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InternalMed_Harrison. CLINICAL PRESENTATION OF ANEMIA Signs and Symptoms Anemia is most often recognized by abnormal screening laboratory tests. Patients less commonly present with advanced anemia and its attendant signs and symptoms. Acute anemia is due to blood loss or hemolysis. If blood loss is mild, enhanced O2 delivery is achieved through changes in the O2–hemoglobin dissociation curve mediated by a decreased pH or increased CO2 (Bohr effect). With acute blood loss, hypovolemia dominates the clinical picture, and the hematocrit and hemoglobin levels do not reflect the volume of blood lost. Signs of vascular instability appear with acute losses of 10–15% of the total blood volume. In such patients, the issue is not anemia but hypotension and decreased organ perfusion. When >30% of the blood volume is lost suddenly, patients are unable to compensate with the usual mechanisms of vascular contraction and changes in regional blood flow. The patient prefers to remain supine and will show postural


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InternalMed_Harrison. is lost suddenly, patients are unable to compensate with the usual mechanisms of vascular contraction and changes in regional blood flow. The patient prefers to remain supine and will show postural hypotension and tachycardia. If the volume of blood lost is >40% (i.e., >2 L in the average-sized adult), signs of hypovolemic shock including confusion, dyspnea, diaphoresis, hypotension, and tachycardia appear (Chap. 129). Such patients have significant deficits in vital organ perfusion and require immediate volume replacement.


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InternalMed_Harrison. With acute hemolysis, the signs and symptoms depend on the mechanism that leads to red cell destruction. Intravascular hemolysis with release of free hemoglobin may be associated with acute back pain, free hemoglobin in the plasma and urine, and renal failure. Symptoms associated with more chronic or progressive anemia depend on the age of the patient and the adequacy of blood supply to critical organs. Symptoms associated with moderate anemia include fatigue, loss of stamina, breathlessness, and tachycardia (particularly with physical exertion). However, because of the intrinsic compensatory mechanisms that govern the O2–hemoglobin dissociation curve, the gradual onset of anemia—particularly in young patients—may not be associated with signs or symptoms until the anemia is severe (hemoglobin <70–80 g/L [7–8 g/dL]). When anemia develops over a period of days or weeks, the total blood volume is normal to slightly increased, and changes in cardiac output and regional blood flow help


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InternalMed_Harrison. <70–80 g/L [7–8 g/dL]). When anemia develops over a period of days or weeks, the total blood volume is normal to slightly increased, and changes in cardiac output and regional blood flow help compensate for the overall loss in O2-carrying capacity. Changes in the position of the O2–hemoglobin dissociation curve account for some of the compensatory response to anemia. With chronic anemia, intracellular levels of 2,3-bisphosphoglycerate rise, shifting the dissociation curve to the right and facilitating O2 unloading. This compensatory mechanism can only maintain normal tissue O2 delivery in the face of a 20–30 g/L (2–3 g/dL) deficit in hemoglobin concentration. Finally, further protection of O2 delivery to vital organs is achieved by the shunting of blood away from organs that are relatively rich in blood supply, particularly the kidney, gut, and skin.


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InternalMed_Harrison. Certain disorders are commonly associated with anemia. Chronic inflammatory states (e.g., infection, rheumatoid arthritis, cancer) are associated with mild to moderate anemia, whereas lymphoproliferative disorders, such as chronic lymphocytic leukemia and certain other B cell neoplasms, may be associated with autoimmune hemolysis. APPROACH TO THE PATIENT:


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InternalMed_Harrison. The evaluation of the patient with anemia requires a careful history and physical examination. Nutritional history related to drugs or alcohol intake and family history of anemia should always be assessed. Certain geographic backgrounds and ethnic origins are associated with an increased likelihood of an inherited disorder of the hemoglobin molecule or intermediary metabolism. Glucose-6phosphate dehydrogenase (G6PD) deficiency and certain hemoglobinopathies are seen more commonly in those of Middle Eastern or African origin, including African Americans who have a high frequency of G6PD deficiency. Other information that may be useful includes exposure to certain toxic agents or drugs and symptoms related to other disorders commonly associated with anemia. These include symptoms and signs such as bleeding, fatigue, malaise, fever, weight loss, night sweats, and other systemic symptoms. Clues to the mechanisms of anemia may be provided on physical examination by findings of infection,


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InternalMed_Harrison. such as bleeding, fatigue, malaise, fever, weight loss, night sweats, and other systemic symptoms. Clues to the mechanisms of anemia may be provided on physical examination by findings of infection, blood in the stool, lymphadenopathy, splenomegaly, or petechiae. Splenomegaly and lymphadenopathy suggest an underlying lymphoproliferative disease, whereas petechiae suggest platelet dysfunction. Past laboratory measurements are helpful to determine a time of onset.


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InternalMed_Harrison. In the anemic patient, physical examination may demonstrate a forceful heartbeat, strong peripheral pulses, and a systolic “flow” murmur. The skin and mucous membranes may be pale if the hemoglobin is <80–100 g/L (8–10 g/dL). This part of the physical examination should focus on areas where vessels are close to the surface such as the mucous membranes, nail beds, and palmar creases. If the palmar creases are lighter in color than the surrounding skin when the hand is hyperextended, the hemoglobin level is usually <80 g/L (8 g/dL).


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InternalMed_Harrison. Table 77-1 lists the tests used in the initial workup of anemia. A routine complete blood count (CBC) is required as part of the evaluation and includes the hemoglobin, hematocrit, and red cell indices: the mean cell volume (MCV) in femtoliters, mean cell hemoglobin (MCH) in picograms per cell, and mean concentration of hemoglobin per volume of red cells (MCHC) in grams per liter (non-SI: grams per deciliter). The red cell indices are calculated as shown in Table 77-2, and the normal variations in the hemoglobin and hematocrit with age are shown in Table 77-3. A number of physiologic factors affect the CBC, including age, sex, pregnancy, smoking, and altitude. High-normal hemoglobin values may be seen in men and women who live at altitude or smoke heavily. Hemoglobin elevations due to smoking reflect normal compensation due to the displacement of O2 by CO in hemoglobin binding. Other important information is provided by the reticulocyte count and measurements of iron supply including


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InternalMed_Harrison. reflect normal compensation due to the displacement of O2 by CO in hemoglobin binding. Other important information is provided by the reticulocyte count and measurements of iron supply including serum iron, total iron-binding capacity (TIBC; an indirect measure of serum transferrin), and serum ferritin. Marked alterations in the red cell indices usually reflect disorders of maturation or iron deficiency. A careful evaluation of the peripheral blood smear is important, and clinical laboratories often provide a description of both the red and white cells, a white cell differential count, and the platelet count. In patients with severe anemia and abnormalities in red blood cell morphology and/or low reticulocyte counts, a bone marrow aspirate or biopsy can assist in the diagnosis. Other tests of value in the diagnosis of specific anemias are discussed in chapters on specific disease states.


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InternalMed_Harrison. The components of the CBC also help in the classification of anemia. Microcytosis is reflected by a lower than normal MCV (<80), whereas high values (>100) reflect macrocytosis. The MCH and MCHC reflect defects in hemoglobin synthesis (hypochromia). Automated cell counters describe the red cell volume distribution width (RDW). The MCV (representing the peak of the distribution curve) is insensitive to the appearance of small populations of macrocytes or microcytes. An experienced laboratory technician I. Complete blood count (CBC) A. Red blood cell count 1. 2. 3. B. Red blood cell indices 1. 2. 3. 4. C. White blood cell count 1. 2. Nuclear segmentation of neutrophils D. Platelet count E. Cell morphology 1. 2. 3. 4. 5. II. A. B. C. III. A. 1. 2. 3. B. Biopsy 1. 2. Morphology aM/E ratio, ratio of myeloid to erythroid precursors. PART 2 Cardinal Manifestations and Presentation of Diseases


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InternalMed_Harrison. 2. 3. 4. 5. II. A. B. C. III. A. 1. 2. 3. B. Biopsy 1. 2. Morphology aM/E ratio, ratio of myeloid to erythroid precursors. PART 2 Cardinal Manifestations and Presentation of Diseases Mean cell hemoglobin concentration = (hemoglobin × 33 ± 2% 10)/hematocrit, or MCH/MCV TABLE 77-3 CHAngES in noRMAL HEMogLoBin/HEMAToCRiT vALuES wiTH AgE, SEx, AnD PREgnAnCy Age/Sex Hemoglobin, g/dL Hematocrit, % Source: From RS Hillman et al: Hematology in Clinical Practice, 5th ed. New York, McGraw-Hill, 2010. FIguRE 77-3 Normal blood smear (Wright stain). High-power field showing normal red cells, a neutrophil, and a few platelets. (From RS Hillman et al: Hematology in Clinical Practice, 5th ed. New York, McGraw-Hill, 2010.) will be able to identify minor populations of large or small cells or hypochromic cells before the red cell indices change.


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InternalMed_Harrison. Peripheral Blood Smear The peripheral blood smear provides important information about defects in red cell production (Chap. 81e). As a complement to the red cell indices, the blood smear also reveals variations in cell size (anisocytosis) and shape (poikilocytosis). The degree of anisocytosis usually correlates with increases in the RDW or the range of cell sizes. Poikilocytosis suggests a defect in the maturation of red cell precursors in the bone marrow or fragmentation of circulating red cells. The blood smear may also reveal polychromasia—red cells that are slightly larger than normal and grayish blue in color on the Wright-Giemsa stain. These cells are reticulocytes that have been prematurely released from the bone marrow, and their color represents residual amounts of ribosomal RNA. These cells appear in circulation in response to EPO stimulation or to architectural damage of the bone marrow (fibrosis, infiltration of the marrow by malignant cells, etc.) that results in their


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InternalMed_Harrison. These cells appear in circulation in response to EPO stimulation or to architectural damage of the bone marrow (fibrosis, infiltration of the marrow by malignant cells, etc.) that results in their disordered release from the marrow. The appearance of nucleated red cells, Howell-Jolly bodies, target cells, sickle cells, and others may provide clues to specific disorders (Figs. 77-3 to 77-11).


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InternalMed_Harrison. Reticulocyte Count An accurate reticulocyte count is key to the initial classification of anemia. Reticulocytes are red cells that FIguRE 77-4 Severe iron-deficiency anemia. Microcytic and hypo-chromic red cells smaller than the nucleus of a lymphocyte associated with marked variation in size (anisocytosis) and shape (poikilocytosis). (From RS Hillman et al: Hematology in Clinical Practice, 5th ed. New York, McGraw-Hill, 2010.) FIguRE 77-5 Macrocytosis. Red cells are larger than a small lympho-cyte and well hemoglobinized. Often macrocytes are oval shaped (macro-ovalocytes). FIguRE 77-8 Target cells. Target cells have a bull’s-eye appearance and are seen in thalassemia and in liver disease. (From RS Hillman et al: Hematology in Clinical Practice, 5th ed. New York, McGraw-Hill, 2010.) FIguRE 77-6 Howell-Jolly bodies. In the absence of a functional spleen, nuclear remnants are not culled from the red cells and remain as small homogeneously staining blue inclusions on Wright stain.


