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Disease Information and Courses from MediaLab, Inc.

These are the MediaLab courses that cover Disease and links to relevant pages within the course.

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Alpha Thalassemia
Defining thalassemia

Thalassemia is best thought of as a group of disorders rather than a single disease. They demonstrate a hemoglobin synthesis disorder in which there exists a defect in the rate of production of one or more of the globin chains. This defect results from either a heterozygous or homozygous deletion or inactivation of a globin chain gene.

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Alpha thalassemia states

Heterozygous states of alpha thalassemia express themselves as silent carrier (one loci deleted) thalassemia minor (two loci deleted) hemoglobin H disease (three loci deleted) The homozygous state (all four loci deleted), alpha thalassemia major, is incompatible with life.

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Alpha Thalassemia Intermedia

Alpha thalassemia intermedia (Hemoglobin H Disease) is a result from a deletion of three out of four alpha chain loci. Infants born with alpha thalassemia intermedia appear normal at birth but often develop anemia and splenomegaly by the end of their first year. Hepatomegaly is not a common finding and there may be some association with mental retardation. Due to the hemolytic nature of this anemia, there may be an increase in respiratory infections, leg ulcers and gallstones. Skeletal changes are not commonly seen in hemoglobin H disease. Every ethnic group can have occurrences of hemoglobin H disease; but it is most often seen in Southeast Asian, the Middle East and the Mediterranean islands. Development and life expectancy are usually normal, but some may require splenectomy and transfusion therapy.

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Alpha thalassemia minor

Deletion of two out of four alpha chain loci results in alpha thalassemia minor. The deletions may be homozygous (two on the same chromosome) or heterozygous (one from each of two chromosomes). Alpha thalassemia minor does not produce a clinical disease but may be discovered upon routine testing. Both the homozygous and heterozygous form are common in Southeast Asians. The homozygous form is also seen in American Blacks.

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Silent Carrier

The Silent Carrier form of alpha thalassemia results from one alpha chain loci deletion. Individuals who are silent carriers show no clinical disease and demonstrate normal results during routine laboratory testing. This form of alpha thalassemia is usually discovered upon family studies.

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Hemoglobin H disease is found in which ethnic group?View Page
Match alpha thalassemia variants with their genotypic notation.View Page
References

Burtis, CA. & Ashwood, ER. Tietz Textbook of Clinical Chemistry 2nd ed. W. B. Saunders. 1994.Harmening, DM. Clinical Hematology and Fundamentals of Hemostatis 5th ed., F.A. Davis, 2008Lotspeich-Steininger, Stiene-Martin and Koepke, Clinical Hematology Principles, Procedures, Correlations, Lippincott 1992McKenzie, SB., Textbook of Hematology 2nd ed., Williams and Wilkins 1996.Miale, JB, Laboratory Medicine Hematology 6th ed., Mosby 1982.Nouwens, J and Spahn, M. Hemoglobin H Disease: A self-instructional unit 3rd ed., Educational Materials for Health Professionals, Inc. 1991.Doig, K. Rodak's Diagnostic Hematology 3rd ed. W.B.Sunders Co., 2007.

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Summary

The normal RBC count (4.84 x 1012/L) in this case, together with the decreased hemoglobin (8.4 g/dL) and MCV (59 fl) is an indicator of ineffective erythropoeisis that often points to thalassemia.The RBC morphology shows slight hypochromic microcytosis with codocytes, schizocytes, and basophilic stippling. Schizocytes form by several mechanisms, one being the removal of rbc inclusions.This patient's elevated bilirubin correlates with her presentation of sclera icterus; and her splenomegaly is consistent with increased rbc destruction.The Hb electrophoresis demonstrated a normal pattern, initially, but the unstable Hemoglobin H was revealed upon repeat electrophoresis with reduced incubation time. Hemoglobin H is the result of beta globin chain tetramer formation due to the insufficient supply of alpha globin chains in alpha thalassemia intermedia.People with Hemoglogin H disease (alpha thalassemia intermedia) usually have a normal life expectancy without treatment. However, hemolysis may lead to moderate anemia that may be treated with splenectomy.

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Serum Iron

The serum iron for normal adults is about 50-150ug/dl.The iron binding capacity is normally 250-400ug/dl.The transferrin saturation is usually between 20-50%Persons with alpha thalassemia, especially Hb H disease, may have a slightly increased level of serum iron with a slightly decreased iron binding capacity. The percent of transferrin saturation is usually increased.An iron stain of bone marrow smears usually demonstrate increased levels of hemosiderin. Sideroblasts are present along with an occasional ringed sideroblast.

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Cerebrospinal Fluid
Clot/Pellicle

Clot formation is always abnormal and is often due to increased levels of protein, especially fibrinogen. When the protein level is 1000 mg/dL, clot formation will most likely occur but clots may also form at lower levels of protein. Some clots may be very fine and appear as a thin membrane or "scum" on the surface of the CSF specimen. This type of clot is referred to as a pellicle. Pellicles are composed of fibrinogen and white blood cells. The type of clot formed may give some specific information about the disease state. Some examples are provided in the following table: Example of ConditionType of Clotbacterial meningitispellicle forms in a short time; large clot formation followsTB meningitisweb-like clot (pellicle) after 12-24 hours (enhanced by refrigeration)paresis (type of neurosyphilis)incomplete clotblockage of CSF circulationcompletely clotted due to protein

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Chemical Screening of Urine by Reagent Strip
Match the following reagent strip tests to the disease or disorder that would most likely cause a positive test result.View Page
Clinical Significance

Urinary urobilinogen may be increased in the presence of a hemolytic process such as hemolytic anemia. It may also be increased with infectious hepatitis, or with cirrhosis. Comparing the urinary bilirubin result with the urobilinogen result may assist in distinguishing between red cell hemolysis, hepatic disease, and biliary obstruction. Urobilinogen is increased in hemolytic disease and urine bilirubin is negative. Urobilinogen is increased in hepatic disease, and urine bilirubin may be positive or negative. Urobilinogen is low with biliary obstruction, and urine bilirubin is positive. Reagent strips methods however, cannot distinguish normal urobilinogen from absent urobilinogen, as might be seen in complete biliary obstruction.

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CLIA Blood Banking Review
Which BBP is not covered in the OSHA Bloodborne Pathogen Standard?View Page
Which of the following antibodies is the most common cause of hemolytic disease of the newborn:View Page
The use of the direct antiglobulin test is indicated in all the following except:View Page
Which of the following conditions is most frequently associated with anti-I:View Page
Which of the following set of conditions would preclude hemolytic disease of the newborn as a result of ABO incompatibility:View Page
Which one of the following statements about directed donations is true:View Page
To detect the presence of blocking antibodies fixed on the red cells of a newborn infant:View Page
Gamma irradiation of cellular blood components is required in which of the following situations:View Page

CLIA Chemistry / Urinalysis Review
Identify the urine sediment elements shown by the arrow:View Page
Identify the urine sediment elements present in this illustration:View Page
Which one of the following crystals is not found in normal urine:View Page
Identify the urine sediment element indicated by the arrow in the illustration:View Page
What type of cast is shown in the illustration:View Page
Identify the urine sediment elements present in this illustration:View Page
Match Increased Analyte with the associated disease:View Page
Which one of the following statements about TSH is true:View Page
Elevation in CSF total protein may be seen in all of the following conditions except:View Page
In a normal CSF the protein concentration as compared to that in the serum is generally:View Page
A spectrophotometric scan of amniotic fluid may be valuable in the determination of which of the following conditions:View Page
Increases in the MB electrophoretic fraction of CK is associated with:View Page
Increases in LD fractions 4 and 5 are indicative of:View Page
The following LDH Isoenzyme pattern would be seen in:View Page
The following LDH Isoenzyme pattern would be seen in:View Page
The following LDH Isoenzyme pattern would be seen in:View Page
The following CK isoenzyme pattern would be seen in:View Page
This SPE scan most likely represents which of the following disease states:View Page
This serum protein electrophoresis scan most likely represents which condition?View Page
Which one of the following are not associated with a polyclonal (broadbased) increase in gamma globulins?View Page
Which of the following conditions is associated with elevated serum uric acid levels:View Page
Which of the following conditions would be suggested by a marked rise in alkaline phosphatase, jaundice, and a moderate rise in ALT:View Page
Which of the following cells when found upon microscopic examination of the urine would be most indicative of kidney disease:View Page

