without complication.^[101] Some types of low-molecular-weight heparin have been given in HIT, but reactivity of the particular low-molecular-weight heparin with the patient's platelets should be confirmed in vitro. Supplementing heparin administration with pharmacologic platelet inhibition using prostacyclin, iloprost, aspirin, or aspirin and dipyridamole have been reported, all with favorable outcomes. Recently, the use of tirofiban with unfractionated heparin has been used in this clinical circumstance. Plasmapheresis may be used to reduce antibody levels. The use of heparin could be avoided altogether by anticoagulating with direct thrombin inhibitors such as argatroban, hirudin, or bivalirudin. These thrombin inhibitors have become the standard of care in the management of the patient with HIT type II.^{[102] [103] [104]}

Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

Monitoring Platelet Function

Platelet Function Tests: Point of Care

Point-of-care platelet function testing is critical to have an impact on acute medical management. The need for small sample size, rapid turnaround, ease of use, and clinical applicability make point-of-care monitoring the gold standard in the perioperative setting. Platelet function monitors can be divided into three basic and non-mutually exclusive categories: static tests, dynamic tests (nonactivated), and tests of the platelet response to an activating stimulus.

Static Tests of Platelet Function

Static tests such as the measure of β-thromboglobulin, ADP release, or the number of platelet receptors present on the surface capture only a single point in time and do not accurately reflect the dynamic environment encountered after cardiopulmonary bypass. Neither do they reflect the platelet ability to respond to an agonist.

Dynamic Tests of Platelet Function

Dynamic tests such as the bleeding time or the viscoelastic measures of clot formation better reflect the contribution of platelet function to overall clot formation because they take into account the time-dependent nature of platelet-mediated hemostasis. They are, however, nonspecific in nature owing to the absence of a platelet-specific agonist, but the tests can generally be modified to overcome this limitation.

TEG (Haemoscope, Skokie, IL) is a whole blood test of viscoelastic blood clot formation that has been used in many different clinical scenarios to diagnose coagulation abnormalities. Within 10 to 20 minutes information is obtained regarding the integrity of the coagulation cascade, platelet function, platelet-fibrin interactions, and fibrinolysis. Whole blood (360 μL) is placed into an oscillating cuvette. A piston connected to a transducer and oscillograph is immersed into the blood sample. The movement of the piston becomes coupled to the oscillating cuvette as the blood clots. This generates a signature tracing with the following parameters: reaction time (R value), coagulation time (K value), α angle, maximum amplitude (MA), amplitude 60 minutes after the maximal amplitude (A60). Respectively, these parameters measure fibrin formation, fibrinogen turnover, speed of clot formation, plateletfibrin interactions, and fibrinolysis.

Recent modifications to the TEG have allowed for improved monitoring capabilities. Use of recombinant human tissue factor as an activator accelerates the rate of thrombin formation and shortens the time required for development of MA. Because MA is primarily reflective of clot strength and platelet function, this information can be obtained more quickly with tissue factor enhancement (5 to 10 minutes). An application of thromboelastography in the clinical arena is its use in monitoring fibrinolysis and antiplatelet therapy using either the GPIIbIIIa receptor blockers, aspirin, or clopidogrel. This has predominantly been done using modifications to the point-of-care system and is being further developed. In-vitro addition of a large dose of abciximab to the test cuvette enhances the diagnostic ability of the test to discriminate between hypofibrinogenemia and platelet dysfunction as a cause of decreased MA.^{[105] [106]}

Tests of Platelet Response to an Agonist Stimulus

The newest group of platelet function tests includes point-of-care monitors specifically designed to measure agonist-induced platelet-mediated hemostasis.