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InternalMed_Harrison. FIguRE 77-6 Howell-Jolly bodies. In the absence of a functional spleen, nuclear remnants are not culled from the red cells and remain as small homogeneously staining blue inclusions on Wright stain. (From RS Hillman et al: Hematology in Clinical Practice, 5th ed. New York, McGraw-Hill, 2010.) FIguRE 77-9 Red cell fragmentation. Red cells may become frag-mented in the presence of foreign bodies in the circulation, such as mechanical heart valves, or in the setting of thermal injury. (From RS Hillman et al: Hematology in Clinical Practice, 5th ed. New York, McGraw-Hill, 2010.) FIguRE 77-7 Red cell changes in myelofibrosis. The left panel shows a teardrop-shaped cell. The right panel shows a nucleated red cell. These forms can be seen in myelofibrosis.


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InternalMed_Harrison. FIguRE 77-7 Red cell changes in myelofibrosis. The left panel shows a teardrop-shaped cell. The right panel shows a nucleated red cell. These forms can be seen in myelofibrosis. FIguRE 77-10 Uremia. The red cells in uremia may acquire numerous regularly spaced, small, spiny projections. Such cells, called burr cells or echinocytes, are readily distinguishable from irregularly spiculated acanthocytes shown in Fig. 77-11. PART 2 Cardinal Manifestations and Presentation of Diseases FIguRE 77-11 Spur cells. Spur cells are recognized as distorted red cells containing several irregularly distributed thornlike projections. Cells with this morphologic abnormality are also called acanthocytes.


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InternalMed_Harrison. (From RS Hillman et al: Hematology in Clinical Practice, 5th ed. New York, McGraw-Hill, 2010.) have been recently released from the bone marrow. They are identified by staining with a supravital dye that precipitates the ribosomal RNA (Fig. 77-12). These precipitates appear as blue or black punctate spots and can be counted manually or, currently, by fluorescent emission of dyes that bind to RNA. This residual RNA is metabolized over the first 24–36 h of the reticulocyte’s life span in circulation. Normally, the reticulocyte count ranges from 1 to 2% and reflects the daily replacement of 0.8–1.0% of the circulating red cell population. A corrected reticulocyte count provides a reliable measure of effective red cell production.


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InternalMed_Harrison. In the initial classification of anemia, the patient’s reticulocyte count is compared with the expected reticulocyte response. In general, if the EPO and erythroid marrow responses to moderate anemia [hemoglobin <100 g/L (10 g/dL)] are intact, the red cell production rate increases to two to three times normal within 10 days following the onset of anemia. In the face of established anemia, a reticulocyte response less than two to three times normal indicates an inadequate marrow response. To use the reticulocyte count to estimate marrow response, two corrections are necessary. The first correction adjusts the reticulocyte count based on the reduced number of circulating red cells. With anemia, the percentage of reticulocytes may be increased while the absolute number is unchanged. To correct for this effect, the reticulocyte percentage is multiplied by the ratio of the patient’s hemoglobin or hematocrit to the expected hemoglobin/hematocrit


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InternalMed_Harrison. FIguRE 77-12 Reticulocytes. Methylene blue stain demonstrates residual RNA in newly made red cells. (From RS Hillman et al: Hematology in Clinical Practice, 5th ed. New York, McGraw-Hill, 2010.) Correction #1 for Anemia: This correction produces the corrected reticulocyte count. In a person whose reticulocyte count is 9%, hemoglobin 7.5 g/dL, and hematocrit 23%, the absolute reticulocyte count = 9 × (7.5/15) [or × (23/45)] = 4.5% Note. This correction is not done if the reticulocyte count is reported in absolute numbers (e.g., 50,000/μL of blood) Correction #2 for Longer Life of Prematurely Released Reticulocytes in the Blood: This correction produces the reticulocyte production index.


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InternalMed_Harrison. Correction #2 for Longer Life of Prematurely Released Reticulocytes in the Blood: This correction produces the reticulocyte production index. In a person whose reticulocyte count is 9%, hemoglobin 7.5 gm/dL, and hematocrit 23%, the reticulocyte production index (7.5/15)(hemoglobincorrection) =×9 =2.25 for the age and sex of the patient (Table 77-4). This provides an estimate of the reticulocyte count corrected for anemia. To convert the corrected reticulocyte count to an index of marrow production, a further correction is required, depending on whether some of the reticulocytes in circulation have been released from the marrow pre maturely. For this second correction, the peripheral blood smear is examined to see if there are polychromatophilic macrocytes present. These cells, representing prematurely released reticulocytes, are referred to as “shift” cells, and the relationship between the degree of shift and the necessary shift correction factor is shown in


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InternalMed_Harrison. These cells, representing prematurely released reticulocytes, are referred to as “shift” cells, and the relationship between the degree of shift and the necessary shift correction factor is shown in Fig. 77-13. The correction is necessary because these prematurely released cells survive as reticulocytes in circulation for >1 day, thereby providing a falsely high estimate of daily red cell produc tion. If polychromasia is increased, the reticulocyte count, already corrected for anemia, should be divided again by 2 to account for the prolonged reticulocyte maturation time. The second correction fac tor varies from 1 to 3 depending on the severity of anemia. In gen eral, a correction of 2 is simply used. An appropriate correction is shown in Table 77-4. If polychromatophilic cells are not seen on the blood smear, the second correction is not required. The now doubly 1.5 2.5


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InternalMed_Harrison. FIguRE 77-13 Correction of the reticulocyte count. To use the reticulocyte count as an indicator of effective red cell production, the reticulocyte percentage must be corrected based on the level of anemia and the circulating life span of the reticulocytes. Erythroid cells take ∼4.5 days to mature. At a normal hemoglobin, reticulocytes are released to the circulation with ∼1 day left as reticulocytes. However, with different levels of anemia, reticulocytes (and even earlier erythroid cells) may be released from the marrow prematurely. Most patients come to clinical attention with hematocrits in the mid20s, and thus a correction factor of 2 is commonly used because the observed reticulocytes will live for 2 days in the circulation before losing their RNA.


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InternalMed_Harrison. corrected reticulocyte count is the reticulocyte production index, and it provides an estimate of marrow production relative to normal. In many hospital laboratories, the reticulocyte count is reported not only as a percentage but also in absolute numbers. If so, no correction for dilution is required. A summary of the appropriate marrow response to varying degrees of anemia is shown in Table 77-5.


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InternalMed_Harrison. Premature release of reticulocytes is normally due to increased EPO stimulation. However, if the integrity of the bone marrow release process is lost through tumor infiltration, fibrosis, or other disorders, the appearance of nucleated red cells or polychromatophilic macrocytes should still invoke the second reticulocyte correction. The shift correction should always be applied to a patient with anemia and a very high reticulocyte count to provide a true index of effective red cell production. Patients with severe chronic hemolytic anemia may increase red cell production as much as sixto sevenfold. This measure alone confirms the fact that the patient has an appropriate EPO response, a normally functioning bone marrow, and sufficient iron available to meet the demands for new red cell formation. If the reticulocyte production index is <2 in the face of established anemia, a defect in erythroid marrow proliferation or maturation must be present.


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InternalMed_Harrison. Tests of Iron Supply and Storage The laboratory measurements that reflect the availability of iron for hemoglobin synthesis include the serum iron, the TIBC, and the percent transferrin saturation. The percent transferrin saturation is derived by dividing the serum iron level (× 100) by the TIBC. The normal serum iron ranges from 9 to 27 μmol/L (50–150 μg/dL), whereas the normal TIBC is 54–64 μmol/L (300–360 μg/dL); the normal transferrin saturation ranges from 25 to 50%. A diurnal variation in the serum iron leads to a variation in the percent transferrin saturation. The serum ferritin is used to evaluate total body iron stores. Adult males have serum ferritin levels that average ∼100 μg/L, corresponding to iron stores of ∼1 g. Adult females have lower serum ferritin levels averaging 30 μg/L, reflecting lower iron stores (∼300 mg). A serum ferritin level of 10–15 μg/L indicates depletion of body iron stores. However, ferritin is also an acute-phase reactant and, in the presence of


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InternalMed_Harrison. μg/L, reflecting lower iron stores (∼300 mg). A serum ferritin level of 10–15 μg/L indicates depletion of body iron stores. However, ferritin is also an acute-phase reactant and, in the presence of acute or chronic inflammation, may rise several-fold above baseline levels. As a rule, a serum ferritin >200 μg/L means there is at least some iron in tissue stores.


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InternalMed_Harrison. Bone Marrow Examination A bone marrow aspirate and smear or a needle biopsy can be useful in the evaluation of some patients with anemia. In patients with hypoproliferative anemia and normal iron status, a bone marrow is indicated. Marrow examination can diagnose primary marrow disorders such as myelofibrosis, a red cell maturation defect, or an infiltrative disease (Figs. 77-14 to 77-16). The increase or decrease of one cell lineage (myeloid vs erythroid) compared to another is obtained by a differential count of nucleated cells in a bone marrow smear (the myeloid/erythroid [M/E] ratio). A patient with a hypoproliferative anemia (see below) and a reticulocyte production index <2 will demonstrate an M/E ratio of 2 or 3:1. In contrast, patients with hemolytic disease and a production index >3 will have an M/E ratio of at least 1:1. Maturation disorders are identified from the discrepancy between the M/E ratio and the reticulocyte production index (see below). Either the marrow smear or


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InternalMed_Harrison. >3 will have an M/E ratio of at least 1:1. Maturation disorders are identified from the discrepancy between the M/E ratio and the reticulocyte production index (see below). Either the marrow smear or biopsy can be stained for the presence of iron stores or iron in developing red cells. The storage iron is in the form of ferritin or hemosiderin. On carefully prepared bone marrow smears, small ferritin granules can normally be seen under oil immersion in 20–40% of developing erythroblasts. Such cells are called sideroblasts.


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InternalMed_Harrison. FIguRE 77-14 Normal bone marrow. This is a low-power view of a section of a normal bone marrow biopsy stained with hematoxylin and eosin (H&E). Note that the nucleated cellular elements account for ∼40–50% and the fat (clear areas) accounts for ∼50–60% of the area. (From RS Hillman et al: Hematology in Clinical Practice, 5th ed. New York, McGraw-Hill, 2010.) FIguRE 77-15 Erythroid hyperplasia. This marrow shows an increase in the fraction of cells in the erythroid lineage as might be seen when a normal marrow compensates for acute blood loss or hemolysis. The myeloid/erythroid (M/E) ratio is about 1:1. (From RS Hillman et al: Hematology in Clinical Practice, 5th ed. New York, McGraw-Hill, 2010.)