CLIA General Laboratory Review
Which of the following best defines "sensitivity":View Page
Which of the following best defines "specificity":View Page
Which one of the following does not directly regulate clinical laboratories:View Page
Which of the following cells when found upon microscopic examination of the urine would be most indicative of kidney disease:View Page
C-reactive protein:View Page
Which of the following immunoglobulin classes is chiefly responsible for the degranulation of mast cells and basophils:View Page

CLIA Hematology / Hemostasis Review
The abnormal cells seen in this illustration are indicative of:View Page
The abnormal RBCs seen in this illustration are indicative of:View Page
The abnormal RBC shape seen in this illustration is:View Page
The RBCs indicated by the arrows in this illustration are indicative of:View Page
The predominant cells seen in this CSF are suggestive of:View Page
Which two of the following are associated with macrocytic anemia?View Page
Eosinophilia is commonly found in which of the following disorder(s):View Page
Which of the following morphologic changes is most characteristic of sickle cell disease?View Page
Hypersegmentation of granulocytes is most commonly associated with:View Page
Match the disease conditions on the left with appropriate red cell appearances on the right:View Page
Hemophilia A, hemophilia B, and Von Willebrand's disease together constitute approximately what percentage of all hereditary coagulation disorders:View Page
Hemophilia B or Christmas disease is the result of a hereditary deficiency in which coagulation factor:View Page

CLIA Microbiology / Serology Review
Koch's postulates include all of the following except:View Page
Which of the following specimens is the most sensitive for detecting active CMV infection:View Page
Match organism on right to common name on the left.View Page
Match the hepatitis B test with the appropriate disease phaseView Page
Match the virus with its associated disease:View Page
Match the virus with its disease:View Page
Match the virus with its disease:View Page

Confirmatory and Secondary Urinalysis Screening Tests
Diseases Associated with Proteinuria

Normal urine contains very little protein, usually less than 10mg/dL, and the major serum protein that is found in normal urine is albumin. The presence of an increased amount of protein in the urine (proteinuria) can be an indicator of renal disease. The two mechanisms which can lead to proteinuria are glomerular damage or a defect in the reabsorption process of the tubules in the nephron. The concentration of protein in the urine is not necessarily indicative of the severity of renal disease.

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Diseases Associated with Proteinuria

Severe proteinuria (greater than 3.5 g/day) is characteristically seen in patients with glomerulonephritis, lupus nephritis, lipoid nephrosis, and severe venous congestion of the kidney. Moderate proteinuria (0.5-3.5g/day) is seen in nephrosclerosis, multiple myeloma, diabetes nephropathy, malignant hypertension, and pyelonephritis with hypertension. Mild proteinuria (less than 0.5 g/day) may be seen with polycystic kidneys, chronic pyelonephritis, benign orthostatic proteinuria, and some renal tubular diseases. Transient proteinuria can also be due to physiologic conditions such as stress, exercise, cold exposure, and fever, in the absence of renal disease.

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Microalbumin Test

The presence of low levels of albumin (microalbumin) in the urine is an important finding in an individual with either type 1 or type 2 diabetes. The development of clinical nephropathy leads to reduced glomerular filtration and eventually may lead to renal failure. For this reason, early detection of microalbumin is important in order to avert renal complications in a diabetic patient. The presence of microalbuminuria has also been associated with an increased risk for cardiovascular disease. Reagent strips that are used for routine urinalysis cannot detect low levels of albumin excretion (1 to 2 mg/dL). Special reagent strips that are sensitive for these low levels of albumin are useful for periodic monitoring of patients with diabetes, hypertension, or peripheral vascular disease.

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Causes for Bilirubinuria

A screening test for bilirubin in the urine is included in most urine dipsticks and may be present when liver disease or damage is suspected. Bilirubinuria can be detected before other clinical symptoms such as jaundice are present or recognizable. The detection of small quantities is very important in early diagnosis of obstructive and hepatic jaundice. This test is also useful in the differential diagnosis of obstructive jaundice (positive for bilirubinuria) vs. hemolytic jaundice (negative for bilirubinuria).

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The Presence of Glucose in the Urine

The presence of significant amounts of glucose in the urine is called glycosuria (or glucosuria). The amount of glucose present in urine is dependent upon the blood glucose level, the rate of glomerular filtration, and the degree of tubular reabsorption of the sugar. Usually glucose will not be present in the urine until the blood level exceeds 160-189 mg/dl, which is the normal renal threshold for glucose. The main reason for glycosuria is an elevated blood glucose level, called hyperglycemia. Diabetes mellitus is the most common disease that causes hyperglycemia. However, stress, obesity, brain injury, myocardial infarction, hyperthyroidism, pregnancy, and a lowered renal threshold due to kidney damage can all cause glycosuria.

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Current Topics in Clinical Microbiology
Review 2

Smith KR, Fisher HC III, Hook, EW III: Prevalence of fluorescent monoclonal antibody-nonreactive Neisseria gonorrhoeae in five North American sexually transmitted disease clinics.J Clin Microbiol 34:1551-1552, 1996We compared a direct fluorescent monoclonal antibody (DFA) test with alternative enzymatic and fermention tests for identifying presumptive gonococcal isolates in a systematic sample from patients attending five sexually transmitted disease clinics in five cities.Fourteen (2.5%) of 556 isolates from three clinics were nonreactive with the DFA confirmatory reagent and reactive by both the Quad-Ferm and Rapid NH tests. The prevalence of DFA-nonreactive Neisseria gonorrhoeae isolates varies geographically and is independent of local methods for the identification of possible gonococci.On the basis of our findings, we recommend that for use in medicolegal and other instances in which a diagnosis of gonorrhea has the potential to have far-reaching effects, it is appropriate to test DFA reagent-nonreactive, oxidase-positive, gram-negative diplococci by alternative methods of gonococcal confirmation.Although the prevalence of such isolates could change, the fluorescent monoclonal antibody confirmation reagents remain useful for many clinical situations. Their ease of use and ready applicability for screening large numbers of isolates make them useful for many laboratories.

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Acute gonorrhea is the most common cause of septic arthritis in patients under 30 years of age.View Page
Clinical History

A 67 year-old man entered the hospital with cough, right lower chest pain accentuated by deep breathing, and fever. He had a history of chronic obstructive pulmonary disease secondary to a long history of smoking. The temperature on admission was 39.2C, and auscultation of the chest revealed rales in the right lower lung field. The admission white blood count was 13,500/ml with 80% segmented neutrophils and a shift to the left. A blood culture was obtained.