The platelet-activated clotting time, Hemostatus (Medtronic Inc., Parker, CO), measures the activated clotting time without platelet activator and compares this value to the activated clotting time obtained when increasing concentrations of a platelet-activating factor (PAF) are added. The percent reduction of the activated clotting time due to the addition of PAF is related to the ability of platelets to be activated and to shorten clotting time.^[107] The assay is performed using a specific cartridge in a Heparin Management System (HMS) (Medtronic Inc., Parker, CO) device, and the Hemostatus cartridge has been found useful for monitoring platelet function during cardiac surgery.^[108]

Ultegra (Accumetrics, San Diego, CA), or “rapid platelet function assay,” is a point-of-care monitor designed specifically to measure the platelet response to a thrombin receptor agonist peptide (TRAP). In whole blood, it measures TRAP activation-induced platelet agglutination of fibrinogen-coated beads using an optical detection system. Because of the importance of the GPIIbIIIa receptor in mediating fibrinogen-platelet interactions, the Ultegra has been especially useful in accurately measuring receptor inhibition in invasive cardiology patients receiving GPIIbIIIa-inhibiting drugs.^{[109] [110] [111]}

The Platelet Function Analyzer, PFA-100 (Dade Behring, Miami, FL), is a monitor of platelet adhesive capacity that is valuable in its diagnostic abilities to identify drug-induced platelet abnormalities, Bernard-Soulier syndrome, von Willebrand's disease, and other acquired and congenital platelet defects.^{[112] [113]} The test is conducted as a modified in-vitro bleeding time. Whole blood is drawn through a chamber by vacuum and is perfused across an aperture in a collagen membrane coated with an agonist (epinephrine or ADP). Platelet adhesion and formation of aggregates will seal the aperture, thus indicating the “closure time” measured by the PFA-100. This test may be useful in detecting pharmacologic platelet dysfunction before cardiac surgery or may be able to accurately detect hypercoagulability after CPB.

“Plateletworks” (Helena Laboratories, Beaumont, TX) utilizes the principle of the platelet count ratio to assess platelet reactivity. The instrument is a Coulter counter that measures the platelet count in a standard EDTA-containing tube. Platelet count is also measured in tubes containing the platelet agonists (e.g., ADP, collagen). Addition of blood to these agonist tubes causes platelets to activate, adhere to the tube, and to be effectively eliminated from the platelet count. The ratio of the activated platelet count to the nonactivated platelet count is a function of the reactivity of the platelets. Early investigation in cardiac surgical patients indicates that this assay is useful in providing a platelet count and that it is capable of measuring the platelet dysfunction that accompanies cardiopulmonary bypass.^[114]Plateletworks has also been used to study the pharmacokinetics and pharmacodynamics of clopidogrel in conjunction with other drug therapy.^[72]

Platelet Aggregometry

Platelet aggregometry utilizes a photo-optical instrument to measure light transmittance through a sample of platelet-rich plasma. When exposed to a platelet agonist, the initial reversible aggregation phase results in increased light transmittance due to the platelet aggregates that decrease the turbidity of the sample. Aggregometry is considered a “gold standard” of platelet function measure.^[115] It is rather labor and time intensive and is not practical for the immediate perioperative period. This is the reason for the surge in the number of point-of-care platelet function monitors being developed.

Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

References

Points to consider on efficacy evaluation of hemoglobin- and perfluorocarbon-based oxygen carriers. Center for Biologics Evaluation and Research. Transfusion1994; 34:712-713.
Wallace EL, Churchill WH, Surgenor DM, et al: Collection and transfusion of blood and blood components in the United States, 1992. Transfusion1995; 35:802-812.
Wallace EL, Churchill WH, Surgenor DM, et al: Collection and transfusion of blood and blood components in the United States, 1994. Transfusion1998; 38:625-636.
Wallace EL, Surgenor DM, Hao HS, et al: Collection and transfusion of blood and blood components in the United States, 1989. Transfusion1993; 33:139-144.
Shander A: Anemia in the critically ill. Crit Care Clin2004; 20:159-178.
Platelet transfusion therapy. National Institutes of Health Consensus Conference. Transfus Med Rev1987; 1:195-200.
Consensus conference: Perioperative red blood cell transfusion. JAMA1988; 260:2700-2703.
Consensus conference: Platelet transfusion therapy. JAMA1987; 257:1777-1780.
Consensus conference: Fresh-frozen plasma: Indications and risks. JAMA1985; 253:551-553.
Practice Guidelines for blood component therapy: A report by the American Society of Anesthesiologists Task Force on Blood Component Therapy. Anesthesiology1996; 84:732-747.
Nelson AH, Fleisher LA, Rosenbaum SH: Relationship between postoperative anemia and cardiac morbidity in high-risk vascular patients in the intensive care unit. Crit Care Med1993; 21:860-866.
Humphries JE: Transfusion therapy in acquired coagulopathies. Hematol Oncol Clin North Am1994; 8:1181-1201.
Mayer Jr JE, Kersten TE, Humphrey EW: Effects of transfusion of emboli and aged plasma on pulmonary capillary permeability. J Thorac Cardiovasc Surg1981; 82:358-364.
Curran JW, Lawrence DN, Jaffe H, et al: Acquired immunodeficiency syndrome (AIDS) associated with transfusions. N Engl J Med1984; 310:69-75.
Donahue JG, Munoz A, Ness PM, et al: The declining risk of post-transfusion hepatitis C virus infection. N Engl J Med1992; 327:369-373.
Ward JW, Bush TJ, Perkins HA, et al: The natural history of transfusion-associated infection with human immunodeficiency virus: Factors influencing the rate of progression to disease. N Engl J Med1989; 321:947-952.
Lackritz EM, Satten GA, Aberle-Grasse J, et al: Estimated risk of transmission of the human immunodeficiency virus by screened blood in the United States. N Engl J Med1995; 333:1721-1725.
Sloand EM, Pitt E, Klein HG: Safety of the blood supply. JAMA1995; 274:1368-1373.
Brown KE, Tisdale J, Barrett AJ, et al: Hepatitis-associated aplastic anemia. N Engl J Med1997; 336:1059-1064.
Young NS, Maciejewski J: The pathophysiology of acquired aplastic anemia. N Engl J Med1997; 336:1365-1372.
Erbe RW: Genetic aspects of folate metabolism. Adv Hum Genet1979; 9:293-354.367-369
Erbe RW, Salis RJ: Severe methylenetetrahydrofolate reductase deficiency, methionine synthase, and nitrous oxide a cautionary tale. N Engl J Med2003; 349:5-6.
Toh BH, van Driel IR, Gleeson PA: Pernicious anemia. N Engl J Med1997; 337:1441-1448.
Sickle-cell anemia and anaesthesia. BMJ1965; 5473:1263-1264.
Frietsch T, Ewen I, Waschke KF: Anaesthetic care for sickle cell disease. Eur J Anaesthesiol2001; 18:137-150.
Bunn HF: Pathogenesis and treatment of sickle cell disease. N Engl J Med1997; 337:762-769.
Djaiani GN, Cheng DC, Carroll JA, et al: Fast-track cardiac anesthesia in patients with sickle cell abnormalities. Anesth Analg1999; 89:598-603.
Abdulla Al-Ghamdi A: Bilateral total knee replacement with tourniquets in a homozygous sickle cell patient. Anesth Analg2004; 98:543-544.table of contents