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InternalMed_Harrison. FIguRE 77-16 Myeloid hyperplasia. This marrow shows an increase in the fraction of cells in the myeloid or granulocytic lineage as might be seen in a normal marrow responding to infection. The myeloid/ erythroid (M/E) ratio is >3:1. (From RS Hillman et al: Hematology in Clinical Practice, 5th ed. New York, McGraw-Hill, 2010.) Additional laboratory tests may be of value in confirming specific diagnoses. For details of these tests and how they are applied in individual disorders, see Chaps. 126 to 130. PART 2 Cardinal Manifestations and Presentation of Diseases


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InternalMed_Harrison. DEFINITION AND CLASSIFICATION OF ANEMIA Initial Classification of Anemia The functional classification of anemia has three major categories. These are (1) marrow production defects (hypoproliferation), (2) red cell maturation defects (ineffective erythropoiesis), and (3) decreased red cell survival (blood loss/hemolysis). The classification is shown in Fig. 77-17. A hypoproliferative anemia is typically seen with a low reticulocyte production index together with little or no change in red cell morphology (a normocytic, normochromic anemia) (Chap. 126). Maturation disorders typically have a slight to moderately elevated reticulocyte production index that is accompanied by either macrocytic (Chap. 128) or microcytic (Chaps. 126, 127) red cell indices. Increased red blood cell destruction secondary to hemolysis results in an increase in the reticulocyte production index to at least three times normal (Chap. 129), provided sufficient iron is available. Hemorrhagic anemia does not


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InternalMed_Harrison. secondary to hemolysis results in an increase in the reticulocyte production index to at least three times normal (Chap. 129), provided sufficient iron is available. Hemorrhagic anemia does not typically result in production indices of more than 2.0–2.5 times normal because of the limitations placed on expansion of the erythroid marrow by iron availability.


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InternalMed_Harrison. In the first branch point of the classification of anemia, a reticulocyte production index >2.5 indicates that hemolysis is most likely. A reticulocyte production index <2 indicates either a hypoproliferative anemia or maturation disorder. The latter two possibilities can often be distinguished by the red cell indices, by examination of the peripheral blood smear, or by a marrow examination. If the red cell indices are normal, the anemia is almost certainly hypoproliferative in nature. Maturation disorders are characterized by ineffective red cell production and a low reticulocyte production index. Bizarre red cell shapes—macrocytes or hypochromic microcytes—are seen on the peripheral blood smear. With a hypoproliferative anemia, no erythroid


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InternalMed_Harrison. Hemolysis/ hemorrhage Blood loss Intravascular hemolysis Metabolic defect Membrane abnormality Hemoglobinopathy Immune destruction Fragmentation Hypoproliferative Marrow damage • Infiltration/fibrosis • Aplasia Iron deficiency Stimulation • Inflammation Maturation disorder Cytoplasmic defects • Iron deficiency • Thalassemia • Sideroblastic anemia Nuclear defects Normocytic normochromic Micro or macrocytic Red cell morphology Index < 2.5 Index ˜ 2.5 Anemia CBC, reticulocyte count FIguRE 77-17 The physiologic classification of anemia. CBC, complete blood count. hyperplasia is noted in the marrow, whereas patients with ineffective red cell production have erythroid hyperplasia and an M/E ratio <1:1.


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InternalMed_Harrison. Hypoproliferative Anemias At least 75% of all cases of anemia are hypoproliferative in nature. A hypoproliferative anemia reflects absolute or relative marrow failure in which the erythroid marrow has not proliferated appropriately for the degree of anemia. The majority of hypoproliferative anemias are due to mild to moderate iron deficiency or inflammation. A hypoproliferative anemia can result from marrow damage, iron deficiency, or inadequate EPO stimulation. The last may reflect impaired renal function, suppression of EPO production by inflammatory cytokines such as interleukin 1, or reduced tissue needs for O2 from metabolic disease such as hypothyroidism. Only occasionally is the marrow unable to produce red cells at a normal rate, and this is most prevalent in patients with renal failure. With diabetes mellitus or myeloma, the EPO deficiency may be more marked than would be predicted by the degree of renal insufficiency. In general, hypoproliferative anemias are characterized


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InternalMed_Harrison. failure. With diabetes mellitus or myeloma, the EPO deficiency may be more marked than would be predicted by the degree of renal insufficiency. In general, hypoproliferative anemias are characterized by normocytic, normochromic red cells, although microcytic, hypochromic cells may be observed with mild iron deficiency or long-standing chronic inflammatory disease. The key laboratory tests in distinguishing between the various forms of hypoproliferative anemia include the serum iron and iron-binding capacity, evaluation of renal and thyroid function, a marrow biopsy or aspirate to detect marrow damage or infiltrative disease, and serum ferritin to assess iron stores. An iron stain of the marrow will determine the pattern of iron distribution. Patients with the anemia of acute or chronic inflammation show a distinctive pattern of serum iron (low), TIBC (normal or low), percent transferrin saturation (low), and serum ferritin (normal or high). These changes in iron values are brought


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InternalMed_Harrison. inflammation show a distinctive pattern of serum iron (low), TIBC (normal or low), percent transferrin saturation (low), and serum ferritin (normal or high). These changes in iron values are brought about by hepcidin, the iron regulatory hormone that is produced by the liver and is increased in inflammation (Chap. 126). A distinct pattern of results is noted in mild to moderate iron deficiency (low serum iron, high TIBC, low percent transferrin saturation, low serum ferritin) (Chap. 126). Marrow damage by drugs, infiltrative disease such as leukemia or lymphoma, or marrow aplasia is diagnosed from the peripheral blood and bone marrow morphology. With infiltrative disease or fibrosis, a marrow biopsy is required.


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InternalMed_Harrison. Maturation Disorders The presence of anemia with an inappropriately low reticulocyte production index, macroor microcytosis on smear, and abnormal red cell indices suggests a maturation disorder. Maturation disorders are divided into two categories: nuclear maturation defects, associated with macrocytosis, and cytoplasmic maturation defects, associated with microcytosis and hypochromia usually from defects in hemoglobin synthesis. The inappropriately low reticulocyte production index is a reflection of the ineffective erythropoiesis that results from the destruction within the marrow of developing erythroblasts. Bone marrow examination shows erythroid hyperplasia.


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InternalMed_Harrison. Nuclear maturation defects result from vitamin B12 or folic acid deficiency, drug damage, or myelodysplasia. Drugs that interfere with cellular DNA synthesis, such as methotrexate or alkylating agents, can produce a nuclear maturation defect. Alcohol, alone, is also capable of producing macrocytosis and a variable degree of anemia, but this is usually associated with folic acid deficiency. Measurements of folic acid and vitamin B12 are critical not only in identifying the specific vitamin deficiency but also because they reflect different pathogenetic mechanisms (Chap. 128).


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InternalMed_Harrison. Cytoplasmic maturation defects result from severe iron deficiency or abnormalities in globin or heme synthesis. Iron deficiency occupies an unusual position in the classification of anemia. If the iron-deficiency anemia is mild to moderate, erythroid marrow proliferation is blunted and the anemia is classified as hypoproliferative. However, if the anemia is severe and prolonged, the erythroid marrow will become hyperplastic despite the inadequate iron supply, and the anemia will be classified as ineffective erythropoiesis with a cytoplasmic maturation defect. In either case, an inappropriately low reticulocyte production index, microcytosis, and a classic pattern of iron values make the diagnosis clear and easily distinguish iron deficiency from other cytoplasmic maturation defects such as the thalassemias. Defects in heme synthesis, in contrast to globin synthesis, are less common and may be acquired or inherited (Chap. 430). Acquired abnormalities are usually associated with


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InternalMed_Harrison. such as the thalassemias. Defects in heme synthesis, in contrast to globin synthesis, are less common and may be acquired or inherited (Chap. 430). Acquired abnormalities are usually associated with myelodysplasia, may lead to either a macroor microcytic anemia, and are frequently associated with mitochondrial iron loading. In these cases, iron is taken up by the mitochondria of the developing erythroid cell but not incorporated into heme. The iron-encrusted mitochondria surround the nucleus of the erythroid cell, forming a ring. Based on the distinctive finding of so-called ringed sideroblasts on the marrow iron stain, patients are diagnosed as having a sideroblastic anemia—almost always reflecting myelodysplasia. Again, studies of iron parameters are helpful in the differential diagnosis of these patients.


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InternalMed_Harrison. Blood Loss/Hemolytic Anemia In contrast to anemias associated with an inappropriately low reticulocyte production index, hemolysis is associated with red cell production indices ≥2.5 times normal. The stimulated erythropoiesis is reflected in the blood smear by the appearance of increased numbers of polychromatophilic macrocytes. A marrow examination is rarely indicated if the reticulocyte production index is increased appropriately. The red cell indices are typically normocytic or slightly macrocytic, reflecting the increased number of reticulocytes. Acute blood loss is not associated with an increased reticulocyte production index because of the time required to increase EPO production and, subsequently, marrow proliferation. Subacute blood loss may be associated with modest reticulocytosis. Anemia from chronic blood loss presents more often as iron deficiency than with the picture of increased red cell production.


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InternalMed_Harrison. The evaluation of blood loss anemia is usually not difficult. Most problems arise when a patient presents with an increased red cell production index from an episode of acute blood loss that went unrecognized. The cause of the anemia and increased red cell production may not be obvious. The confirmation of a recovering state may require observations over a period of 2–3 weeks, during which the hemoglobin concentration will rise and the reticulocyte production index fall (Chap. 129).


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InternalMed_Harrison. Hemolytic disease, while dramatic, is among the least common forms of anemia. The ability to sustain a high reticulocyte production index reflects the ability of the erythroid marrow to compensate for hemolysis and, in the case of extravascular hemolysis, the efficient recycling of iron from the destroyed red cells to support red cell production. With intravascular hemolysis, such as paroxysmal nocturnal hemoglobinuria, the loss of iron may limit the marrow response. The level of response depends on the severity of the anemia and the nature of the underlying disease process. Hemoglobinopathies, such as sickle cell disease and the thalassemias, present a mixed picture. The reticulocyte index may be high but is inappropriately low for the degree of marrow erythroid hyperplasia (Chap. 127).


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InternalMed_Harrison. Hemolytic anemias present in different ways. Some appear suddenly as an acute, self-limited episode of intravascular or extravascular hemolysis, a presentation pattern often seen in patients with autoimmune hemolysis or with inherited defects of the Embden-Meyerhof pathway or the glutathione reductase pathway. Patients with inherited disorders of the hemoglobin molecule or red cell membrane generally have a lifelong clinical history typical of the disease process. Those with chronic hemolytic disease, such as hereditary spherocytosis, may actually present not with anemia but with a complication stemming from the prolonged increase in red cell destruction such as symptomatic bilirubin gallstones or splenomegaly. Patients with chronic hemolysis are also susceptible to aplastic crises if an infectious process interrupts red cell production.


