Keywords: Chapter 20a, Blood and Lymphoid Tissues I

Activated partial thromboplastin time:

A coagulation test performed by adding a "partial thromboplastin" reagent (contact activating substance such as silica, phospholipid, and calcium) to citrated plasma, and measuring the time to clot (normal 25 - 35 seconds). Measures the integrity of the intrinsic and common coagulation pathways. Typically it is prolonged in hemophilia A, hemophilia B, some cases of von Willebrand disease, disseminated intravascular coagulation, and heparin therapy.
Anemia:
Reduction in total circulating red blood cell mass, diagnosed by a decrease in hemoglobin concentration. Anemic patients have low oxygen-carrying capacity of the blood, with resultant tissue hypoxia. The clinical symptoms are related to the severity of the anemia, and may include pallor, tachycardia, angina, light-headedness and fatigue. Anemia may be due to increased blood loss, decreased red blood cell production (hypoproliferative anemia), or increased red blood cell destruction (hyperproliferative anemia).
Anisocytosis:
Variation in red cell size. Normal red blood cells are 7 to 8 micrometers, and have an average volume of 90 fl, with a normal range of 80-100 fl. RBCs which are smaller than normal are termed microcytic (MCV 100). Macrocytic anemia has many causes, including folate/vitamin B12 deficiency and some drugs (e.g., methotrexate, Zidovudine (AZT), and hydroxyurea).
Aplastic anemia:
Disorder of hemopoietic stem cells, with resultant bone marrow hypocellularity and peripheral blood pancytopenia. Aplastic anemia may be due to radiation, toxins, drugs (e.g, Chloramphenicol), viruses (e.g, Parvovirus) but is often of unknown etiology (idiopathic).
Autoimmune hemolytic anemia:
Anemia due to destruction of RBC's by autoantibodies directed against autologous rbc antigens, with resultant shortened red cell survival. The antibodies are classified as warm (optimum reactivity at 37 oC) or cold (optimum reactivity below 37 oC). These antibodies can also be classified based on the presence or absence of an underlying disorder which is associated with AIHA. If there is no underlying disorder, the anemia is classified as idiopathic or primary. If an associated disorder is present, the anemia is classified as secondary, and includes the presence of underlying lymphoproliferative disorders, SLE, some infections and some drugs, including methyl-dopa and quinidine. Peripheral blood shows polychromasia, spherocytes and a variable anemia; elevation of LDH and mild hyperbilirubinemia may be present.
Bleeding time:
A lab test performed by making a standardized cut on the anterior forearm and measuring the time for blood flow to cease (normal 2 - 8 minutes). Measures the integrity of the blood vessel wall and platelet plug formation mechanism. Typically it is prolonged in diseases affecting the blood vessel wall (vasculitis, amyloidosis, scurvy, hereditary hemorrhagic telangectasia, Ehler-Danlos syndrome), diseases causing thrombocytopenia (chemotherapy, idiopathic thrombocytopenic purpura, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura), drugs or diseases affecting platelet function (aspirin, ibuprofen, renal failure), and von Willebrand disease.
Common coagulation pathway:
The portion of the coagulation cascade that includes factor X, factor V, factor II (prothrombin), and factor I (fibrinogen). Deficiencies of these factors cause a prolonged prothrombin time and partial thromboplastin time. Such deficiencies are typically found in liver disease, vitamin K deficiency, and disseminated intravascular coagulation.
Complete blood count (CBC):
An order to the clinical laboratory for a CBC will include a measurement of several blood parameters, and is attained by analysis of blood by an automated instrument which measures RBC, WBC, platelet count, and red cell indices. In addition, most modern instruments also produce an automated WBC differential count, which is the relative percentages of different WBC's present in the peripheral blood.
Contact activation factors:
Three specific coagulation proteins (factor XII, prekallekrein, high molecualr weight kininogen) that initiate the intrinsic coagulation pathway in vitro when stimulated by highly negatively charged substances (e.g., silica, kaolin). Deficiencies of these proteins are not risk factors for bleeding.