Stein RE, Urbaniak J: Use of the tourniquet during surgery in patients with sickle cell hemoglobinopathies. Clin Orthop Rel Res1980;231-233.
Adu-Gyamfi Y, Sankarankutty M, Marwa S: Use of a tourniquet in patients with sickle-cell disease. Can J Anaesth1993; 40:24-27.
Vichinsky EP, Haberkern CM, Neumayr L, et al: A comparison of conservative and aggressive transfusion regimens in the perioperative management of sickle cell disease. The Preoperative Transfusion in Sickle Cell Disease Study Group. N Engl J Med1995; 333:206-213.
Dix HM: New advances in the treatment of sickle cell disease: Focus on perioperative significance. AANA J2001; 69:281-286.
Griffin TC, Buchanan GR: Elective surgery in children with sickle cell disease without preoperative blood transfusion. J Pediatr Surg1993; 28:681-685.
Koshy M, Chisum D, Burd L, et al: Management of sickle cell anemia and pregnancy. J Clin Apheresis1991; 6:230-233.
Desforges JF, Warth J: The management of sickle cell disease in pregnancy. Clin Perinatol1974; 1:385-394.
Rajab KE, Skerman JH: Sickle cell disease in pregnancy: Obstetric and anesthetic management perspectives. Saudi Med J2004; 25:265-276.
Deutsch S: Anesthetic management in acute and chronic renal failure. Vet Clin North Am1973; 3:57-64.
Deutsch S: Anesthetic management of patients with chronic renal disease. South Med J1975; 68:65-69.
Eschbach JW, Kelly MR, Haley NR, et al: Treatment of the anemia of progressive renal failure with recombinant human erythropoietin. N Engl J Med1989; 321:158-163.
Kam PC, Thompson SA, Liew AC: Thrombocytopenia in the parturient. Anaesthesia2004; 59:255-264.
Lee LH: Idiopathic thrombocytopenia in pregnancy. Ann Acad Med Singapore2002; 31:335-339.
Anglin BV, Rutherford C, Ramus R, et al: Immune thrombocytopenic purpura during pregnancy: Laparoscopic treatment. JSLS2001; 5:63-67.
Zeller B, Helgestad J, Hellebostad M, et al: Immune thrombocytopenic purpura in childhood in Norway: A prospective, population-based registration. Pediatr Hematol Oncol2000; 17:551-558.
Leichtman DA, Friedman BA: The hemorrhagic complications of open-heart surgery. CRC Crit Rev Clin Lab Sci1977; 7:239-254.
Lee JW: Von Willebrand disease, hemophilia A and B, and other factor deficiencies. Int Anesthesiol Clin2004; 42:59-76.
Bowes JB: Anaesthetic management of haemothorax and haemoptysis due to von Willebrand's disease: A case report. Br J Anaesth1969; 41:894-897.
Plumley MH: DDAVP and anaesthesia. Anaesthesia1988; 43:898.
Stedeford JC, Pittman JA: Von Willebrand's disease and neuroaxial anaesthesia. Anaesthesia2000; 55:1228-1229.
Cohen S, Daitch JS, Amar D, Goldiner PL: Epidural analgesia for labor and delivery in a patient with von Willebrand's disease. Reg Anesth1989; 14:95-97.
Hepner DL, Tsen LC: Severe thrombocytopenia, type 2B von Willebrand disease and pregnancy. Anesthesiology2004; 101:1465-1467.
Kadir RA, Lee CA, Sabin CA, et al: Pregnancy in women with von Willebrand's disease or factor XI deficiency. Br J Obstet Gynaecol1998; 105:314-321.
Nichols TC, Bellinger DA, Tate DA, et al: von Willebrand factor and occlusive arterial thrombosis: A study in normal and von Willebrand's disease pigs with diet-induced hypercholesterolemia and atherosclerosis. Arteriosclerosis1990; 10:449-461.
Michelson AD: Flow cytometric analysis of platelet surface glycoproteins: Phenotypically distinct subpopulations of platelets in children with chronic myeloid leukemia. J Lab Clin Med1987; 110:346-354.
Furman MI, Liu L, Benoit SE, et al: The cleaved peptide of the thrombin receptor is a strong platelet agonist. Proc Natl Acad Sci USA1998; 95:3082-3087.