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InternalMed_Harrison. The differential diagnosis of an acute or chronic hemolytic event requires the careful integration of family history, the pattern of clinical presentation, and—whether the disease is congenital or acquired— careful examination of the peripheral blood smear. Precise diagnosis may require more specialized laboratory tests, such as hemoglobin electrophoresis or a screen for red cell enzymes. Acquired defects in red cell survival are often immunologically mediated and require a direct or indirect antiglobulin test or a cold agglutinin titer to detect the presence of hemolytic antibodies or complement-mediated red cell destruction (Chap. 129).


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InternalMed_Harrison. An overriding principle is to initiate treatment of mild to moderate anemia only when a specific diagnosis is made. Rarely, in the acute setting, anemia may be so severe that red cell transfusions are required before a specific diagnosis is available. Whether the anemia is of acute or gradual onset, the selection of the appropriate treatment is determined by the documented cause(s) of the anemia. Often, the cause of the anemia is multifactorial. For example, a patient with severe rheumatoid arthritis who has been taking anti-inflammatory drugs may have a hypoproliferative anemia associated with chronic inflammation as well as chronic blood loss associated with intermittent gastrointestinal bleeding. In every circumstance, it is important to evaluate the patient’s iron status fully before and during the treatment of any anemia. Transfusion is discussed in Chap. 138e; iron therapy is discussed in Chap. 126; treatment of megaloblastic anemia is discussed in Chap. 128; treatment of other


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InternalMed_Harrison. and during the treatment of any anemia. Transfusion is discussed in Chap. 138e; iron therapy is discussed in Chap. 126; treatment of megaloblastic anemia is discussed in Chap. 128; treatment of other entities is discussed in their respective chapters (sickle cell anemia, Chap. 127; hemolytic anemias, Chap. 129; aplastic anemia and myelodysplasia, Chap. 130).


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InternalMed_Harrison. Therapeutic options for the treatment of anemias have expanded dramatically during the past 30 years. Blood component therapy is available and safe. Recombinant EPO as an adjunct to anemia management has transformed the lives of patients with chronic renal failure on dialysis and reduced transfusion needs of anemic cancer patients receiving chemotherapy. Eventually, patients with inherited disorders of globin synthesis or mutations in the globin gene, such as sickle cell disease, may benefit from the successful introduction of targeted genetic therapy (Chap. 91e).


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InternalMed_Harrison. Polycythemia is defined as an increase in the hemoglobin above normal. This increase may be real or only apparent because of a decrease in plasma volume (spurious or relative polycythemia). The term erythrocytosis may be used interchangeably with polycythemia, but some draw a distinction between them: erythrocytosis implies documentation of increased red cell mass, whereas polycythemia refers to any increase in red cells. Often patients with polycythemia are detected through an incidental finding of elevated hemoglobin or hematocrit levels. Concern that the hemoglobin level may be abnormally high is usually triggered at 170 g/L (17 g/dL) for men and 150 g/L (15 g/dL) for women. Hematocrit levels >50% in men or >45% in women may be abnormal. Hematocrits >60% in men and >55% in women are almost invariably associated with an increased red cell mass. Given that the machine that quantitates red cell parameters actually measures hemoglobin concentrations and calculates hematocrits,


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InternalMed_Harrison. are almost invariably associated with an increased red cell mass. Given that the machine that quantitates red cell parameters actually measures hemoglobin concentrations and calculates hematocrits, hemoglobin levels may be a better index.


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InternalMed_Harrison. Features of the clinical history that are useful in the differential diagnosis include smoking history; current living at high altitude; or a history of congenital heart disease, sleep apnea, or chronic lung disease.


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InternalMed_Harrison. Patients with polycythemia may be asymptomatic or experience symptoms related to the increased red cell mass or the underlying disease process that leads to the increased red cell mass. The dominant symptoms from an increased red cell mass are related to hyperviscosity and thrombosis (both venous and arterial), because the blood viscosity increases logarithmically at hematocrits >55%. Manifestations range from digital ischemia to Budd-Chiari syndrome with hepatic vein thrombosis. Abdominal vessel thromboses are particularly common. Neurologic symptoms such as vertigo, tinnitus, headache, and visual disturbances may occur. Hypertension is often present. Patients with polycythemia vera may have aquagenic pruritus and symptoms related to hepatosplenomegaly. Patients may have easy bruising, epistaxis, or bleeding from the gastrointestinal tract. Peptic ulcer disease is common. Patients with hypoxemia may develop cyanosis on minimal exertion or have headache, impaired mental acuity, and


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InternalMed_Harrison. epistaxis, or bleeding from the gastrointestinal tract. Peptic ulcer disease is common. Patients with hypoxemia may develop cyanosis on minimal exertion or have headache, impaired mental acuity, and fatigue.


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InternalMed_Harrison. The physical examination usually reveals a ruddy complexion. Splenomegaly favors polycythemia vera as the diagnosis (Chap. 131).


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InternalMed_Harrison. 400 The presence of cyanosis or evidence of a right-to-left shunt suggests congenital heart disease presenting in the adult, particularly tetralogy of Fallot or Eisenmenger’s syndrome (Chap. 236). Increased blood viscosity raises pulmonary artery pressure; hypoxemia can lead to increased pulmonary vascular resistance. Together, these factors can produce cor pulmonale. Polycythemia can be spurious (related to a decrease in plasma volume; Gaisbock’s syndrome), primary, or secondary in origin. The secondary causes are all associated with increases in EPO levels: either a physiologically adapted appropriate elevation based on tissue hypoxia (lung disease, high altitude, CO poisoning, high-affinity hemoglobinopathy) or an abnormal overproduction (renal cysts, renal artery stenosis, tumors with ectopic EPO production). A rare familial form of polycythemia is associated with normal EPO levels but hyper-responsive EPO receptors due to mutations. APPROACH TO THE PATIENT:


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InternalMed_Harrison. APPROACH TO THE PATIENT: PART 2 Cardinal Manifestations and Presentation of Diseases As shown in Fig. 77-18, the first step is to document the presence of an increased red cell mass using the principle of isotope dilution by administering 51Cr-labeled autologous red blood cells to the patient and sampling blood radioactivity over a 2-h period. If the red cell mass is normal (<36 mL/kg in men, <32 mL/kg in women), the patient has spurious or relative polycythemia. If the red cell mass is increased (>36 mL/kg in men, >32 mL/kg in women), serum EPO levels should be measured. If EPO levels are low or unmeasurable, the patient most likely has polycythemia vera. A mutation in JAK2 (Val617Phe), a key member of the cytokine intracellular signaling pathway, can be found in 90–95% of patients with polycythemia vera. Many of those without this particular JAK2 mutation have mutations in exon 12. As a practical matter, few centers assess red


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InternalMed_Harrison. Dx: Relative erythrocytosis Measure RBC mass Measure serum EPO levels Measure arterial O2 saturation elevated elevated Dx: O2 affinity hemoglobinopathy increased elevated normal Dx: Polycythemia vera Confirm JAK2mutation smoker? normal normal Dx: Smoker’s polycythemia normal Increased hct or hgb low low Diagnostic evaluation for heart or lung disease, e.g., COPD, high altitude, AV or intracardiac shunt Measure hemoglobin O2 affinity Measure carboxyhemoglobin levels Search for tumor as source of EPO IVP/renal ultrasound (renal Ca or cyst) CT of head (cerebellar hemangioma) CT of pelvis (uterine leiomyoma) CT of abdomen (hepatoma) no yes FIguRE 77-18 An approach to the differential diagnosis of patients with an elevated hemoglobin (possible polycythemia). AV, atrioventricular; COPD, chronic obstructive pulmonary disease; CT, computed tomography; EPO, erythropoietin; hct, hematocrit; hgb, hemoglobin; IVP, intravenous pyelogram; RBC, red blood cell.


InternalMed_Harrison

InternalMed_Harrison. AV, atrioventricular; COPD, chronic obstructive pulmonary disease; CT, computed tomography; EPO, erythropoietin; hct, hematocrit; hgb, hemoglobin; IVP, intravenous pyelogram; RBC, red blood cell. cell mass in the setting of an increased hematocrit. The short workup is to measure EPO levels, check for JAK2 mutation, and perform an abdominal ultrasound to assess spleen size. Tests that support the diagnosis of polycythemia vera include elevated white blood cell count, increased absolute basophil count, and thrombocytosis.


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InternalMed_Harrison. If serum EPO levels are elevated, one needs to distinguish whether the elevation is a physiologic response to hypoxia or related to autonomous EPO production. Patients with low arterial O2 saturation (<92%) should be further evaluated for the presence of heart or lung disease, if they are not living at high altitude. Patients with normal O2 saturation who are smokers may have elevated EPO levels because of CO displacement of O2. If carboxyhemoglobin (COHb) levels are high, the diagnosis is “smoker’s polycythemia.” Such patients should be urged to stop smoking. Those who cannot stop smoking require phlebotomy to control their polycythemia. Patients with normal O2 saturation who do not smoke either have an abnormal hemoglobin that does not deliver O2 to the tissues (evaluated by finding elevated O2–hemoglobin affinity) or have a source of EPO production that is not responding to the normal feedback inhibition. Further workup is dictated by the differential diagnosis of EPO-producing


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InternalMed_Harrison. elevated O2–hemoglobin affinity) or have a source of EPO production that is not responding to the normal feedback inhibition. Further workup is dictated by the differential diagnosis of EPO-producing neoplasms. Hepatoma, uterine leiomyoma, and renal cancer or cysts are all detectable with abdominopelvic computed tomography scans. Cerebellar hemangiomas may produce EPO, but they present with localizing neurologic signs and symptoms rather than polycythemia-related symptoms.


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InternalMed_Harrison. Barbara A. Konkle The human hemostatic system provides a natural balance between procoagulant and anticoagulant forces. The procoagulant forces include platelet adhesion and aggregation and fibrin clot formation; anticoagulant forces include the natural inhibitors of coagulation and fibrinolysis. Under normal circumstances, hemostasis is regulated to promote blood flow; however, it is also prepared to clot blood rapidly to arrest blood flow and prevent exsanguination. After bleeding is successfully halted, the system remodels the damaged vessel to restore normal blood flow. The major components of the hemostatic system, which function in concert, are (1) platelets and other formed elements of blood, such as monocytes and red cells; (2) plasma proteins (the coagulation and fibrinolytic factors and inhibitors); and (3) the vessel wall.


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InternalMed_Harrison. On vascular injury, platelets adhere to the site of injury, usually the denuded vascular intimal surface. Platelet adhesion is mediated primarily by Von Willebrand factor (VWF), a large multimeric protein present in both plasma and the extracellular matrix of the subendothelial vessel wall, which serves as the primary “molecular glue,” providing sufficient strength to withstand the high levels of shear stress that would tend to detach them with the flow of blood. Platelet adhesion is also facilitated by direct binding to subendothelial collagen through specific platelet membrane collagen receptors.