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Clinical isolates of Escherichia coli and Klebsiella pneumoniae may possess ESBL activity. Therefore, clinical laboratories should be screening all clinically significant isolates of these two species.View Page
Review 2

Suppola JP. Kuikka A. Vaara M. Valtonen VV. Comparison of risk factors and outcome in patients with Enterococcus faecalis vs Enterococcus faecium bacteremia. Scandinavian Journal of Infectious Diseases. 30(2):153-7, 1998.The purpose of our study was to determine retrospectively the risk factors for the acquisition of Enterococcus faecalis vs E. faecium bacteremia, as well as the clinical outcomes of these patients.62 patients with Enterococcus faecalis bacteremia were compared to 31 patients with E. faecium bacteremia. Haematologic malignancies, neutropenia, high-risk source and previous use of aminoglycosides, carbapenems, cephalosporins and clindamycin were significantly associated with E. faecium bacteremia. Instead, urinary catheterization was found to be related to Enterococcus faecalis bacteremia. The mortality rates within 7 d and 30 d were 13% and 27%, respectively, in patients with E. faecalis bacteremia and 6% and 29%, respectively, in patients with E. faecium bacteremia.There was no difference in mortality between E. faecalis and E. faecium bacteremia, nor was there a difference in seriousness of disease at the time of bacteremia. In the subgroups of patients with monomicrobial or clinically significant E. faecalis vs E. faecium bacteremia, the mortality rates were similar to the results of all subjects.Our results do not support the theory that E. faecium would be a more virulent organism than E. faecalis

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Each of the following statements is true concerning Clostridium septicum infections except:View Page
Factors predisposing to infections with methicillin resistant Staphylococcus aureus (MRSA) include:View Page
Thus, in follow-up to the previous discussion, the reaction shown in the photograph establishes the identification of a group A, beta hemolytic streptococcus.View Page
Review 1

Spencer RC.: Invasive streptococcEuropean Journal of Clinical Microbiology & Infectious Diseases. 14 Suppl. 1:S26-32, 1995.Before the introduction of antibiotics, serious infections caused by Streptococcus pyogenes (Lancefield Group A streptococci) were common. Before World War II, this bacterium was responsible for as many as 50% of postpartum deaths and was the major cause of death in patients with burns. Also common were the sequelae of streptococcal infections-rheumatic fever and post-streptococcal glomerulonephritis.With the use of penicillin, however, Streptococcus pyogenes was believed to be virtually eliminated as a pathogen. The organism was consigned to the history books, but not for long.In the mid-1980s, focal resurgences of rheumatic fever began to be reported from different areas in the USA, such as Salt Lake City, Utah. In such communities, where increases in cases of rheumatic fever had been reported, the serotypes M-1, 3, 5, 6 and 18 were isolated which, on culture, produced characteristic mucoid colonies. At the same time, reports of increases in invasive streptococcal disease began to surface in both the USA and Europe.Two syndromes were described; invasive streptococcal infection, occurring in previously healthy children and adults, commonly associated with septicaemia resulting from a deep focus of infection such as bone or lung; and streptococcal toxic shock syndrome, involving a cutaneous focus, accompanied by necrotizing or bullous soft tissue changes. Septicaemia is rare in streptococcal toxic shock syndrome, but the most characteristic feature is one of rapidly progressing multi-organ failure. A high proportion of the strains of Streptococcus pyogenes associated with this condition are serotype M-1, and fatality rates approaching 50% have been reported.

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Review 2

Low JC. Donachie W.: A review of Listeria monocytogenes and listeriosis. Veterinary Journal. 153:9-29, 1997Following the initial isolation and description in 1926, Listeria monocytogenes has been shown to be of world-wide prevalence and is associated with serious disease in a wide variety of animals, including man.Our knowledge of this bacterial pathogen and the various forms of listeriosis that it causes has until recently been extremely limited, but recent advances in taxonomy, isolation methods, bacterial typing, molecular biology and cell biology have extended our knowledge. It is an exquisitely adaptable environmental bacterium capable of existing both as an animal pathogen and plant saprophyte with a powerful array of regulated virulence factors.Most cases of listeriosis arise from the ingestion of contaminated food and in the UK the disease is particularly common in ruminants fed on silage.Although a number of forms of listeriosis are easily recognized, such as encephalitis, abortion and septicaemia, the epidemiological aspects and pathogenesis of infection in ruminants remain poorly understood. The invasion of peripheral nerve cells and rapid entry into the brain is postulated as a unique characteristic of its virulence, but relevant and practical disease models are still required to investigate this phenomenon.

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Review 2

Low JC. Donachie W.: A review of Listeria monocytogenes and listeriosis. Veterinary Journal. 153:9-29, 1997Following the initial isolation and description in 1926, Listeria monocytogenes has been shown to be of world-wide prevalence and is associated with serious disease in a wide variety of animals, including man.Our knowledge of this bacterial pathogen and the various forms of listeriosis that it causes has until recently been extremely limited, but recent advances in taxonomy, isolation methods, bacterial typing, molecular biology and cell biology have extended our knowledge. It is an exquisitely adaptable environmental bacterium capable of existing both as an animal pathogen and plant saprophyte with a powerful array of regulated virulence factors.Most cases of listeriosis arise from the ingestion of contaminated food and in the UK the disease is particularly common in ruminants fed on silage.Although a number of forms of listeriosis are easily recognized, such as encephalitis, abortion and septicaemia, the epidemiological aspects and pathogenesis of infection in ruminants remain poorly understood. The invasion of peripheral nerve cells and rapid entry into the brain is postulated as a unique characteristic of its virulence, but relevant and practical disease models are still required to investigate this phenomenon.

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Erythrocyte Inclusions - Wright Stained Smears
The presence of erythrocyte inclusions may indicate the presence of disease.View Page

Fundamentals of Hemostasis
The product administered to treat Von Willebrands Disease is?View Page
An Introduction to the Fundamentals of Coagulation

As we will discover later in the course, there are other variables which impact the effectiveness of hemostatic mechanisms as well, such as acquired disease states, and inborn metabolic pathway defects. For now, however, our focus will be on the mechanisms, processes, and components which work together to achieve coagulation, or the cessation of blood flow from a damaged vessel. Note: The terms coagulation and hemostasis are used interchangeably throughout this course.

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Tests of Hemostatic Function - Platelet Function Assay

A platelet function assay (PFA) is a screening test for the evaluation of platelets/primary hemostasis. Common clinical applications include the following: Preoperative evaluation of platelet function Determining the presence of drug-induced platelet dysfunction Determining platelet functionality in high-risk pregnancy Evaluation of patients with suspected inherited or acquired platelet disorders such as von Willebrand disease Evaluation of a bleeding patientA PFA instrument is able to differentiate between drug-induced platelet defects and other platelet defects. PFA tests are superior to the bleeding time test. The bleeding time is often not reproducible and, in spite of attempts at standardization, remains prone to variations in test results between persons performing the test. It is also relatively insensitive to platelet function. The bleeding time cannot be used to identify patients who may have recently ingested aspirin or non-steroidal anti-inflammatory drugs or patients who may have a platelet defect attributable to these drugs. The bleeding time is used to assess platelet function, but may be affected by platelet quantity. NOTE: Aspirin, and some other drugs, may falsely prolong bleeding times. Patients must be asked about aspirin use, and be aspirin free for 7-10 days prior to testing, for valid results.

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Coagulation Disorders

This course began with a discussion on homeostasis, the body’s desire to maintain a status of physiological equilibrium. Our inborn system of chemical checks and balances, activators and inhibitors, can be disrupted by numerous factors, two of the more common being acquired disease states and disorders passed on to offspring via inheritance. In regard to coagulation, both disease status and genetics can adversely affect the functionality of many hemostatic processes. Impaired hemostatic mechanisms, be it acquired in cases of disease or inherent, may result in situations of either hemorrhage or thrombosis. A situation of hemorrhage, or bleeding external to the vasculature, most often stems from physical vessel trauma, but may also arise from a wide variety of disease states. Thrombosis does not require physical trauma, and is the activation of hemostatic processes at an inappropriate time in an inappropriate place, and may arise from a number of inherited or acquired disease states. The following pages are intended to serve as an introduction to some of the more commonly encountered coagulation disorders.