Bodzenta-Lukaszyk A, Gabryelewicz A, Lukaszyk A, et al: Nitric oxide synthase inhibition and platelet function. Thromb Res1994; 75:667-672.
Chen LY, Mehta JL: Inhibitory effect of high-density lipoprotein on platelet function is mediated by increase in nitric oxide synthase activity in platelets. Life Sci1994; 55:1815-1821.
Aoki H, Inoue M, Mizobe T, et al: Platelet function is inhibited by nitric oxide liberation during nitroglycerin-induced hypotension anaesthesia. Br J Anaesth1997; 79:476-481.
Laight DW, Anggard EE, Carrier MJ: Modulation of nitric oxide-dependent vascular and platelet function in vitro by the novel phosphodiesterase type-V inhibitor ONO-1505. J Pharm Pharmacol1999; 51:1429-1433.
Albert J, Norman M, Wallen NH, et al: Inhaled nitric oxide does not influence bleeding time or platelet function in healthy volunteers. Eur J Clin Invest1999; 29:953-959.
Albert J, Wallen NH, Broijersen A, et al: Effects of inhaled nitric oxide compared with aspirin on platelet function in vivo in healthy subjects. Clin Sci (Lond)1996; 91:225-231.
Cheung PY, Salas E, Schulz R, Radomski MW: Nitric oxide and platelet function: Implications for neonatology. Semin Perinatol1997; 21:409-417.
Bath PM, Pathansali R, Iddenden R, Bath FJ: The effect of transdermal glyceryl trinitrate, a nitric oxide donor, on blood pressure and platelet function in acute stroke. Cerebrovasc Dis2001; 11:265-272.
Bereczki C, Tur S, Nemeth I, et al: The roles of platelet function, thromboxane, blood lipids and nitric oxide in hypertension of children and adolescents. Prostaglandins Leukot Essent Fatty Acids2000; 62:293-297.
Mellgren K, Mellgren G, Lundin S, et al: Effect of nitric oxide gas on platelets during open heart operations. Ann Thorac Surg1998; 65:1335-1341.
Kikura M, Lee MK, Safon RA, et al: The effects of milrinone on platelets in patients undergoing cardiac surgery. Anesth Analg1995; 81:44-48.
Azar RR, McKay RG, Thompson PD, et al: Abciximab in primary coronary angioplasty for acute myocardial infarction improves short- and medium-term outcomes. J Am Coll Cardiol1998; 32:1996-2002.
Bhatt DL, Marso SP, Lincoff AM, et al: Abciximab reduces mortality in diabetics following percutaneous coronary intervention. J Am Coll Cardiol2000; 35:922-928.
Brown DL, Fann CS, Chang CJ: Meta-analysis of effectiveness and safety of abciximab versus eptifibatide or tirofiban in percutaneous coronary intervention. Am J Cardiol2001; 87:537-541.
Lemmer Jr JH: Clinical experience in coronary bypass surgery for abciximab-treated patients. Ann Thorac Surg2000; 70(2 Suppl):S33-S37.
Dyke CM, Bhatia D, Lorenz TJ, et al: Discussion: Immediate coronary artery bypass surgery after platelet inhibition with eptifibatide: Results from PURSUIT. Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrelin Therapy. Ann Thorac Surg2000; 70:866-871.discussion 871-872
Bizzarri F, Scolletta S, Tucci E, et al: Perioperative use of tirofiban hydrochloride (Aggrastat) does not increase surgical bleeding after emergency or urgent coronary artery bypass grafting. J Thorac Cardiovasc Surg2001; 122:1181-1185.
Lau WC, Waskell LA, Watkins PB, et al: Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: A new drug-drug interaction. Circulation2003; 107:32-37.
Ng FH, Wong SY, Chang CM, et al: High incidence of clopidogrel-associated gastrointestinal bleeding in patients with previous peptic ulcer disease. Aliment Pharmacol Ther2003; 18:443-449.
Savi P, Combalbert J, Gaich C, et al: The antiaggregating activity of clopidogrel is due to a metabolic activation by the hepatic cytochrome P450-1A. Thromb Haemost1994; 72:313-317.