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InternalMed_Harrison. Platelet adhesion results in subsequent platelet activation and aggregation. This process is enhanced and amplified by humoral mediators in plasma (e.g., epinephrine, thrombin); mediators released from activated platelets (e.g., adenosine diphosphate, serotonin); and vessel wall extracellular matrix constituents that come in contact with adherent platelets (e.g., collagen, VWF). Activated platelets undergo the release reaction, during which they secrete contents that further promote aggregation and inhibit the naturally anticoagulant endothelial cell factors. During platelet aggregation (platelet-platelet interaction), additional platelets are recruited from the circulation to the site of vascular injury, leading to the formation of an occlusive platelet thrombus. The platelet plug is anchored and stabilized by the developing fibrin mesh.


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InternalMed_Harrison. The platelet glycoprotein (Gp) IIb/IIIa (αIIbβ3) complex is the most abundant receptor on the platelet surface. Platelet activation converts the normally inactive Gp IIb/IIIa receptor into an active receptor, enabling binding to fibrinogen and VWF. Because the surface of each platelet has about 50,000 Gp IIb/IIIa–binding sites, numerous activated platelets recruited to the site of vascular injury can rapidly form an occlusive aggregate by means of a dense network of intercellular fibrinogen bridges. Because this receptor is the key mediator of platelet aggregation, it has become an effective target for antiplatelet therapy.


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InternalMed_Harrison. Plasma coagulation proteins (clotting factors) normally circulate in plasma in their inactive forms. The sequence of coagulation protein reactions that culminate in the formation of fibrin was originally described as a waterfall or a cascade. Two pathways of blood coagulation have been described in the past: the so-called extrinsic, or tissue factor, pathway and the so-called intrinsic, or contact activation, pathway. We now know that coagulation is normally initiated through tissue factor (TF) exposure and activation through the classic extrinsic pathway but with critically important amplification through elements of the classic intrinsic pathway, as illustrated in Fig. 78-1. These reactions take place on phospholipid surfaces, usually the activated platelet surface. Coagulation testing in the laboratory can reflect other influences due to the artificial nature of the in vitro systems used (see below).


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InternalMed_Harrison. The immediate trigger for coagulation is vascular damage that exposes blood to TF that is constitutively expressed on the surfaces of subendothelial cellular components of the vessel wall, such as smooth muscle cells and fibroblasts. TF is also present in circulating microparticles, presumably shed from cells including monocytes and platelets. TF binds the serine protease factor VIIa; the complex activates factor X to factor Xa. Alternatively, the complex can indirectly activate factor X by initially converting factor IX to factor IXa, which then activates factor X. The participation of factor XI in hemostasis is not dependent on its activation by factor XIIa but rather on its positive feedback acti-


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InternalMed_Harrison. FIguRE 78-2 Fibrin formation and dissolution. (A) Fibrinogen is a trinodular structure consisting of two D domains and one E domain. Thrombin activation results in an ordered lateral assembly of protofibrils (B) with noncovalent associations. Factor XIIIa cross-links the D domains on adjacent molecules (C). Fibrin and fibrinogen (not shown) lysis by plasmin occurs at discrete sites and results in intermediary fibrin(ogen) degradation products (not shown). D-Dimers are the product of complete lysis of fibrin (D), maintaining the cross-linked D domains. vation by thrombin. Thus, factor XIa functions in the propagation and amplification, rather than in the initiation, of the coagulation cascade. Factor Xa can be formed through the actions of either the TF/ factor VIIa complex or factor IXa (with factor VIIIa as a cofactor) and converts prothrombin to thrombin, the pivotal protease of the coagulation system. The essential cofactor for this reaction is factor


InternalMed_Harrison

InternalMed_Harrison. Va. Like the homologous factor VIIIa, factor Va is produced by thrombininduced limited proteolysis of factor V. Thrombin is a multifunctional enzyme that converts soluble plasma fibrinogen to an insoluble fibrin matrix. Fibrin polymerization involves an orderly process of intermolecular associations (Fig. 78-2). Thrombin also activates factor XIII (fibrin-stabilizing factor) to factor XIIIa, which covalently cross-links and thereby stabilizes the fibrin clot.


InternalMed_Harrison

InternalMed_Harrison. The assembly of the clotting factors on activated cell membrane surfaces greatly accelerates their reaction rates and also serves to localize blood clotting to sites of vascular injury. The critical cell membrane components, acidic phospholipids, are not normally exposed on resting cell membrane surfaces. However, when Vessel injury TFPI IX IX XI VIIIa IXa (Prothrombin) Thrombin (IIa) Fibrinogen Fibrin XIaX Va Xa II X VIIa platelets, monocytes, and endothelial cells are activated by vascular injury or FIguRE 78-1 Coagulation is initiated by tissue factor (TF) exposure, which, with factor (F) VIIa, inflammatory stimuli, the procoagulant activates FIX and FX, which in turn, with FVIII and FV as cofactors, respectively, results in thrombin head groups of the membrane anionic formation and subsequent conversion of fibrinogen to fibrin. Thrombin activates FXI, FVIII, and FV, phospholipids become translocated to amplifying the coagulation signal. Once the TF/FVIIa/FXa complex is formed,


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InternalMed_Harrison. subsequent conversion of fibrinogen to fibrin. Thrombin activates FXI, FVIII, and FV, phospholipids become translocated to amplifying the coagulation signal. Once the TF/FVIIa/FXa complex is formed, tissue factor pathway the surfaces of these cells or released inhibitor (TFPI) inhibits the TF/FVIIa pathway, making coagulation dependent on the amplification as part of microparticles, making them loop through FIX/FVIII. Coagulation requires calcium (not shown) and takes place on phospholipid available to support and promote the surfaces, usually the activated platelet membrane. plasma coagulation reactions.


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InternalMed_Harrison. Several physiologic antithrombotic mechanisms act in concert to prevent clotting under normal circumstances. These mechanisms operate to preserve blood fluidity and to limit blood clotting to specific focal sites of vascular injury. Endothelial cells have many antithrombotic effects. They produce prostacyclin, nitric oxide, and ectoADPase/ CD39, which act to inhibit platelet binding, secretion, and aggregation. Endothelial cells produce anticoagulant factors including heparan proteoglycans, antithrombin, TF pathway inhibitor, and thrombomodulin. They also activate fibrinolytic mechanisms through the production of tissue plasminogen activator 1, urokinase, plasminogen activator inhibitor, and annexin-2. The sites of action of the major physiologic antithrombotic pathways are shown in Fig. 78-3.


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InternalMed_Harrison. Antithrombin (or antithrombin III) is the major plasma protease inhibitor of thrombin and the other clotting factors in coagulation. Antithrombin neutralizes thrombin and other activated coagulation factors by forming a complex between the active site of the enzyme and the reactive center of antithrombin. The rate of formation of these inactivating complexes increases by a factor of several thousand in the presence of heparin. Antithrombin inactivation of thrombin and other activated clotting factors occurs physiologically on vascular surfaces, where glycosoaminoglycans, including heparan sulfates, are present to catalyze these reactions. Inherited quantitative or qualitative deficiencies of antithrombin lead to a lifelong predisposition to venous thromboembolism.


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InternalMed_Harrison. Protein C is a plasma glycoprotein that becomes an anticoagulant when it is activated by thrombin. The thrombin-induced activation of protein C occurs physiologically on thrombomodulin, a transmembrane proteoglycan-binding site for thrombin on endothelial cell surfaces. The binding of protein C to its receptor on endothelial cells places it in PART 2 Cardinal Manifestations and Presentation of Diseases FIguRE 78-3 Sites of action of the four major physiologic anti-thrombotic pathways: antithrombin (AT); protein C/S (PC/PS); tissue factor pathway inhibitor (TFPI); and the fibrinolytic system, consisting of plasminogen, plasminogen activator (PA), and plasmin. PT, prothrombin; Th, thrombin; FDP, fibrin(ogen) degradation products.


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InternalMed_Harrison. (Modified from BA Konkle, AI Schafer, in DP Zipes et al [eds]: Braunwald’s Heart Disease, 7th ed. Philadelphia, Saunders, 2005.) proximity to the thrombin-thrombomodulin complex, thereby enhancing its activation efficiency. Activated protein C acts as an anticoagulant by cleaving and inactivating activated factors V and VIII. This reaction is accelerated by a cofactor, protein S, which, like protein C, is a glycoprotein that undergoes vitamin K–dependent posttranslational modification. Quantitative or qualitative deficiencies of protein C or protein S, or resistance to the action of activated protein C by a specific mutation at its target cleavage site in factor Va (factor V Leiden), lead to hypercoagulable states.


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InternalMed_Harrison. Tissue factor pathway inhibitor (TFPI) is a plasma protease inhibitor that regulates the TF-induced extrinsic pathway of coagulation. TFPI inhibits the TF/factor VIIa/factor Xa complex, essentially turning off the TF/factor VIIa initiation of coagulation, which then becomes dependent on the “amplification loop” via factor XI and factor VIII activation by thrombin. TFPI is bound to lipoprotein and can also be released by heparin from endothelial cells, where it is bound to glycosaminoglycans, and from platelets. The heparin-mediated release of TFPI may play a role in the anticoagulant effects of unfractionated and low-molecular-weight heparins.


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InternalMed_Harrison. Any thrombin that escapes the inhibitory effects of the physiologic anticoagulant systems is available to convert fibrinogen to fibrin. In response, the endogenous fibrinolytic system is then activated to dispose of intravascular fibrin and thereby maintain or reestablish the patency of the circulation. Just as thrombin is the key protease enzyme of the coagulation system, plasmin is the major protease enzyme of the fibrinolytic system, acting to digest fibrin to fibrin degradation products. The general scheme of fibrinolysis and its control is shown in Fig. 78-4.


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InternalMed_Harrison. The plasminogen activators, tissue type plasminogen activator (tPA) and the urokinase-type plasminogen activator (uPA), cleave the Arg560-Val561 bond of plasminogen to generate the active enzyme plasmin. The lysine-binding sites of plasmin (and plasminogen) permit it to bind to fibrin, so that physiologic fibrinolysis is “fibrin specific.” Both plasminogen (through its lysine-binding sites) and tPA possess specific affinity for fibrin and thereby bind selectively to clots. The assembly of a ternary complex, consisting of fibrin, plasminogen, and tPA, promotes the localized interaction between plasminogen and tPA and greatly accelerates the rate of plasminogen activation to plasmin. Moreover, partial degradation of fibrin by plasmin exposes new plasminogen and tPA-binding sites in carboxy-terminus lysine FIguRE 78-4 A schematic diagram of the fibrinolytic system.