Cytochemistry:
Microscopic study of chemical constituents of cells. In hematopathology, this technique is useful to help determine the cell lineage. For example, myeloperoxidase is present in all stages of granulocytic maturation, non-specific esterase is present in monocytes and '"block" PAS positivity is present in some cases of ALL. By running a panel of cytochemical stains, information can be gained as to the cell lineage of leukemic blasts, which may otherwise appear morphologically undifferentiated.
Disseminated intravascular coagulation:
An acquired disorder caused by overactivation of the coagulation and fibrinolytic system, resulting in microvascular thrombosis, consumption of platelets and coagulation factors, and bleeding. This disorder is typically found in shock, trauma, sepsis, malignancy, retained dead fetus, placental abruption.
Erythroblastosis fetalis (hemolytic disease of the newborn):
Hemolytic disease in the fetus or neonate due to maternal antibodies against fetal RBC's. Hemolytic disease may occur when the maternal antibody is against a fetal antigen of the RH or ABO blood group system. Alloimmunization of RH negative mother by fetal Rh positive cells may occur at delivery, and therefore, it is future pregnancies which are at risk of developing hemolytic disease. The use of RhoGam has greatly reduced the incidence of RH hemolytic disease.
Erythropoiesis:
Synthesis of red blood cells. As erythroid precursors mature, they undergo changes in metabolism, globin synthesis and eventual extrusion of the nucleus. The life span of a RBC is approximately 120 days, so continued renewal is ongoing. Erythropoiesis requires normal supply of vitamins (folate and B12) , nutrients and essential minerals (iron). Dyserythropoiesis is abnormal RBC synthesis, characterized by nuclear abnormalities, including abnormal chromatin pattern, bizarre shapes, and nuclear fragmentation. The control of erythropoiesis is multifactorial, and the bone marrow can respond to a need for increase in RBCs by releasing reticulocytes into blood and developing a sustained increase in red cell synthesis.
Erythropoietin:
A growth factor for red blood cells. It is produced primarily in the kidney, where hypoxia initiates erythropoietin gene activation. High levels of erythropoietin are found in people living at high altitude. Synthetic erythropoietin is used for treatment of anemia of chronic renal failure, with variable success.
Extramedullary hematopoiesis:
Synthesis of blood cells outside the bone marrow, usually seen in the spleen and/or liver. EMH is observed in patients whose bone marrow has been destroyed or replaced by neoplasia, thus decreasing intramedullary hemopoiesis. EMH is most commonly associated with agnogenic myeloid metaplasia.
Extrinsic coagulation pathway:
The portion of the coagulation cascade that includes factor VII and tissue factor. Deficiency of factor VII causes a prolonged prothrombin time.
Ferritin:
A protein-iron complex composed of apoferritin and ferric iron. It is found in all tissue but is most abundant in the bone marrow, liver and spleen. Serum ferritin levels are a reflection of total body iron stores, but must be interpreted with knowledge of ferritin kinetics, since ferritin is an acute phase reactant. Low level of ferritin (5 mg/L).
Fibrin degradation products:
Proteolytic fragments that are produced by the breakdown of fibrin by plasmin. Increased amounts of fibrin degradation products (FDP) are found in hyper-fibrinolytic states such as disseminated intravascular coagulation. Increased FDP can also be found in the urine in such cases.
Fibrinolysis:
The process by which the fibrin clot is removed from the site of vascular injury during the healing process. Damaged endothelial cells release tissue plasminogen activator, which converts plasminogen into plasmin. Plasmin cleaves fibrin into circulating fibrin degradation products.
G-6-PD (glucose-6-phosphate dehydrogenase):
Enzyme of hexose monophate shunt that maintains glutathione in its reduced (active) form. RBCs with a decreased G-6-PD are at increased risk of oxidation when stressed by infection and oxidant drugs. G-6-PD deficiency is an X-linked hereditary disease, most common in Mediterranean descent. These people can develop severe hemolysis after eating fava beans (favism).
Gamma-carboxy-glutamic acid:
A unique amino acid that is produced by post-translational gamma-carboxylation of glutamic acid. Vitamin K is an essential cofactor for this enzymatic carboxylation. This amino acid allows the vitamin K-dependent coagulation factors (factors II, VII, IX, X, protein C, and protein S) to bind to calcium and subsequently bind negatively charged phospholipids on activated platelets.