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Coagulation Disorders - Inherited

Von Willebrands Disease is a platelet disorder. This disorder is characterized by a functional defect in Von Willebrands factor (vWF) itself. This disease often clinically manifests with a concurrent deficiency of factor VIII, but will present with a normal platelet count. As far as genetics and inheritance, both men and women are affected equally. Von Willebrands factor is essential for platelet binding, therefore, a defect in vWF causes impaired platelet adhesion and aggregation. The treatment of Von Willebrands Disease involves the administration cryoprecipitate, as it is rich in vWF.

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Coagulation Disorders - Acquired

Disseminated Intravascular Coagulation (DIC) is best described as a disorder of consumption, because clotting factors are depleted from the blood. Basically, clotting occurs randomly throughout the body, as opposed to just in the localized areas where vascular damage has occurred, consuming clotting factors and other components such as platelets in the process. Symptoms may range from a mild bleed, to severe, profuse bleeding, primarily dependant upon the availability of clotting factors. As more and more coagulation factors and components are consumed, the disorder progresses and symptoms worsen. Most heavily impacted are the levels of factors I, V, and VIII as well as the number of available platelets. Clinically, DIC is detected via an elevated (positive) FDP, positive D-dimer test, a prolonged PT and APTT, plus the manifestation of hemorrhagic episodes. DIC is diagnosed as two primary types, acute and chronic. Acute DIC manifests in a few hours or a few days, has a high mortality rate, and is seen in infections, obstetric complications, liver disease, and tissue injury. Chronic DIC is a secondary condition to some other disease state. Once you treat the primary disease, this type of DIC will go away. Treatment is often factor replacement therapy through the use of fresh frozen plasma and/or cryoprecipitate.

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Coagulation Disorders and Liver Disease

The liver is the site of production for the vast majority of our clotting factors. Therefore, impaired liver function could adversely affect these hemostatic proteins. Some early indicators of a potential liver problem include: An increase in factor VIII. It is not produced in the liver and will be present in elevated numbers as the body attempts to compensate. The PT is sensitive to liver function, so an unexpected, prolonged PT should be evaluated. A lack of fibrinogen is often indicative of severe liver disease. It is difficult to treat liver disease, so therapy typically centers around replacing the missing factors by way of administration of fresh frozen plasma.

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Which of the following statements regarding coagulation disorders is incorrect?View Page

Fundamentals of Molecular Diagnostics
Targets

Molecular based clinical diagnostic test methodologies differ according to the target of interest. For example, patients suspected of having different diseases will require the identification of different targets. These targets might be found in different cells of the body and may therefore require different specimens to provide the answers. Patient A suspected of having Disease 1-requires the identification of a target of missequenced DNA- might require specimen of whole blood Patient B suspected of having Disease 2-requires identification of a target of antibody production-methodology might require specimen of serum Using this specific approach of disease diagnosis based on unique target identification, tests can provide answers that are more rapid sensitive specific

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Overview

To aid in the diagnosis of disease or identification of infectious agents, clinical laboratorians use a variety of methodologies to assist them. Knowing what to look for, or the right question to ask, is vital to obtaining the correct answer. Many diseases and agents have unique causes. The cause of the condition then becomes the "target" to be identified and perhaps even quantified. For example: If Patient A is suspected of having disease X, and disease X requires treatment, it is necessary to prove that disease X exists within patient A. We must know something about what causes disease X; is disease X an antigen, a bacteria, a viral particle, a missequenced piece of DNA?Once the target of interest (in this case Disease X) has been identified, the clinical laboratorian can choose the methodology most appropriate to answering the question, "Does disease X exist within Patient A?"

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Human Genome

Much research has been conducted to identify the alphabet of the human cellular language otherwise known as the human genome. This identification or roadmap of the human genetic material has opened the door to the mainstreaming of molecular diagnostics within the clinical laboratory setting.While the mapping of the human genome project is complete, many times it is not necessary to be able to identify the entire sequence; rather, we can use the specific portion of the code that is unique to the disease or condition in question. These short portions of the genetic molecular sequence or oligonucleotides, can then be used as probes to seek out and detect or amplify the target sequence.

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When Nucleic Acids Get Altered

The reason to chose a particular molecular method can be influenced by disease detection, monitoring or therapy in certain patient populations. Molecular methodologies can be used to identify alterations or variations or changes in DNA sequencing that can cause disease. Sequence alterations that are known to cause disease are termed mutations. These changes or mutations can be applied to areas of the clinical lab such as infectious disease, paternity, genetic testing, and pharmacogenetics. Some of the more common alterations are:Deletion: a missing nucleotide or other portion of DNA sequence Insertion: an extra DNA nucleotide or other portion of DNA sequence Missense: a nucleotide or sequence substitution that codes for a different amino acidNonsense: a nucleotide substitution that ends in early termination of the protein manufacturing process; usually due to a stop codon.The most common alteration is a single base change or single nucleotide polymorphism (SNP)

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HIPAA Privacy and Security Regulations
Case Study: Authorization You are working in a physicians office. The doctor orders laboratory and other diagnostic tests on a patient with suspected Alzheimer's disease. He then asks you to give the patient's name and contact information to the local Alzheimer support group without getting permission from the patient or his legal guardian. Does the doctor need authorization from the patient or his legal guardian to do this?View Page

HIV Safety for Florida
A person commits a misdemeanor of the first degree by:View Page
Risk factors associated with increased HIV infection

The risk factors that increase the risk of an exposure leading to HIV infection are: larger quantity of blood from source person, and blood from source person in terminal stage of HIV disease.

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Confidentiality

A person who receives the results of an HIV test shall maintain the confidentiality of the information received and of the person tested.A person who violates the confidentiality provisions commits a misdemeanor of the first degree.A person who obtains information that identifies an individual who has a sexually transmissible disease and maliciously, or for monetary gain, disseminates this information commits a felony of the third degree.

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Introduction to Bioterrorism
Category B

Agents in Category B are considered the second highest priority agents and are included in this group because they: Are moderately easy to disseminate Cause moderate morbidity and low mortality Require specific enhancements of Centers for Disease Control and Prevention’s (CDC) diagnostic capacity and enhanced disease surveillance

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Agent: Pneumonic plague (Bacterium)

Most likely means of dissemination: AerosolPrimary route of entry: InhalationGeneral signs and symptoms: High fever, chills, headache, coughing up of blood (hemoptysis), and toxemia, progressing rapidly to difficulty in breathing (dyspnea), and bluish discoloration of the skin and mucous membranes (cyanosis).There is another form of the disease called “bubonic plague”. While it is caused by the same organism, it is not transmissible through human contact. Pneumonic plague is transmissible through human contact.

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Agent: Tularemia (bacterium)

Most likely means of dissemination: Solid or aerosolPrimary route of entry: Inhalation, absorption, or ingestionGeneral signs and symptoms: Sudden fever, chills, headaches, muscle aches, joint pain, dry cough, progressive weakness, and pneumonia.The disease is not transmissible through human contact.  When used as a WMD, infection would be acquired by handling infected material, eating or drinking contaminated food or water or by breathing in the bacterium.

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Laboratory Response

The broad base of clinical laboratories in this country is an essential component of our nation’s public health and healthcare system and is an essential link in addressing biological and chemical terrorism. In 1999 the Centers for Disease Control and Prevention (CDC) initiated the concept of a Laboratory Response Network (LRN).  The LRN is a network of local, state, federal, and military laboratories across the United States and internationally which work together in an integrated and coordinated way for a rapid response to public health emergencies. The LRN concept of operations is based on a system of safety and proficiency.