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InternalMed_Harrison. FIguRE 78-4 A schematic diagram of the fibrinolytic system. Tissue plasminogen activator (tPA) is released from endothelial cells, binds the fibrin clot, and activates plasminogen to plasmin. Excess fibrin is degraded by plasmin to distinct degradation products (FDPs). Any free plasmin is complexed with α2-antiplasmin (α2Pl). PAI, plasminogen activator inhibitor; UPA, urokinase-type plasminogen activator. residues of fibrin fragments to enhance these reactions further. This creates a highly efficient mechanism to generate plasmin focally on the fibrin clot, which then becomes plasmin’s substrate for digestion to fibrin degradation products.


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InternalMed_Harrison. Plasmin cleaves fibrin at distinct sites of the fibrin molecule, leading to the generation of characteristic fibrin fragments during the process of fibrinolysis (Fig. 78-2). The sites of plasmin cleavage of fibrin are the same as those in fibrinogen. However, when plasmin acts on covalently cross-linked fibrin, d-dimers are released; hence, d-dimers can be measured in plasma as a relatively specific test of fibrin (rather than fibrinogen) degradation. d-Dimer assays can be used as sensitive markers of blood clot formation and have been validated for clinical use to exclude the diagnosis of deep venous thrombosis (DVT) and pulmonary embolism in selected populations. In addition, d-dimer measurement can be used to stratify patients, particularly women, for risk of recurrent venous thromboembolism (VTE) when measured 1 month after discontinuation of anticoagulation given for treatment of an initial idiopathic event. d-Dimer levels may be elevated in the absence of VTE in elderly people.


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InternalMed_Harrison. Physiologic regulation of fibrinolysis occurs primarily at three levels: (1) plasminogen activator inhibitors (PAIs), specifically PAI-1 and PAI-2, inhibit the physiologic plasminogen activators; (2) the thrombin-activatable fibrinolysis inhibitor (TAFI) limits fibrinolysis; and (3) α2-antiplasmin inhibits plasmin. PAI-1 is the primary inhibitor of tPA and uPA in plasma. TAFI cleaves the N-terminal lysine residues of fibrin, which aid in localization of plasmin activity. α2-Antiplasmin is the main inhibitor of plasmin in human plasma, inactivating any nonfibrin clot-associated plasmin. APPROACH TO THE PATIENT:


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InternalMed_Harrison. APPROACH TO THE PATIENT: Disorders of hemostasis may be either inherited or acquired. A detailed personal and family history is key in determining the chronicity of symptoms and the likelihood of the disorder being inherited, as well as providing clues to underlying conditions that have contributed to the bleeding or thrombotic state. In addition, the history can give clues as to the etiology by determining (1) the bleeding (mucosal and/or joint) or thrombosis (arterial and/ or venous) site and (2) whether an underlying bleeding or clotting tendency was enhanced by another medical condition or the introduction of medications or dietary supplements.


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InternalMed_Harrison. History of Bleeding A history of bleeding is the most important predictor of bleeding risk. In evaluating a patient for a bleeding disorder, a history of at-risk situations, including the response to past surgeries, should be assessed. Does the patient have a history of spontaneous or trauma/surgery-induced bleeding? Spontaneous hemarthroses are a hallmark of moderate and severe factor VIII and IX deficiency and, in rare circumstances, of other clotting factor deficiencies. Mucosal bleeding symptoms are more suggestive of underlying platelet disorders or Von Willebrand disease (VWD), termed disorders of primary hemostasis or platelet plug formation. Disorders affecting primary hemostasis are shown in Table 78-1.


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InternalMed_Harrison. A bleeding score has been validated as a tool to predict patients more likely to have type 1 VWD (International Society on Thrombosis and Haemostasis Bleeding Assessment Tool [www.isth .org/resource/resmgr/ssc/isth-ssc_bleeding_assessment.pdf ]). This is most useful tool in excluding the diagnosis of a bleeding disorder, and thus avoiding unnecessary testing. One study found that a low bleeding score (≤3) and a normal activated partial thromboplastin time (aPTT) had 99.6% negative predictive value for the diagnosis of VWD. Bleeding symptoms that appear to be more common in patients with bleeding disorders include prolonged bleeding with surgery, dental procedures and extractions, and/or trauma, menorrhagia or postpartum hemorrhage, and large bruises (often described with lumps). Defects of Platelet Aggregation Glanzmann’s thrombasthenia (absence or dysfunction of platelet glycoprotein [Gp] IIb/IIIa) Defects of Platelet Secretion


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InternalMed_Harrison. Defects of Platelet Aggregation Glanzmann’s thrombasthenia (absence or dysfunction of platelet glycoprotein [Gp] IIb/IIIa) Defects of Platelet Secretion Drug-induced (aspirin, nonsteroidal anti-inflammatory agents, thienopyridines) Inherited Nonspecific inherited secretory defects Nonspecific drug effects Uremia Platelet coating (e.g., paraprotein, penicillin) Defect of Platelet Coagulant Activity


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InternalMed_Harrison. Nonspecific inherited secretory defects Nonspecific drug effects Uremia Platelet coating (e.g., paraprotein, penicillin) Defect of Platelet Coagulant Activity Easy bruising and menorrhagia are common complaints in patients with and without bleeding disorders. Easy bruising can also be a sign of medical conditions in which there is no identifiable coagulopathy; instead, the conditions are caused by an abnormality of blood vessels or their supporting tissues. In Ehlers-Danlos syndrome, there may be posttraumatic bleeding and a history of joint hyperextensibility. Cushing’s syndrome, chronic steroid use, and aging result in changes in skin and subcutaneous tissue, and subcutaneous bleeding occurs in response to minor trauma. The latter has been termed senile purpura.


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InternalMed_Harrison. Epistaxis is a common symptom, particularly in children and in dry climates, and may not reflect an underlying bleeding disorder. However, it is the most common symptom in hereditary hemorrhagic telangiectasia and in boys with VWD. Clues that epistaxis is a symptom of an underlying bleeding disorder include lack of seasonal variation and bleeding that requires medical evaluation or treatment, including cauterization. Bleeding with eruption of primary teeth is seen in children with more severe bleeding disorders, such as moderate and severe hemophilia. It is uncommon in children with mild bleeding disorders. Patients with disorders of primary hemostasis (platelet adhesion) may have increased bleeding after dental cleanings and other procedures that involve gum manipulation.


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InternalMed_Harrison. Menorrhagia is defined quantitatively as a loss of >80 mL of blood per cycle, based on the quantity of blood loss required to produce iron-deficiency anemia. A complaint of heavy menses is subjective and has a poor correlation with excessive blood loss. Predictors of menorrhagia include bleeding resulting in iron-deficiency anemia or a need for blood transfusion, passage of clots >1 inch in diameter, and changing a pad or tampon more than hourly. Menorrhagia is a common symptom in women with underlying bleeding disorders and is reported in the majority of women with VWD, women with factor XI deficiency, and symptomatic carriers of hemophilia. Women with underlying bleeding disorders are more likely to have other bleeding symptoms, including bleeding after dental extractions, postoperative bleeding, and postpartum bleeding, and are much more likely to have menorrhagia beginning at menarche than women with menorrhagia due to other causes.


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InternalMed_Harrison. Postpartum hemorrhage (PPH) is a common symptom in women with underlying bleeding disorders. In women with type 1 VWD and symptomatic carriers of hemophilia A in whom levels of VWF and factor VIII usually normalize during pregnancy, PPH may be delayed. Women with a history of PPH have a high risk of recurrence with subsequent pregnancies. Rupture of ovarian cysts with intraabdominal hemorrhage has also been reported in women with underlying bleeding disorders.


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InternalMed_Harrison. Tonsillectomy is a major hemostatic challenge, because intact hemostatic mechanisms are essential to prevent excessive bleeding from the tonsillar bed. Bleeding may occur early after surgery or after approximately 7 days postoperatively, with loss of the eschar at the operative site. Similar delayed bleeding is seen after colonic polyp resection. Gastrointestinal (GI) bleeding and hematuria are usually due to underlying pathology, and procedures to identify and treat the bleeding site should be undertaken, even in patients with known bleeding disorders. VWD, particularly types 2 and 3, has been associated with angiodysplasia of the bowel and GI bleeding.


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InternalMed_Harrison. Hemarthroses and spontaneous muscle hematomas are characteristic of moderate or severe congenital factor VIII or IX deficiency. They can also be seen in moderate and severe deficiencies of fibrinogen, prothrombin, and factors V, VII, and X. Spontaneous hemarthroses occur rarely in other bleeding disorders except for severe VWD, with associated factor VIII levels <5%. Muscle and soft tissue bleeds are also common in acquired factor VIII deficiency. Bleeding into a joint results in severe pain and swelling, as well as loss of function, but is rarely associated with discoloration from bruising around the joint. Life-threatening sites of bleeding include bleeding into the oropharynx, where bleeding can obstruct the airway, into the central nervous system, and into the retroperitoneum. Central nervous system bleeding is the major cause of bleeding-related deaths in patients with severe congenital factor deficiencies. Prohemorrhagic Effects of Medications and Dietary Supplements


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InternalMed_Harrison. Prohemorrhagic Effects of Medications and Dietary Supplements Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit cyclooxygenase 1 impair primary hemostasis and may exacerbate bleeding from another cause or even unmask a previously occult mild bleeding disorder such as VWD. All NSAIDs, however, can precipitate GI bleeding, which may be more severe in patients with underlying bleeding disorders. The aspirin effect on platelet function as assessed by aggregometry can persist for up to 7 days, although it has frequently returned to normal by 3 days after the last dose. The effect of other NSAIDs is shorter, as the inhibitor effect is reversed when the drug is removed. Thienopyridines (clopidogrel and prasugrel) inhibit ADP-mediated platelet aggregation and, like NSAIDs, can precipitate or exacerbate bleeding symptoms.


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InternalMed_Harrison. Many herbal supplements can impair hemostatic function (Table 78-2). Some are more convincingly associated with a bleeding risk than others. Fish oil or concentrated omega-3 fatty acid supplements impair platelet function. They alter platelet biochemistry to produce more PGI3, a more potent platelet inhibitor than prostacyclin (PGI2), and more thromboxane A3, a less potent platelet activator than thromboxane A2. In fact, diets naturally rich in omega-3 fatty acids can result in a prolonged bleeding time and abnormal platelet aggregation studies, but the actual associated bleeding risk is unclear. Vitamin E appears to inhibit protein kinase C–mediated platelet aggregation and nitric oxide production. In patients with unexplained bruising or bleeding, it is prudent to review any new medications or supplements and discontinue those that may be associated with bleeding.