Defreyn G, Gachet C, Savi P, et al: Ticlopidine and clopidogrel (SR 25990C) selectively neutralize ADP inhibition of PGE1-activated platelet adenylate cyclase in rats and rabbits. Thromb Haemost1991; 65:186-190.
Savi P, Beauverger P, Labouret C, et al: Role of P2Y1 purinoceptor in ADP-induced platelet activation. FEBS Lett1998; 422:291-295.
Savi P, Bornia J, Salel V, et al: Characterization of P2×1 purinoreceptors on rat platelets: Effect of clopidogrel. Br J Haematol1997; 98:880-886.
Savi P, Pereillo JM, Uzabiaga MF, et al: Identification and biological activity of the active metabolite of clopidogrel [In Process Citation]. Thromb Haemost2000; 84:891-896.
Herbert JM, Dol F, Bernat A, et al: The antiaggregating and antithrombotic activity of clopidogrel is potentiated by aspirin in several experimental models in the rabbit. Thromb Haemost1998; 80:512-518.
Cavusoglu E, Cheng J, Bhatt R, et al: Clopidogrel in the management of ischemic heart disease. Heart Dis2003; 5:144-152.
Chen KK, Ginges I, Manolios N: Clopidogrel-associated acute arthritis. Intern Med J2003; 33:618-619.
Chen L, Bracey AW, Radovancevic R, et al: Clopidogrel and bleeding in patients undergoing elective coronary artery bypass grafting. J Thorac Cardiovasc Surg2004; 128:425-431.
Chen WH, Lee PY, Ng W, et al: Aspirin resistance is associated with a high incidence of myonecrosis after non-urgent percutaneous coronary intervention despite clopidogrel pretreatment. J Am Coll Cardiol2004; 43:1122-1126.
Kuchulakanti P, Kapetanakis EI, Lew R, et al: Impact of continued hospitalization in patients pre-treated with clopidogrel prior to coronary angiography and undergoing coronary artery bypass grafting. J Invasive Cardiol2005; 17:5-7.
Waksman R, Ajani AE, Pinnow E, et al: Twelve versus six months of clopidogrel to reduce major cardiac events in patients undergoing gamma-radiation therapy for in-stent restenosis: Washington Radiation for In-Stent restenosis Trial (WRIST) 12 versus WRIST PLUS. Circulation2002; 106:776-778.
Practice parameter for the use of fresh-frozen plasma, cryoprecipitate, and platelets. Fresh-Frozen Plasma, Cryoprecipitate, and Platelets Administration Practice Guidelines Development Task Force of the College of American Pathologists. JAMA1994; 271:777-781.
Kaluza GL, Joseph J, Lee JR, et al: Catastrophic outcomes of noncardiac surgery soon after coronary stenting. J Am Coll Cardiol2000; 35:1288-1294.
Wilson SH, Fasseas P, Orford JL, et al: Clinical outcome of patients undergoing non-cardiac surgery in the two months following coronary stenting. J Am Coll Cardiol2003; 42:234-240.
McFadden EP, Stabile E, Regar E, et al: Late thrombosis in drug-eluting coronary stents after discontinuation of antiplatelet therapy. Lancet2004; 364:1519-1521.
Vinckier F, Vermylen J: Dental extractions in hemophilia: Reflections on 10 years' experience. Oral Surg Oral Med Oral Pathol1985; 59:6-9.
Nicholson SC, Keeling DM, Sinclair ME, Evans RD: Heparin pretreatment does not alter heparin requirements during cardiopulmonary bypass. Br J Anaesth2001; 87:844-847.
Kanbak M: The treatment of heparin resistance with antithrombin III in cardiac surgery. Can J Anaesth1999; 46:581-585.
Heller EL, Paul L: Anticoagulation management in a patient with an acquired antithrombin III deficiency. J Extra Corpor Technol2001; 33:245-248.
Shore-Lesserson L, Manspeizer HE, Bolastig M, et al: Anticoagulation for cardiac surgery in patients receiving preoperative heparin: Use of the high-dose thrombin time. Anesth Analg2000; 90:813-818.
Donahue BS, Gailani D, Higgins MS, et al: Factor V Leiden protects against blood loss and transfusion after cardiac surgery. Circulation2003; 107:1003-1008.