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What if: Biological Attack

Biological attacks involve bacteria, viruses or natural toxins. The effects of toxins can be immediate but for bacteria and viruses the effects may not be apparent for weeks. A bio-terrorist may attack by infecting animals, contaminating food and water, spraying bacteria or viruses into the air. In infections such as smallpox and plague, once a few individuals are infected they can further spread the disease from person to person. An attack could also come from through a building’s ventilation system, the mail, or even through exposure to an infected terrorist seeking to spread disease during an infectious stage.

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In Case of a Biological Attack

Listen to the radio for instructions from authorities on whether to evacuate or stay put. If told to stay inside, seek shelter in an internal room or a room with as few doors and windows as possible. Turn off all ventilation and as best as possible seal all openings in windows and doors. Continue to monitor the radio. Some biological attacks may be more immediately apparent than others. Monitor your radio, television, or medical alert for instructions from authorities regarding disease symptoms and how and where to seek medical attention. If you do come in contact with a visible, potentially infectious substance, you should remove and bag your clothes and personal items, wash yourself with warm soapy water immediately, and seek medical assistance.

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Additional Information

Below is additional information that you can obtain off the internet to help you “Be Prepared”.www.ready.gov: This site has emergency preparedness guidance from the United States Dept. of Homeland Security. It also has an excellent training program for kids.www.redcross.org: Preparedness information from the International Red Cross.www.neighborhoodpreparedness.info: From the Los Angeles Fire Department. www.americaswaterwaywatch.org: Prepared by the United States Coast Guard. Discusses what to look for as far as suspicious activities.www.bt.cdc.gov: Discusses agents, disease, and other threats.www.ojp.usdoj.gov: The Citizens’ Preparedness Guide provides suggestions for preparedness in homes, neighborhoods, and schools.www.fema.gov/areyouready: FEMA’s most comprehensive source on individual, family, and  community preparedness.

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Introduction to Bone Marrow
Collection of Bone Marrow Biopsy

A bone marrow biopsy involves removing a small portion of the bone marrow without destroying the architecture of the marrow. This type of biopsy is necessary when the marrow cannot be aspirated (dry tap) due to a disease process, and also provides additional information complementary to that derived from the aspirate: biopsy specimens are more accurate for assessing cellularity, and infiltrative processes, such as metastatic carcinoma, fibrosis, amyloid, and lymphoma. A biopsy specimen is processed as follows: touch preparation tissue section

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Gaucher Cell

A Gaucher cell is a histiocyte (macrophage) whose cytoplasm is filled with linear or fibrillar material (kerasin). This cell is characteristic of the congenital glycolipid disorder, Gaucher's disease. Gaucher cells may also be seen in the marrow of patients with chronic granulocytic leukemia. When seen in this condition, they are referred to as pseudo-Gaucher cells.

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After Marrow Evaluation

After the marrow is evaluated, the diagnosis is established and extent of the disease is determined. Follow up bone marrow examinations may be needed to monitor changes in the marrow following treatment or when signs and symptoms of relapse occur. To summarize, a bone marrow examination can provide valuable information to aid in the diagnosis of a variety of disorders. Due to the expense involved and the discomfort to the patient, clear indications of need should be present before this examination is undertaken.

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Examples of Conditions

Examples of conditions in which examination of the bone marrow may provide diagnostic information include:Erythrocyte Disordersanemiamegaloblasticsideroblasticiron deficiencyerythrocytosispolycythemia veraLeukocyte DisordersneutropenialeukemialymphomaPlatelet DisordersthrombocytopeniathrombocytosisMiscellaneous Disordersprotein abnormalitiesmultiple myelomaWaldenstrom's Macroglobulinemiadiseases of the RE systemhypersplenismmetastatic carcinomagranulomatous infectionsstorage diseasesGaucher's diseaseNiemann-Pick disease

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Introduction to the ABO Blood Group System
Immunoglobulin

The predominant immunoglobulin class for the B antibodies produced by individuals with group A phenotype and the A antibodies produced by individuals with group B phenotype is IgM. Small quantities of IgG may also be present. IgG is the predominant immunoglobulin for the anti-A and anti-B antibodies found in individuals with group O phenotype. Infants of group O mothers are at higher risk for hemolytic disease of the newborn (HDN) than those born to mothers with group A or B because IgG immunoglobulins readily cross the placenta. IgM molecules do not readily cross the placenta because of their larger size. It is important to note that immune antibodies are usually IgG. Both naturally occurring and immune ABO antibodies are critically important in transfusion since both sensitize and usually hemolyze red cells with the corresponding antigen.

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Laws and Rules of the Florida Board of Clinical Laboratory Personnel
Description of Specialties (3)

Specialists in radioassay use radionuclides to determine the chemical makeup of body fluids such as blood and urine. Specialists in blood gas analysis evaluate lung and breathing function by levels of oxygen, carbon dioxide, pH, and hemoglobin with automated tests. Specialists in histology examine cellular and tissue samples using fixation, dehydration, embedding, microtomy, frozen sectioning, staining, and other similar techniques. Histology specialists licensed as technicians can perform specimen processing, embedding, cutting, staining, and frozen sectioning only under the general supervision of a director, supervisor, or technologist. Specialists in cytology process and interpret samples relating cytopathological disease. Non-gynecological cytology preparations can be screen by a specialist in cytology but final review and interpretation must be done by a physician.

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Description of Specialties (4)

Specialists in cytogenetics detect chromosome abnormalities and genetic disorders. Cytogenetics counseling may only be performed by an individual licenses in the cytogenetics specialty at the director level. Specialists in molecular genetics analyze DNA and RNA to find disease-related genotypes, mutations, and phenotypes in order to detect or predict disease and identify carriers. Specialists in histocompatibility test to determine tissue compatibility, prevent infections, and investigate and post-transplant problems. Techniques include blood typing, HLA typing, HLA antibody screening, disease markers, flow cytometry, crossmatching, HLA antibody identification, lymphocyte immunophenotyping, immunosuppressive drug assays, allogenic, isogeneic and autologous bone marrow processing and storage, mixed lymphocyte culture, stem cell culture, cell mediated assays, and assays for the presence of cytokines. Specialists in andrology and embryology examine gametes and embryos, including production, morphology, number, and motility, to address issues of fertility and infertility.

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Medicare Compliance for Clinical Laboratories
Billing and medical necessity

Billing: Highest risk activity a laboratory has. All laboratory activities contribute to the billing process. Many of the risk areas included in this program are components of the billing function. Medical necessity: Medicare is only allowed, by law, to pay for tests that are reasonable and necessary for the diagnosis and treatment of disease. Medical necessity is an underlying principle of the Medicare program. Tests performed for screening or routine exams are not considered medically necessary by the Medicare program.

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Coding

CPT (Current Procedural Terminology) codes are used to describe specific tests or services. The amount of payment for a test is dependent on the CPT code. It is against the law to use the wrong CPT code for a test for the purpose of causing or increasing payment for a test. ICD-9CM (International Classification of Disease, 9th Edition, Clinical Modification) codes are used to classify diseases and conditions, and describe signs, symptoms and medical circumstances. ICD-9CM codes are used to indicate the medical necessity of a particular test. It is against the law to use the wrong ICD-9CM code for the purpose of causing or increasing payment for a test.