Granulopoiesis:
Synthesis of granulocytes. Granulopoiesis is under control of multiple growth factors, including GM-CSF (granulocyte-monocyte colony stimulating factor). Maturation from a stem cell to a mature neutrophil proceeds in an orderly sequence, with morphologic stages of cells identifiable as follow: myeloblast-promyelocyte-myelocyte-metamyelocyte-band-segmented neutrophil. As the blast matures, there is maturation from the "left to the right"; an increase in immature precursors is referred to as a "left shift".
Heinz body:
Red cell inclusion identified with special stains, which represent denatured or precipitated hemoglobin. Heinz bodies are observed in RBCs in patients with thalassemia, hemoglobinopathy and other disorders.
Hematopoiesis:
Synthesis of blood cells, including red blood cells, white blood cells, and platelets. The multipotential stem cell theory of hematopoiesis states that a pluripotent hemopoietic stem cell gives rise to committed myeloid and lymphoid stem cells, which can replicate and differentiate into mature leukocytes. The site of hematopoiesis in the adult is the medullary space of the pelvis, ribs, vertebrae, skull, sternum and proximal long bones.
Hemoglobinopathy:
Heterogeneous group of diseases which have an abnormal hemoglobin, some of which have been characterized at the molecular level, such as identification of specific point mutations. Hemoglobin variants were initially named by letters, and later by the place where they were identified. Examples include sickle cell disease and hemoglobin C disease.
Hemophilia A and B:
X-linked recessive bleeding disorders caused by deficiency of either factor VIII (hemophilia A) of factor IX (hemophilia B). Typical clinical features include hemarthrosis, hematomas, ecchymosis, mucosal bleeding (e.g., epistaxis), and intracranial bleeding. Typical laboratory features include a prolonged partial thromboplastin time.
Hypersplenism:
Triad of splenomegaly, bone marrow hyperplasia and peripheral cytopenia (variable degree of anemia, leukopenia and/or thrombocytopenia). Splenomegaly causes inappropriate sequestration of blood cells and platelets within the spleen. As an example, up to 90% of platelets may be sequestered in the spleen, with resultant thrombocytopenia. Hypersplenism can be associated with splenomegaly due to various causes, such as in portal hypertension associated with cirrhosis.
Hypochromasia:
Decrease in hemoglobin concentration per red cell. Morphologically, this is reflected by increased size of the central pallor of the RBC when observed on a peripheral blood smear.
Idiopathic thrombocytopenia purpura (ITTP):
An autoimmune disorder characterized by the production of anti-platelet antibodies. Platelet-antibody complexes are removed by the spleen resulting in thrombocytopenia. Typical clinical features include petechiae, ecchymosis, and mucosal bleeding. Typical laboratory findings include thrombocytopenia and a prolonged bleeding time.
Intrinsic coagulation pathway:
The portion of the coagulation cascade that includes factor XII, prekallekrein, high molecular weight kininogen, factor XI, factor IX, and factor VIII. Deficiencies of these proteins cause prolongation of the partial thromboplastin time.
Intrinsic factor:
A protein synthesized by gastric parietal cells, which is necessary for absorption of vitamin B12. A decrease in intrinsic factor is observed in pernicious anemia.
Iron deficiency anemia:
Iron is utilized in the production of hemoglobin. Iron deficiency is the most common cause of anemia in the world, and is most often due to decreased intake (iron-poor diet), or increased utilization, especially chronic blood loss, intravascular hemolysis, pregnancy and lactation. Peripheral blood smear shows microcytic, hypochromic red cells. Bone marrow shows absent iron stores. Low serum iron and decreased ferritin level are also seen. Clinical symptoms are those of general anemia, however, symptoms may not correlate with severity of anemia. A craving to eat clay (pica) is an unusual, but well-known, symptom.
Jaundice:
Staining of the skin by bile pigment. The serum bilirubin concentration must be above 2 or 3 mg/dl before jaundice is becomes evident.
Koilonychia:
A nail disorder characterized by thin nails of concave shape ("spoon nails"). Observed in association with iron deficiency anemia.