InternalMed_Harrison

InternalMed_Harrison. underlying Systemic Diseases That Cause or Exacerbate a Bleeding Tendency Acquired bleeding disorders are commonly secondary to, or associated with, systemic disease. The clinical evaluation of a patient with a bleeding tendency must therefore include a thorough assessment for evidence of underlying disease. Bruising or mucosal bleeding may be the presenting complaint in liver disease, severe renal impairment, hypothyroidism, paraproteinemias or amyloidosis, and conditions causing bone marrow failure. All coagulation factors are synthesized in the liver, and hepatic failure results in combined factor deficiencies. This is often compounded by thrombocytopenia from splenomegaly due to portal PART 2 Cardinal Manifestations and Presentation of Diseases Herbs with Potential Antiplatelet Activity


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InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases Herbs with Potential Antiplatelet Activity Ginkgo (Ginkgo biloba L.) Garlic (Allium sativum) Bilberry (Vaccinium myrtillus) Ginger (Gingiber officinale) Dong quai (Angelica sinensis) Feverfew (Tanacetum parthenium) Asian ginseng (Panax ginseng) American ginseng (Panax quinquefolius) Siberian ginseng/eleuthero (Eleutherococcus senticosus) Turmeric (Circuma longa) Meadowsweet (Filipendula ulmaria) Willow (Salix spp.) Chamomile (Matricaria recutita, Chamaemelum mobile) hypertension. Coagulation factors II, VII, IX, and X and proteins C, S, and Z are dependent on vitamin K for posttranslational modi fication. Although vitamin K is required in both procoagulant and anticoagulant processes, the phenotype of vitamin K deficiency or the warfarin effect on coagulation is bleeding. The normal blood platelet count is 150,000–450,000/μL.


InternalMed_Harrison

InternalMed_Harrison. The normal blood platelet count is 150,000–450,000/μL. Thrombocytopenia results from decreased production, increased destruction, and/or sequestration. Although the bleeding risk varies somewhat by the reason for the thrombocytopenia, bleeding rarely occurs in isolated thrombocytopenia at counts <50,000/μL and usually not until <10,000–20,000/μL. Coexisting coagulopathies, as is seen in liver failure or disseminated coagulation; infection; all increase the risk of bleeding in the thrombocytopenic patient. Most procedures can be performed in patients with a platelet count of 50,000/μL. The level needed for major surgery will depend on the type of surgery and the patient’s underlying medical state, although a count of approximately 80,000/μL is likely sufficient.


InternalMed_Harrison

InternalMed_Harrison. The risk of thrombosis, like that of bleeding, is influenced by both genetic and environmental influences. The major risk factor for arterial thrombosis is atherosclerosis, whereas for venous throm bosis, the risk factors are immobility, surgery, underlying medical conditions such as malignancy, medications such as hormonal therapy, obesity, and genetic predispositions. Factors that increase risks for venous and for both venous and arterial thromboses are shown in Table 78-3.


InternalMed_Harrison

InternalMed_Harrison. The most important point in a history related to venous throm bosis is determining whether the thrombotic event was idiopathic tated event. In patients without underlying malignancy, having an idiopathic event is the strongest predictor of recurrence of VTE. In patients who have a vague history of thrombosis, a history of being treated with warfarin suggests a past DVT. Age is an important risk factor for venous thrombosis—the risk of DVT increases per decade, with an approximate incidence of 1/100,000 per year in early childhood to 1/200 per year among octogenarians. Family history is helpful in determining if there is a genetic predisposition and how strong that predisposition appears to be. A genetic thrombophilia that confers a relatively small increased risk, such as being a het erozygote for the prothrombin G20210A or factor V Leiden muta tion, may be a minor determinant of risk in an elderly individual


InternalMed_Harrison

InternalMed_Harrison. Age Previous thrombosis Immobilization Major surgery Pregnancy and puerperium Hospitalization Obesity Infection APC resistance, nongenetic Smoking Elevated factor II, IX, XI Elevated TAFI levels Low levels of TFPI aUnknown whether risk is inherited or acquired. Abbreviations: APC, activated protein C; TAFI, thrombin-activatable fibrinolysis inhibitor; TFPI, tissue factor pathway inhibitor. undergoing a high-risk surgical procedure. As illustrated in Fig. 78-5, a thrombotic event usually has more than one contributing factor. Predisposing factors must be carefully assessed to determine the risk of recurrent thrombosis and, with consideration of the patient’s bleeding risk, determine the length of anticoagulation.


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InternalMed_Harrison. FIguRE 78-5 Thrombotic risk over time. Shown schematically is an individual’s thrombotic risk over time. An underlying factor V Leiden mutation provides a “theoretically” constant increased risk. The thrombotic risk increases with age and, intermittently, with oral contraceptive (OCP) or hormone replacement therapy (HRT) use; other events may increase the risk further. At some point, the cumulative risk may increase to the threshold for thrombosis and result in deep venous thrombosis (DVT). Note: The magnitude and duration of risk portrayed in the figure are meant for example only and may not precisely reflect the relative risk determined by clinical study. (From BA Konkle, A Schafer, in DP Zipes et al [eds]: Braunwald’s Heart Disease, 7th ed. Philadelphia, Saunders, 2005; modified with permission from FR Rosendaal: Venous thrombosis: A multicausal disease. Lancet 353:1167, 1999.)


InternalMed_Harrison

InternalMed_Harrison. Similar consideration should be given in determining the need, if any, to test the patient and family members for thrombophilias. Careful history taking and clinical examination are essential components in the assessment of bleeding and thrombotic risk. The use of laboratory tests of coagulation complement, but cannot substitute for, clinical assessment. No test exists that provides a global assessment of hemostasis. The bleeding time has been used to assess bleeding risk; however, it does not predict bleeding risk with surgery and it is not recommended for this indication. The PFA-100, an instrument that measures platelet-dependent coagulation under flow conditions, is more sensitive and specific for VWD than the bleeding time; however, it is not sensitive enough to rule out mild bleeding disorders. PFA-100 closure times are prolonged in patients with some, but not all, inherited platelet disorders. Also, its utility in predicting bleeding risk has not been determined.


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InternalMed_Harrison. For routine preoperative and preprocedure testing, an abnormal prothrombin time (PT) may detect liver disease or vitamin K deficiency that had not been previously appreciated. Studies have not confirmed the usefulness of an aPTT in preoperative evaluations in patients with a negative bleeding history. The primary use of coagulation testing should be to confirm the presence and type of bleeding disorder in a patient with a suspicious clinical history.


InternalMed_Harrison

InternalMed_Harrison. Because of the nature of coagulation assays, proper sample acquisition and handling is critical to obtaining valid results. In patients with abnormal coagulation assays who have no bleeding history, repeat studies with attention to these factors frequently results in normal values. Most coagulation assays are performed in sodium citrate anticoagulated plasma that is recalcified for the assay. Because the anticoagulant is in liquid solution and needs to be added to blood in proportion to the plasma volume, incorrectly filled or inadequately mixed blood collection tubes will give erroneous results. Vacutainer tubes should be filled to >90% of the recommended fill, which is usually denoted by a line on the tube. An elevated hematocrit (>55%) can result in a false value due to a decreased plasma-to-anticoagulant ratio.


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InternalMed_Harrison. Screening Assays The most commonly used screening tests are the PT, aPTT, and platelet count. The PT assesses the factors I (fibrinogen), II (prothrombin), V, VII, and X (Fig. 78-6). The PT measures the time for clot formation of the citrated plasma after recalcification and addition of thromboplastin, a mixture of TF and phospholipids. The sensitivity of the assay varies by the source of thromboplastin. The relationship between defects in secondary hemostasis (fibrin formation) and coagulation test abnormalities is shown in Table 78-4. To adjust for this variability, the overall sensitivity of different thromboplastins to reduction of the vitamin K–dependent clotting factors II, VII, IX, and X in anticoagulation patients is now expressed as the International Sensitivity Index (ISI). An inverse relationship exists between ISI and thromboplastin sensitivity. The international normalized ratio (INR) is then determined based on the formula: INR = (PTpatient/PT )ISI.


InternalMed_Harrison

InternalMed_Harrison. The INR was developed to assess stable anticoagulation due to reduction of vitamin K–dependent coagulation factors; it is commonly used in the evaluation of patients with liver disease. Although it does allow comparison between laboratories, reagent sensitivity as used to determine the ISI is not the same in liver disease as with warfarin anticoagulation. In addition, progressive liver failure is associated with variable changes in coagulation factors; the degree of prolongation of either the PT or the INR only roughly predicts the bleeding risk. Thrombin generation has been shown to be normal in many patients with mild to moderate liver dysfunction. Because the PT only measures one aspect of hemostasis affected by liver dysfunction, we likely overestimate the bleeding risk of a mildly elevated INR in this setting. The aPTT assesses the intrinsic and common coagulation pathways; factors XI, IX, VIII, X, V, and II; fibrinogen; prekallikrein;


InternalMed_Harrison

InternalMed_Harrison. The aPTT assesses the intrinsic and common coagulation pathways; factors XI, IX, VIII, X, V, and II; fibrinogen; prekallikrein; HMWK PK FXII FXI FIX FVIII FVII FX FV Prothrombin (FII) Fibrinogen (FI) aPTTPTFIguRE 78–6 Coagulation factor activity tested in the activated partial thromboplastin time (aPTT) in red and prothrombin time (PT) in green, or both. F, factor; HMWK, high-molecular-weight kininogen; PK, prekallikrein. No clinical bleeding—↓ factor XII, high-molecular-weight kininogen, prekallikrein Variable, but usually mild, bleeding—↓ factor XI, mild ↓ factor VIII and factor IX


InternalMed_Harrison

InternalMed_Harrison. No clinical bleeding—↓ factor XII, high-molecular-weight kininogen, prekallikrein Variable, but usually mild, bleeding—↓ factor XI, mild ↓ factor VIII and factor IX Frequent, severe bleeding—severe deficiencies of factors VIII and IX Heparin and direct thrombin inhibitors high-molecular-weight kininogen; and factor XII (Fig. 78-6). The aPTT reagent contains phospholipids derived from either animal or vegetable sources that function as a platelet substitute in the coagulation pathways and includes an activator of the intrinsic coagulation system, such as nonparticulate ellagic acid or the particulate activators kaolin, celite, or micronized silica.


InternalMed_Harrison

InternalMed_Harrison. The phospholipid composition of aPTT reagents varies, which influences the sensitivity of individual reagents to clotting factor deficiencies and to inhibitors such as heparin and lupus anticoagulants. Thus, aPTT results will vary from one laboratory to another, and the normal range in the laboratory where the testing occurs should be used in the interpretation. Local laboratories can relate their aPTT values to the therapeutic heparin anticoagulation by correlating aPTT values with direct measurements of heparin activity (anti-Xa or protamine titration assays) in samples from heparinized patients, although correlation between these assays is often poor. The aPTT reagent will vary in sensitivity to individual factor deficiencies and usually becomes prolonged with individual factor deficiencies of 30–50%.