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Medical coverage policies (LMRPs)

LMRPs (Local Medical Review Policies) are published by Medicare for some laboratory tests. Developed for tests that can be used for screening or diagnosis of disease. CPT codes describe laboratory tests and ICD-9CM codes determine when coverage is allowed. If an LMRP test is ordered by a physician, an ICD-9CM code that is included in the LMRP must be given to the laboratory or the Medicare program will not pay for the test. It is against the law for laboratory to change or add an ICD-9 code submitted by a physician. The Balanced Budget Act of 1997 made it illegal for physicians to order LMRP tests and not supply an ICD-9CM code with the order.

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Medical necessity

Medical necessity means that Medicare is not allowed by law to pay for any tests that are not necessary for diagnosis or treatment of disease.A laboratory may not submit a claim to Medicare or other government payers for any test it knows is not medically necessary except in certain cases: When the patient has signed an advance notice. When a patient has requested the lab to submit such a claim for a determination by Medicare. Medicare does not pay for screening tests or tests that are ordered in the absence of signs or symptoms.Billing department employees are responsible to follow all policies and procedures related to the submission of claims to reduce erroneous billings.

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ICD-9CM coding

ICD-9CM (International Classification of Disease, 9th Edition, Clinical Modification) codes are used for the classification of disease and conditions and for describing signs, symptoms and medical circumstances.These codes are used to indicate the medical necessity of a particular test.ICD-9 codes can only be supplied by the ordering physician or a representative of that physician. "Code steering" means to steer or direct a physician to supply an ICD-9 code that is payable. ICD-9 codes cannot be used from a previous laboratory order. If a physician supplies a narrative description instead of an ICD-9 code the laboratory must accurately translate that code using only certified coders.It is against the law to use the wrong ICD-9 code for the purpose of causing or increasing payment for a test.

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Local medical review policies (LMRPs)

LMRPs (Local Medical Review Policies) are published by Medicare for some laboratory tests. They are usually developed for tests that can be used for screening or diagnosis of disease. LMRPs use CPT codes to identify the tests and ICD-9 codes to determine when coverage is allowed. If an LMRP test is ordered by a physician, an ICD-9 code that is included in the LMRP must be given to the laboratory or the Medicare program will not pay for the test. It is against the law for laboratory to change or add an ICD-9 code submitted by a physician. A laboratory should not submit a claim for an LMRP test that is not accompanied by an acceptable ICD-9 code. The Balanced Budget Act of 1997 made it illegal for physicians to order LMRP tests and not supply an ICD-9CM code with the order.

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Mycology: Hyaline and Dematiaceous Fungi
Match each of the names of the fungi listed in the left column with its most likely associated disease listed in the right column.View Page
The fungus illustrated in this photomicrograph was recovered from an induced sputum specimen from a 74 year old man with chronic obstructive pulmonary disease. This isolate is most likely:View Page
Match the name of each dematiaceous fungus listed in the drop-down box with its most likely disease.View Page
The disease with which the dematiaceous fungus illustrated in this photomicrograph is most likely associated is:View Page

Mycology: Yeasts and Dimorphic Pathogens
Match each of the names of the dimorphic fungi listed with the names of the animals that most commonly may be related to transmission of disease to humans.View Page
Match the names of each of the diseases listed with its appropriate situation:View Page
Each of the following dimorphic fungal infections have been observed in animals living in their natural environment except:View Page
Which of the following fungal infections was once known as "Chicago disease" because so many cases had occurred in the Chicago area?View Page
Match the complications that are most likely to be associated with each of the two yeast diseases that are listed in the drop-down box:View Page
The growth of the yeast-like colonies shown in the upper image was obtained on blood agar from a skin culture only in the area overlaid by virgin olive oil. The lower image is a photomicrograph of a lactophenol blue mount made from a portion of the colony. The disease associated with this fungus is:View Page
Although only a few human cases have been reported, brewers and bakers may in particular be at increased risk for developing infections with:View Page
Of the following responses, the one observation that would rule out cryptococcosis as the cause of meningoencephalitis is:View Page

Normal Peripheral Blood Cells
Definition of a Segmented Cell continued.

Since these recommendations have been adopted by many groups, including the College of American Pathologists and the Centers for Disease Control, we will be using them as our criteria for differentiating between bands and segs.This definition was first reported by the Committee for Clarification of the Nomenclature of Cells and Diseases of the Blood and Blood Forming Organs, in the American Journal of Clinical Pathology (18:443-450, 1948).

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Pharmacology in the Clinical Lab: Therapeutic Drug Monitoring and Pharmacogenomics
Unexpected Concentrations

TDM provides a quantitative measure of the circulating concentration of a drug. The physician determines if the dosage of the drug needs to be adjusted based on this information.If a drug concentration is determined to be outside the therapeutic range, it may be for one of the reasons listed in the table below. Reason Discussion Noncompliance Patients may (intentionally or unintentionally) not take the drug. TDM can thus help monitor compliance. Dosing errors The dose may have been erroneous or inappropriate given the patient's condition. Malabsorption The TDM result will reveal if the drug cannot be absorbed well through the gut and an alternative route of administration will be needed. Drug interactions Many drugs interfere with the absorption or metabolism of other drugs. These interactions will be revealed by TDM. Kidney or liver disease Any pathology that affects elimination will cause an elevation in a drug level that will be unmasked by TDM. Altered protein binding Changes in serum proteins can lead to big changes in the amount of free drug in serum. Variations in the genetics of drug-metabolizing enzymes can also affect drug concentrations in the body. This is the field of pharmacogenomics that will be discussed later in the course.

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TDM for Theophylline

Theophylline is used as a bronchodilator for treatment of moderate to severe asthma and chronic obstructive pulmonary disease (COPD). TDM is needed for theophylline because the kinetics of the drug are highly variable. It has a narrow therapeutic window, and overdose can result in elevated heart rate, arrhythmia, and CNS excitability. Clearance of the drug is increased in children, smokers, persons with cystic fibrosis, and persons with hyperthyroidism. Elimination is slowed in congestive heart failure and in the elderly.

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Protein Availability and Drug Dosing

Drug-binding proteins in serum can fluctuate in disease states. For example, if albumin levels fall, as can occur in liver failure or nephrotic syndrome, less albumin will be available for drug binding; a subsequent dose may produce a toxic concentration of free drug.The image on the right illustrates the loss of equilibrium between a protein-bound drug and a free drug when drug-binding proteins are diminished.Doses of drugs that are highly protein-bound may need to be adjusted in patients with lower drug-binding protein levels. Examples of some common drugs that are highly protein-bound include thyroxine, warfarin, diazepam, heparin, imipramine and phenytoin. �

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Warfarin cont.

The genes involved in warfarin metabolism are CYP2C9 and vitamin K epoxide reductase complex subunit 1 (VKOR). Warfarin owes its anticoagulant action to its inhibition of VKOR. This enzyme recycles vitamin K, a critical element for the clotting factors II, VII, IX, and X, as well as for proteins C, S, and Z. There are six CYP2C9 alleles that are known to cause prolonged metabolism of warfarin: CYP2C9 *2, *3, *4, *5, *6, and *11. (Polymorphisms in CYP450 genes are denoted with asterisks.)One-third of the patients that receive warfarin metabolize it differently than expected and experience a higher risk of bleeding.Genetic testing for the two most common polymorphisms (CYP2C9*2 and *3) as well as for VKOR may be able to reduce the variability associated with warfarin dosing response. Labs performing PGx testing can provide general warfarin dosing recommendations based on the patient's genotype analysis. The lab report will indicate whether a patient has a normal, mild, moderate, high, or very high sensitivity to warfarin. For example, a patient who has one CYP2C9 normal wild-type allele (CYP2C9 *1), one polymorphism (CYP2C9*3), and also a VKOR polymorphism is predicted to have a moderate sensitivity to warfarin. This patient should have frequent INR monitoring and possible warfarin dose reduction. It is important to recognize that knowing a genotype does not necessarily guarantee accurate dose prediction; other drugs and/or environmental or disease factors can also alter CYP2C9 activity. Therefore, monitoring the INR is still very important.