Langerhans cell histiocytosis:
Proliferation of Langerhans type histiocyte, which is a dendritic macrophage normally present in the skin which functions in antigen presentation. Langerhans cells have a folded nucleus with prominent nuclear grooves, and contain a characteristic racquet-shaped ultrastructural inclusion called a Birbeck granule. Langerhans cell histiocytosis has only recently been shown to be a clonal disorder (Cheryl Willman,et al., NEJM, 1994). The clinical course is variable, and three different forms of the disease are recognized. Eosinophilic granuloma is a solitary tumor site, usually involving bone or soft tissue. Hand-Schuller- Christian syndrome is multifocal tumor sites. Letterer-Siwe is the acute disseminated form, occurring in children less than 2 years of age, which involves skin, viscera, and organs of the reticuloendothelial system(spleen, liver, lymph nodes and bone marrow).
Leukemoid reaction:
Marked neutrophilia (increase in WBC's in peripheral blood), usually observed in association with an acute bacterial infection, but also can be due to exercise, emotional stress, use of some drugs such as epinephrine and glucocorticoids and in association with physical stimuli such as burns, cold, pain, surgery, anesthesia and labor. The WBC count may be as high as 50,000, with a left shift of the granulocytic series present. A left shift refers to the presence of immature WBCs in the peripheral blood, and usually is composed predominantly of bands, with lesser numbers of metamyelocytes, myelocytes and occasional promyelocytes.
Megakaryocyte:
Multinucleate cell in the bone marrow which gives rise to platelets, which bud from the megakaryocyte cytoplasm and enter the peripheral blood. Circulating platelets have a life span of 7-10 days.
Megaloblastic maturation:
Abnormal cellular maturation which shows nuclear-cytoplasmic dissynchrony. In folate/B12 deficiency, the nuclear maturation lags behind the cytoplasmic maturation due to impaired DNA synthesis. This results in cells of abnormally large size with an immature chromatin pattern. Peripheral smear shows macrocytes, teardrops, ovalocytes and hypersegmented neutrophils in cases of megaloblastic anemia due to folate/B12 deficiency.
Neutropenia:
Decrease in the number of WBC's in the peripheral blood. Severe neutropenia (absolute neutrophil count
Pancytopenia:
Decrease in the number of all types of blood cells (RBC, WBC, and platelets) in the peripheral blood. The etiology of pancytopenia includes bone marrow failure due to toxins and drugs, aplastic anemia, bone marrow replacement by neoplasm, and myelodysplastic syndrome.
Paroxymal nocturnal hemoglobinuria (PNH):
PNH is an acquired clonal stem cell disorder, with a membrane defect affecting hemopoietic cells present. RBCs undergo complement-mediated lysis intermittently. Clinical findings include pancytopenia, thrombosis and "red morning urine".
Pernicious anemia:
Megaloblastic anemia due to deficiency of vitamin B12 due to decreased synthesis of intrinsic factor due to gastric mucosal atrophy. This occurs in the setting of chronic gastritis, with anti-parietal cell autoantibodies often detectable, supporting the pathogenesis to be due to immune destruction of the gastric mucosa. There are often other autoimmune disorders present in these patients, such as autoimmune thyroid disease. It is unclear whether Helicobacter pylori has any role in the pathogenesis of pernicious anemia.
Platelet adhesion:
The process by which platelets adhere to the basement membrane at sites of vascular injury. von Willebrand factor functions as the glue which sticks the platelet to the basement membrane collagen. Platelet adhesion is defective in von Willebrand disease.
Platelet aggregation:
The process by which platelets stick to each other at the site of vascular injury, forming a platelet plug. Platelets are activated by agonists (thrombin, collagen, ADP) which activates fibrinogen receptors and allow platelets to become cross-linked by fibrinogen. Strong aggregation responses require platelets to synthesize thromboxane A2, which requires the enzyme cyclo-oxygenase. Fibrin degradation products can inhibit platelet aggregation by blocking fibrinogen receptors. Platelet aggregation is abnormal with the use of certain drugs (e.g.,aspirin, ibuprofen), and in disseminated intravascular coagulation and renal failure.