Fanashawe MP, Shore-Lesserson L, Reich DL: Two cases of fatal thrombosis after aminocaproic acid therapy and deep hypothermic circulatory arrest. Anesthesiology2001; 95:1525-1527.
Warkentin TE, Greinacher A: Heparin-induced thrombocytopenia and cardiac surgery. Ann Thorac Surg2003; 76:638-648.
Warkentin TE, Kelton JG: Heparin-induced thrombocytopenia. Prog Hemost Thromb1991; 10:1-34.
Warkentin TE: Laboratory testing for heparin-induced thrombocytopenia. J Thromb Thrombolysis2000; 10(Suppl 1):35-45.
Visentin GP, Malik M, Cyganiak KA, Aster RH: Patients treated with unfractionated heparin during open heart surgery are at high risk to form antibodies reactive with heparin:platelet factor 4 complexes. J Lab Clin Med1996; 128:376-383.
Warkentin TE, Kelton JG: Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med2001; 344:1286-1292.
Koster A, Crystal GJ, Kuppe H, Mertzlufft F: Acute heparin-induced thrombocytopenia type II during cardiopulmonary bypass. J Cardiothorac Vasc Anesth2000; 14:300-303.
Koster A, Hansen R, Grauhan O, et al: Hirudin monitoring using the TAS ecarin clotting time in patients with heparin-induced thrombocytopenia type II. J Cardiothorac Vasc Anesth2000; 14:249-252.
Koster A, Hansen R, Kuppe H, et al: Recombinant hirudin as an alternative for anticoagulation during cardiopulmonary bypass in patients with heparin-induced thrombocytopenia type II: A 1-year experience in 57 patients. J Cardiothorac Vasc Anesth2000; 14:243-248.
Kettner SC, Panzer OP, Kozek SA, et al: Use of abciximab-modified thrombelastography in patients undergoing cardiac surgery. Anesth Analg1999; 89:580-584.
Mousa SA, Khurana S, Forsythe MS: Comparative in vitro efficacy of different platelet glycoprotein IIb/IIIa antagonists on platelet-mediated clot strength induced by tissue factor with use of thromboelastography: Differentiation among glycoprotein IIb/IIIa antagonists. Arterioscler Thromb Vasc Biol2000; 20:1162-1167.
Bode AP, Lust RM: Masking of heparin activity in the activated coagulation time (ACT) by platelet procoagulant activity. Thromb Res1994; 73:285-300.
Despotis GJ, Levine V, Filos KS, et al: Evaluation of a new point-of-care test that measures PAF-mediated acceleration of coagulation in cardiac surgical patients. Anesthesiology1996; 85:1311-1323.
Coller BS, Lang D, Scudder LE: Rapid and simple platelet function assay to assess glycoprotein IIb/IIIa receptor blockade. Circulation1997; 95:860-867.
Smith JW, Steinhubl SR, Lincoff AM, et al: Rapid platelet-function assay: An automated and quantitative cartridge-based method. Circulation1999; 99:620-625.
Steinhubl SR, Talley JD, Braden GA, et al: Point-of-care measured platelet inhibition correlates with a reduced risk of an adverse cardiac event after percutaneous coronary intervention: Results of the GOLD (AU-Assessing Ultegra) multicenter study. Circulation2001; 103:2572-2578.
Bock M, De Haan J, Beck KH, et al: Standardization of the PFA-100(R) platelet function test in 105 mmol/L buffered citrate: Effect of gender, smoking, and oral contraceptives. Br J Haematol1999; 106:898-904.
Escolar G, Cases A, Vinas M, et al: Evaluation of acquired platelet dysfunctions in uremic and cirrhotic patients using the platelet function analyzer (PFA-100): Influence of hematocrit elevation. Haematologica1999; 84:614-619.
Carville DG, Schleckser PA, Guyer KE, et al: Whole blood platelet function assay on the ICHOR point-of-care hematology analyzer. J Extra Corpor Technol1998; 30:171-177.
Ray MJ, Hawson GA, Just SJ, et al: Relationship of platelet aggregation to bleeding after cardiopulmonary bypass. Ann Thorac Surg1994; 57:981-986.

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