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Phlebotomy
Plasma lipids

Lipids are fats dispersed in plasma. They include: Triglycerides Cholesterol Lipoproteins The amount and ratios of various lipids in the blood will determine a person’s risk of getting coronary artery disease.

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Quality Control
Calculating Sensitivity

Sensitivity is the ability of a test to correctly identify individuals who do have a particular disease or disorder. To determine sensitivity, we use the following equation: True Positives (TP) Divided by True Positives (TP) plus False Negatives (FN) Times 100 or (TP ÷ (TP + FN)) x 100 The result will be a percentage.

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Specificity vs. Sensitivity

To review, specificity is “disease focused”. The more specific a test is, the fewer false positive results will occur. Remember that a false positive result can possibly lead to a misdiagnosis with the possible consequence of unnecessary diagnostic procedures and therapies. Sensitivity, on the other hand, is “wellness or normal focused”. The more sensitive a test is, the fewer false negative results it produces.

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What is Non-waived Testing?

In 2003, the Center for Disease Control and Prevention and the Center for Medicare and Medicaid Services published the Clinical Laboratory Improvement Amendment (CLIA).Under CLIA, the term "Non-waived" replaces the terms “Moderate” and “High Complexity” testing. Before a laboratory can report patient results for a non-waived, FDA-approved test for the first time, the laboratory must verify that the test’s performance is similar to the manufacturer’s claims for accuracy, precision, and reportable range.

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Reading Gram Stained Direct Smears
Cellular elements

The gram stain reaction and appearance can be used to identify most cellular material seen in a direct smear. Identification of cellular elements present in a direct clinical smear is important because most of these elements play an important role in the disease process. For example, the quality of a sputum sample can be assessed by determining the relative numbers of squamous epithelial cells and polymorphonuclear leukocytes (segmented neutrophils) present.

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Red Cell Disorders: Peripheral Blood Clues to Nonneoplastic Conditions
Note the view of a peripheral blood smear in the photograph. Pictured are scattered acanthocytes, echinocytes, target cells, spherocytes, and schistocytes. The condition in which each of these atypical RBC's may be found in varying numbers in the same peripheral blood smear is:View Page
An 8 year old girl is protected from severe hemolytic anemia by an elevated fetal hemoglobin level ( hemoglobin F).View Page
The nucleated red blood cell and myelocyte photographed here were found on scanning of a peripheral blood smear. In context they are suggestive of metastatic carcinoma to the bone marrow.View Page
The erythrocyte at the tip of the arrow is an echinocycte (burr cell).View Page
The peripheral blood picture is consistent with each of the following conditions except:View Page
Leukoerythroblastosis

Illustrated in this field is a normoblast and a myelocyte, representing leukoerythroblastosis, a term associated with the release of immature cells from a disrupted marrow. Metastatic disease in the bone marrow, particularly in patients with primary breast or prostate cancer, is usually the culprit. Leukoerythroblastosis in the absence of anemia or thrombocytopenia is a signal to search for cancer metastic to the marrow. Nucleated RBCs were not identified on the blood smear seen here but were detected by an automated analyzer.The mortality rate of elderly patients with increased NRBCs, especially following accidents or general surgery, is greater.

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Schistocytes vs. bite cells

Schistocyte is a general term for a fragmented red blood cell that may assume various shapes, some with horn-like projections (keratocytes), triangle-forms (triangulocytes), and helmet shapes, as illustrated in the upper photograph. Schistocytes are formed when erythrocytes are forced through a vessel blocked with interlacing fibrin strands and the red cells are sliced into fragments. True schistocytes are devoid of central pallor. These damaged cells continue to circulate while healing their torn edges. Finally, they are removed by the spleen. Bite cells (lower photograph) appear when an abnormal hemoglobin aggregate (Heinz body) is nibbled out of a red cell's cytoplasm by the spleen leaving a bitten apple appearance. Glucose 6-PD deficiency secondary to chemical poisoning or injury by oxidant drugs are settings for Heinz body formation, and the telltale bite cells remain as evidence. Hemolytic anemia associated with severe liver disease is another setting where bite cells are formed.

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DIC: graft vs. host disease

The peripheral smear illustrated in the photograph was obtained from a patient with a recent renal transplant. The patient developed a rash, accompanied by nausea and diarrhea. Graft vs. host disease was clinically suspected. The peripheral smear findings are consistent with that diagnosis. The presence of spherocytes suggests a hemolytic process which is supported by the presence of nucleated RBCs. A few scattered schistocytes and the decrease of platelets suggests DIC. The presence of target cells presents the possibility of associated liver disease. Additional tests, particularly coagulation studies, should confirm the diagnosis of microangiopathic hemolytic anemia.

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Hemolytic disease of the newborn

Jaundice was recognized in a day-old infant. Notice particularly the size variation (anisocytosis) of the erythrocytes on the infant's peripheral smear. What does this observation mean? Does it provide immediate information that might serve as guidance in expediting diagnosis and treatment? Note that normal-sized red blood cells, microcytes, microspherocytes, macrocytes, and nucleated red blood cells are all present. Red cell variations are expected findings in healthy neonates, but the variations here are exaggerated. Hyposplenic functional features may appear, including acanthocytes, spherocytes, and possibly Howell-Jolly bodies, especially if hemolysis is particularly vigorous. A high (3-7%) reticulocyte count is not unusual during the first three or four days after birth, however, the marrow in this jaundiced infant is proliferating vigorously in response to hemolysis. A call for more red cells is urgent. Immature red cells (in the form of nucleated red cells) and red cells with stippling of RNA (basophilic stippling) are readily identified. Red cell maturation sequence has not been totally processed in the marrow nor is all residual red cell debris removed by the spleen. In the lower photograph are reticulocytes stained by supravital stain (new methylene blue). Basophilic stippling (specks of RNA) stains with both supravital stains and with routine Wright-Giemsa stain.

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Warm antibody hemolytic disease

A 49-year-old male with pneumonia was treated with penicillin. He became jaundiced with yellow sclera. Observe the photograph of his peripheral blood smear. Anisocytosis was observed with pale-centered microcytes and polychromatophilic macrocytes. Since penicillin is a classic offender for autoimmune hemolytic disease, the clinician asked for an antihuman globulin (AHG) test, also known as the Coombs test. A positive AHG reaction occurs when the antibody stimulated by penicillin becomes attached to red blood cells. Hemolysis follows, leaving the patient with jaundice and a peripheral blood smear, as demonstrated in the photograph.

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Sickle cells

This photograph of a peripheral blood smear from an 18-year-old North African woman with anemia reveals sickle cells. Target cells are not conspicuous. This shifts the diagnostic evidence away from HbSC disease. Cells tagged by arrows are variants of sickle cells. These may appear when multiple abnormal hemoglobin combinations are responsible for the clinical problem. The cell marked by the single arrow is an envelope formed not only in HbS disease but in HbC disease as well. Two arrows tag a blister cell, which, when seen in several fields, should prompt a hemoglobin electrophoresis to determine the presence of an undiagnosed hemoglobinopathy. Blister cells with fuzzy edged pseudo-vacuoles (see photo) are to be distinguished from the pseudo-vacuoles (blister)with razor sharp edges suggesting a microangiopathic state.