Pluripotential stem cell:
An undifferentiated cell in the bone marrow which is capable of self-replication and of differentiation to committed progenitor cells, which give rise to myeloid and lymphoid stem cells. Of interest, a very small number of stem cells circulate in the peripheral blood, and techniques to collect these cells for future use in bone marrow transplant are in use.
Poikilocytosis:
Variation in red blood cell shape. Certain abnormal red blood cell shapes are associated with specific disorders, and are therefore useful in identifying the underlying disease process. Examples are teardrops, schistocytes, sickle cells, target cells and elliptocytes.
Polychromasia:
Blue-gray coloration of young (anucleate) red cells when observed on a Wright-stained peripheral smear, due to the presence of residual RNA in the cytosol of the immature red cell. Polychromatic cells which are macrocytic suggest that this cell is a reticulocyte. Increased polychromasia occurs when the bone marrow releases immature RBC's into the peripheral blood in response to stress such as a hemolytic crisis.
Polycythemia:
Also termed erythrocytosis, polycythemia is an increase in red cell mass, which may be primary or secondary. An increase in red blood cell count and hematocrit occurs. Symptoms are partially due to increase in blood viscosity, with "ruddy cyanosis", headaches, and tinnitus.
Prothrombin time:
A coagulation test performed by adding a "thromboplastin" reagent (phospholipid, calcium, tissue factor) to citrated plasma, and measuring the time to clot (normal 10-13 seconds). Measures the integrity of the extrinsic and common coagulation pathways. Typically it is prolonged in liver disease, vitamin K deficiency, disseminated intravascular coagulation, and coumarin therapy.
Pure red cell aplasia:
Anemia due to isolated depletion of erythroid precursors in the marrow, and may be acute or chronic. Acute pure red cell aplasia often follows a viral illness, notably Parvovirus B19 infection. Chronic inherited PRCA is termed Diamond-Blackfan anemia, and is responsive to steroids. Chronic acquired PRCA is felt to have an underlying immunologic etiology, and may be seen in association with thymoma.
Red blood cell (RBC, erythrocyte):
A bi-concave disc of 7-8 um, 90 fL volume, and observed on a peripheral blood smear as a round, anucleate cell with a central pallor. A mature red blood cell is without a nucleus or mitochondria, and therefore does not synthesize protein, DNA or RNA. ATP is generated through anaerobic metabolism, primarily by the Emben-Meirhoff pathway. RBCs function to transport oxygen and carbon dioxide.
Red cell distribution width (RDW):
A measure of variation of red blood cell size, i.e., a measure of anisocytosis. RDW is calculated as the coefficient of variation of MCV.
Red cell indices:
Measurement of red cell parameters, to include MCV, MCHC and MCH.
Reticulocyte:
A young (anucleate) red blood cell which contains RNA in the cytosol. The RNA can be visualized after precipitation with a supravital stain such as crystal violet when applied to unfixed RBCs. (Using the standard Wright-Giemsa stain on a peripheral blood smear, the reticulocyte will stain slightly bluish-gray, which is termed polychromasia.) The normal reticulocyte count in the peripheral blood is 1%. The reticulocyte count is a measure of effective erythropoiesis.
Rouleaux:
Red blood cells appear stuck together like stacks of coins when observed on a peripheral smear. This is due to the presence of an abnormal protein, such as a paraprotein. The diagnosis of multiple myeloma or Waldenstrom macroglobulinemia is associated with the presence of rouleaux.
Schistocyte:
Fragmented red blood cell, which may be irregular in shape with pointed ends. Schistocytes are formed when previously normal RBCs pass through abnormal small peripheral vessels present in microangiopathic anemia, due to DIC or TTP (fibrin strands partially obstruct small vessels, and red cells are torn apart as they pass through). Schistocytes are also formed in macroangiopathic anemia, due to passage of RBCs across abnormal heart valves or prosthetic valves.