InternalMed_Harrison

InternalMed_Harrison. Mixing Studies Mixing studies are used to evaluate a prolonged aPTT or, less commonly PT, to distinguish between a factor deficiency and an inhibitor. In this assay, normal plasma and patient plasma are mixed in a 1:1 ratio, and the aPTT or PT is determined immediately and after incubation at 37°C for varying times, typically 30, 60, and/or 120 min. With isolated factor deficiencies, the aPTT will correct with mixing and stay corrected with incubation. With aPTT prolongation due to a lupus anticoagulant, the mixing and incubation will show no correction. In acquired neutralizing factor antibodies, notably an acquired factor VIII inhibitor, the initial assay may or may not correct immediately after mixing but will prolong or remain prolonged with incubation at 37°C. Failure to correct with mixing can also be due to the presence of other inhibitors or interfering substances such as heparin, fibrin split products, and paraproteins.


InternalMed_Harrison

InternalMed_Harrison. Specific Factor Assays Decisions to proceed with specific clotting factor assays will be influenced by the clinical situation and the results of coagulation screening tests. Precise diagnosis and effective management of inherited and acquired coagulation deficiencies necessitate quantitation of the relevant factors. When bleeding is severe, specific assays are urgently required to guide appropriate therapy. Individual factor assays are usually performed as modifications of the mixing study, where the patient’s plasma is mixed with plasma deficient in the factor being studied. This will correct all factor deficiencies to >50%, thus making prolongation of clot formation due to a factor deficiency dependent on the factor missing from the added plasma.


InternalMed_Harrison

InternalMed_Harrison. Testing for Antiphospholipid Antibodies Antibodies to phospholipids (cardiolipin) or phospholipid-binding proteins (β2-microglobulin and others) are detected by enzyme-linked immunosorbent assay (ELISA). When these antibodies interfere with phospholipid-dependent coagulation tests, they are termed lupus anticoagulants. The aPTT has variability sensitivity to lupus anticoagulants, depending in part on the aPTT reagents used. An assay using a sensitive reagent has been termed an LA-PTT. The dilute Russell viper venom test (dRVVT) and the tissue thromboplastin inhibition (TTI) test are modifications of standard tests with the phospholipid reagent decreased, thus increasing the sensitivity to antibodies that interfere with the phospholipid component. The tests, however, are not specific for lupus anticoagulants, because factor deficiencies or other inhibitors will also result in prolongation. Documentation of a lupus anticoagulant requires not only prolongation of a phospholipid-dependent


InternalMed_Harrison

InternalMed_Harrison. anticoagulants, because factor deficiencies or other inhibitors will also result in prolongation. Documentation of a lupus anticoagulant requires not only prolongation of a phospholipid-dependent coagulation test but also lack of correction when mixed with normal plasma and correction with the addition of activated platelet membranes or certain phospholipids (e.g., hexagonal phase).


InternalMed_Harrison

InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases Factor VII deficiency Vitamin K deficiency—early Warfarin anticoagulation Direct Xa inhibitors (rivaroxaban, apixaban) Factor II, V, X, or fibrinogen deficiency Vitamin K deficiency—late Direct thrombin inhibitors Heparin or heparin-like inhibitors Direct thrombin inhibitors (e.g., dabigatran, argatroban, bivalirudin) Mild or no bleeding—dysfibrinogenemia Frequent, severe bleeding—afibrinogenemia Prolonged PT and/or aPTT Not Corrected with Mixing with Normal Plasma Bleeding—specific factor inhibitor No symptoms, or clotting and/or pregnancy loss—lupus anticoagulant Disseminated intravascular coagulation Heparin or direct thrombin inhibitor Deficiency of α2-antiplasmin or plasminogen activator inhibitor 1 Treatment with fibrinolytic therapy


InternalMed_Harrison

InternalMed_Harrison. Other Coagulation Tests The thrombin time and the reptilase time measure fibrinogen conversion to fibrin and are prolonged when the fibrinogen level is low (usually <80–100 mg/dL) or qualitatively abnormal, as seen in inherited or acquired dysfibrinogenemias, or when fibrin/fibrinogen degradation products interfere. The thrombin time, but not the reptilase time, is prolonged in the presence of heparin. The thrombin time is markedly prolonged in the presence of the direct thrombin inhibitor, dabigatran; a dilute thrombin time can be used to assess drug activity. Measurement of anti–factor Xa plasma inhibitory activity is a test frequently used to assess lowmolecular-weight heparin (LMWH) levels, as a direct measurement of unfractionated heparin (UFH) activity, or to assess activity of the new direct Xa inhibitors rivaroxaban or apixaban. Drug in the patient sample inhibits the enzymatic conversion of an Xa-specific chromogenic substrate to colored product by factor Xa. Standard curves


InternalMed_Harrison

InternalMed_Harrison. new direct Xa inhibitors rivaroxaban or apixaban. Drug in the patient sample inhibits the enzymatic conversion of an Xa-specific chromogenic substrate to colored product by factor Xa. Standard curves are created using multiple concentrations of drug and are used to calculate the concentration of anti-Xa activity in the patient plasma.


InternalMed_Harrison

InternalMed_Harrison. Laboratory Testing for Thrombophilia Laboratory assays to detect thrombophilic states include molecular diagnostics and immunologic and functional assays. These assays vary in their sensitivity and specificity for the condition being tested. Furthermore, acute thrombosis, acute illnesses, inflammatory conditions, pregnancy, and medications affect levels of many coagulation factors and their inhibitors. Antithrombin is decreased by heparin and in the setting of acute thrombosis. Protein C and S levels may be increased in the setting of acute thrombosis and are decreased by warfarin. Antiphospholipid antibodies are frequently transiently positive in acute illness. Testing for genetic thrombophilias should, in general, only be performed when there is a strong family history of thrombosis and results would affect clinical decision making.


InternalMed_Harrison

InternalMed_Harrison. Because thrombophilia evaluations are usually performed to assess the need to extend anticoagulation, testing should be performed in a steady state, remote from the acute event. In most instances, warfarin anticoagulation can be stopped after the initial 3–6 months of treatment, and testing can be performed at least 3 weeks later. As a sensitive marker of coagulation activation, the quantitative d-dimer assay, drawn 4 weeks after stopping anticoagulation, can be used to stratify risk of recurrent thrombosis in patients who have an idiopathic event.


InternalMed_Harrison

InternalMed_Harrison. Measures of Platelet Function The bleeding time has been used to assess bleeding risk; however, it has not been found to predict bleeding risk with surgery, and it is not recommended for use for this indication. The PFA-100 and similar instruments that measure platelet-dependent coagulation under flow conditions are generally more sensitive and specific for platelet disorders and VWD than the bleeding time; however, data are insufficient to support their use to predict bleeding risk or monitor response to therapy, and they will be normal in some patients with platelet disorders or mild VWD. When they are used in the evaluation of a patient with bleeding symptoms, abnormal results, as with the bleeding time, require specific testing, such as VWF assays and/or platelet aggregation studies. Because all of these “screening” assays may miss patients with mild bleeding disorders, further studies are needed to define their role in hemostasis testing.


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InternalMed_Harrison. For classic platelet aggregometry, various agonists are added to the patient’s platelet-rich plasma and platelet aggregation is measured. Tests of platelet secretion in response to agonists can also be measured. These tests are affected by many factors, including numerous medications, and the association between minor defects in aggregation or secretion in these assays and bleeding risk is not clearly established. Robert I. Handin, MD, contributed this chapter in the 16th edition, and some material from that chapter has been retained here. Enlargement of Lymph nodes Patrick H. Henry, Dan L. Longo This chapter is intended to serve as a guide to the evaluation of patients who present with enlargement of the lymph nodes (lymphadenopathy) or the spleen (splenomegaly). Lymphadenopathy is a rather common clinical finding in primary care settings, whereas palpable splenomegaly is less so.


InternalMed_Harrison

InternalMed_Harrison. Lymphadenopathy may be an incidental finding in patients being examined for various reasons, or it may be a presenting sign or symptom of the patient’s illness. The physician must eventually decide whether the lymphadenopathy is a normal finding or one that requires further study, up to and including biopsy. Soft, flat, submandibular nodes (<1 cm) are often palpable in healthy children and young adults; healthy adults may have palpable inguinal nodes of up to 2 cm, which are considered normal. Further evaluation of these normal nodes is not warranted. In contrast, if the physician believes the node(s) to be abnormal, then pursuit of a more precise diagnosis is needed. APPROACH TO THE PATIENT:


InternalMed_Harrison

InternalMed_Harrison. APPROACH TO THE PATIENT: Lymphadenopathy may be a primary or secondary manifestation of numerous disorders, as shown in Table 79-1. Many of these disorders are infrequent causes of lymphadenopathy. In primary care practice, more than two-thirds of patients with lymphadenopathy have nonspecific causes or upper respiratory illnesses (viral or bacterial), and <1% have a malignancy. In one study, 84% of patients referred for evaluation of lymphadenopathy had a “benign” diagnosis. The remaining 16% had a malignancy (lymphoma or metastatic adenocarcinoma). Of the patients with benign lymphadenopathy, 63% had a nonspecific or reactive etiology (no causative agent found), and the remainder had a specific cause demonstrated, most commonly infectious mononucleosis, toxoplasmosis, or tuberculosis. Thus, the vast majority of patients with lymphadenopathy will have a nonspecific etiology requiring few diagnostic tests.


InternalMed_Harrison

InternalMed_Harrison. The physician will be aided in the pursuit of an explanation for the lymphadenopathy by a careful medical history, physical examination, selected laboratory tests, and perhaps an excisional lymph node biopsy. The medical history should reveal the setting in which lymphadenopathy is occurring. Symptoms such as sore throat, cough, fever, night sweats, fatigue, weight loss, or pain in the nodes should be sought. The patient’s age, sex, occupation, exposure to pets, sexual behavior, and use of drugs such as diphenylhydantoin are other important historic points. For example, children and young adults usually have benign (i.e., nonmalignant) disorders that account for the observed lymphadenopathy such as viral or bacterial upper respiratory infections; infectious mononucleosis; toxoplasmosis; and, in some countries, tuberculosis. In contrast, after age 50, the incidence of malignant disorders increases and that of benign disorders decreases.


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InternalMed_Harrison. The physical examination can provide useful clues such as the extent of lymphadenopathy (localized or generalized), size of nodes, texture, presence or absence of nodal tenderness, signs of inflammation over the node, skin lesions, and splenomegaly. A thorough ear, nose, and throat (ENT) examination is indicated in adult patients CHAPTER 79 Enlargement of Lymph Nodes and Spleen 1. Infectious diseases a. Viral—infectious mononucleosis syndromes (EBV, CMV), infectious hepatitis, herpes simplex, herpesvirus-6, varicella-zoster virus, rubella, measles, adenovirus, HIV, epidemic keratoconjunctivitis, vaccinia, herpesvirus-8 b. Bacterial—streptococci, staphylococci, cat-scratch disease, brucellosis, tularemia, plague, chancroid, melioidosis, glanders, tuberculosis, atypical mycobacterial infection, primary and secondary syphilis, diphtheria, leprosy, Bartonella c. Fungal—histoplasmosis, coccidioidomycosis, paracoccidioidomycosis d. Chlamydial—lymphogranuloma venereum, trachoma e.