Sickle cell disease:
Hemoglobinopathy in which sickling of red cells occurs, and chronic hemolytic anemia is present. The abnormal hemoglobin is termed Hemoglobin S, and is due to a substitution of valine for glutamic acid at position 6 of the beta-globin chain, due to a point mutation from adenine to thymine. Patients with sickle cell anemia are homozygous for the hemoglobin SS gene, which is the result of inheriting one gene from each parent, and occurs in one in 650 African-Americans. Sickle cell crises can be aplastic, infarctive or sequestration in pathogenesis, and are often precipitated by infection. Many organs are affected, with notable disease affects as follows: splenic infarcts with eventual autosplenectomy, renal papillary necrosis, osteomyelitis, avascular necrosis of the femoral head, gallstones, and iron overload. Sickle cell trait is the heterozygous form of sickle cell disease, occurring in 8-10% of African Americans.
Spectrin:
A protein in the red cell membrane, spectrin is important in maintaining the red cell biconcave shape and red cell deformity. Hereditary spherocytosis is an inherited hemolytic anemia due to a variable deficiency of spectrin, and is characterized by the formation of spherocytes.
Spherocyte:
Round, dense staining red blood cell without central pallor. Spherocytes have a decrease in surface to volume ratio due to loss of red blood cell membrane, and have an increase hemoglobin concentration (increase MCHC). Spherocytes are poorly deformable, and are prematurely removed from circulation by the spleen.
Target cell:
Abnormal red blood cell which has an excess amount of membrane resulting in hemoglobin accumulation in the center of the cell. Target cells have an area of central staining in the center of the cell, and look like a "bull's eye". Target cells are observed in liver disease, asplenia, hypochromic anemia, and hemoglobinopathies (especially hgb C), as well as other diseases.
Teardrop RBC:
Abnormal red blood cell which is shaped like a teardrop. Teardrop cells are a nonspecific finding, but are prominent in megaloblastic anemia and myeloproliferative disorders.
Thalassemia:
Thalassemia is an inherited group of disorders which have a reduced rate of synthesis of the globin chain of hemoglobin. There is a variable degree of anemia, depending on the specific disorder. Thalassemia is classified according to which globin chain is affected: alpha-thalassemia or beta-thalassemia.
Thrombocytopenia:
Decrease in the number of platelets in the peripheral blood below normal (normal range: 150-400/ul). Platelet counts of <10,000 are generally considered to carry a risk of spontaneous hemorrhage.
Thrombotic thrombocytopenic purpura (TTP):
An acquired syndrome caused by excessive platelet aggregation and thrombosis within the microvascualture. Typical clinical features include petechiae, ecchymosis, mucosal bleeding, neurological symptoms, and fever. Typical laboratory features include thrombocytopenia, anemia, prolonged bleeding time, elevated creatinine and BUN, and red cell fragments (schistocytes) on the blood smear. The classic pentad is thrombocytopenia, microangiopathic hemolytic anemia, neurological symptoms, fever, and renal failure.
Toxic granulation:
Prominent staining of granules in neutrophils when observed in peripheral smears. Observed in toxic states, severe infections, burns and other disorders.
Transferrin:
Serum protein which transports iron. Synthesized in the liver.
Vitamin K:
An essential fat soluble vitamin that is required for the post-translational synthesis of gamma-carboxy-glutamic acid, which occurs on the vitamin K dependent coagulation factors. Approximately 50% of the daily vitamin K requirement is supplied by the intestinal bacterial flora, and the other 50% is from the diet. Vitamin K deficiency typically causes a prolonged prothrombin time, and is caused by broad spectrum antibiotics, malnutrition, and malabsorption. It is diagnosed by correction of the prothrombin time after administration of vitamin K.
Von Willebrand disease:
An autosomally inherited (usually dominant) bleeding disorder due to deficiency or abnormality of von Willebrand factor. The result is a defect in platelet adhesion. It occurs in three major forms including Type I (partial quantitative deficiency), Type II (qualitative deficiency), and Type III (complete deficiency, recessive inheritance). von Willebrand factor also prolongs the circulating half-life of factor VIII, thus some cases have low factor VIII levels. Typical clinical features include: petechiae, ecchymosis, mucosal hemorrhage, and in some cases hemarthrosis and hematomas. Typical laboratory findings include a prolonged bleeding time, low von Willebrand factor functional activity, and in some cases a prolonged partial thromboplastin time.