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Hemoglobin H disease

Hemoblobin H disease follows deletions of 3 of the 4 alpha globulin chains. Beta chains, unable to bind with insufficient numbers of alpha chains, form beta chain tetramers, or HbH.These beta chain tetramers appear as numerous dot size inclusions in erythrocyte cytoplasm, best seen in supravital brilliant cresyl blue stains (lower photograph).The most common molecular defect in alpha thalassemia is DELETION, not MUTATION; whereas, in beta thalassemia, the molecular defect is MUTATION.Leptocytes, as illustrated in the upper photograph,(lepto, derived from a Greek word meaning thin, fine, or slight), are characteristic of HbH disease. They have thinner cell membranes than the cells we recognize as target cells. They stain more lightly than normal erythrocytes and their centers are almost colorless.Subtle changes perhaps, but worth keeping in mind

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A peripheral blood smear was submitted for review. The presence of sickle cells and target cells as shown is diagnostic of hemoglobin SC disease.View Page
Atypical smear: Case follow-up

The patient whose blood smear is shown in the photograph was a 32-year-old female from Virginia who came to the high country of Colorado to ski. The day after arrival, she experienced shortness of breath, fatigue, and upper abdominal pain. She was seen in a medical center in the mountains where a working diagnosis of altitude sickness was made. A CBC revealed RBCs 5.1 x 1012/L, hemoglobin 12.8g/dL, MCV 60fL, hematocrit 40.9%, and normal total WBC, differential, and platelet count. The RDW was normal. Further questioning revealed a previous diagnosis of heterozygous beta-chain thalassemia. No other abnormal hemoglobins were found on hemoglobin electrophoresis, but HbA-2 was elevated to 5%, supporting the diagnosis of beta thalassemia. The patient's poikylocytosis and anisocytosis may be a clue to an underlying erythrocyte abnormality. Persons with iron deficiency anemia may experience various degrees of hypoxia upon arriving at high altitudes. Those with sickle cell disease and thalassemia minor (as in this case) may experience bone pain or other symptoms of "crisis" and/or alteration in the appearance of their erythrocytes upon sudden high altitude exposure. The classic teaching is that in differentiating iron deficiency anemia from thalassemia, increased RDW would favor iron deficiency; normal RDW favors thalassemia.

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A peripheral smear with red blood cells photographed in a typical field was submitted for review. Which of the following conditions might be eliminated because of the cell population found here?View Page
The photograph here is of a peripheral smear sent for hematologic review. No clinical information for the patient was sent with the slide. What is the first course of action that the reviewer should take to assist him/her in interpreting the findings on this blood smear?View Page
The photograph is representative of the peripheral blood smear of a five-month-old immigrant from Asia. Her mother was concerned that the child was not eating well. Her spleen was palpable.The hemogram revealed the following:Hb 9.6g/dL (normal 12.0 - 16.0 g/dL)RBC 5.48 X 1012/L (normal 4.2 - 5.9 X 1012/LHCT 30.4% (normal 37 - 48%)MCV 55.4 fl (normal 86 - 98 fl)MCH 17.5 pg (normal 27 - 32 pg)MCHC 31.6 g/dL (normal 31 - 37 g/dL)RDW 34.9% (normal 11 - 15%)Reticulocyte count 10.9% (normal 0.5 - 1.5%)Select the most likely diagnosis based on the clinical information and peripheral blood findings.View Page
Hb E disease (continued)

The family (cited in the previous case history) was from a region of Thailand where the physician knew HbE carriers are prevalent. Homozygous hemoglobin E is common in Southeast Asia and presents with very mild anemia and seldom requires transfusion. Over 30 million people in the world are HbE carriers, making this abnormal hemoglobin almost as common as HbS. Hemoglobin E is uncommon in North America and in Europe, but with changing immigration patterns, hemoglobinopathy E cannot be ignored. Peripheral blood smear findings of target cells, microspherocytes, red cell hypochromia, a few red blood cell fragments, and nucleated red blood cells require evidence from hemoglobin electrophoresis to establish a diagnosis. Clinically, a very important and severe syndrome is hemoglobin E/beta thalassemia in which there is hemolysis requiring repeated transfusions. The patient has a severe anemia, low MCV (50's), and high RBC. This is characteristic of Hgb E/beta thalassemia.

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The patient, an 8-month-old girl, was anemic, jaundiced, and had splenomegaly. Her family had immigrated from the Middle East. Based on the history and the peripheral blood picture, the most probable diagnosis is thalassemia.View Page
Leptocytes and target cells

The peripheral blood smear of HbH disease presented before is reviewed in the upper photograph.As mentioned, these leptocytes are pale-staining with hemoglobin confined to a thin, flat, cell membrane.Illustrated in the lower photograph are target cells or codocytes (a term derived from a Greek word for hat)Membrane accumulations of phospholipids and cholesterol (particularly in obstructive jaundice) promote target cell formation.When these cells are spread out on a glass slide, a central bump of hemoglobin appears to produce the target, a manifestation of excess cellular membrane compared to the amount of hemoglobin inside.The early descriptions of thalassemias, then called hereditary leptocytosis (Mediterranean anemia, Cooley's anemia), include description of leptocyes, which may have represented HbH disease.

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The blood study from which this smear was obtained revealed an MCV of 115 femtoliters (fl).Normal MCV values in adults= 80 - 90 fl.Normal MCV values in full-term infants= 98 -108 fl.Which of the following conditions may be indicated by the results seen on this peripheral blood smear?View Page
Reporting of laboratory data in regard to blood cell abnormalities

Laboratory data must be presented to clinicians in a user friendly way to promote effective decision making. Databases must be designed to provide clear information that leads quickly to the best patient care outcome. We continue learning how to collect and retrieve laboratory data from our machines, but we are not always in tune to how entry and retrieval of data is geared to and, more directly, influences patient care outcomes. Examples of blood cell abnormalities on a peripheral blood smear that may immediately direct the physician to a specific diagnosis are: (1) presence of target cells as found in thalassemia or hemoglobinopathies and target cells in liver disease, particularly with obstructive jaundice; (2) burr cells as a signal of chronic renal disease and uremia; and (3)atypical neutrophil inclusions relating to genetic disorders. Critical appraisal of such observations could add valuable clues for a diagnosis. Laboratory professionals must establish a set of principles for orderly observation of blood cell morphology, have a clear vision of the applications of their work, and understand the potential clinical implications of their reports and interpretations. Emphasis on values and relevance focuses on patient care outcomes and their dependency on prompt availability of results and contextual interpretations.

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Red Cell Morphology
Examples of Stomatocytes

Examples of stomatocytes can be seen in the center of this slide and to the left of the center. Conditions in which a significant number of in vivo stomatocytes can be seen include hereditary stomatocytosis, neoplastic disorders, liver disease and Rh null disease. The largest numbers of in vivo stomatocytes are seen in hereditary stomatocytosis and their identification is necessary to make the diagnosis.

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Another Target Cell

Another example of a target cell (or codocyte) is seen in the center of this slide. Notice that the hemoglobin in the center of this cell is somewhat lighter in appearance than in the previous slide. A second codocyte can be seen in the upper left portion of the slide. Codocytes appear in conditions which cause the surface of the red cell to increase disproportionately to its volume. This may result from a decrease in hemoglobin, as in iron deficiency anemia, or an increase in cell membrane. Target cells have excess membrane cholesterol and phospholipid and decreased cellular hemoglobin. Examples of other conditions in which target cells may be present include thalassemias, hgb C disease, post splenectomy and obstructive jaundice. Since their presence can be the result of an in vitro artifact, their value in clinical diagnosis is limited.

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The Urine Microscopic: Microscopic Analysis of Urine Sediment
Match the following:View Page
Formation and Significance of Casts

Casts are cylindrical bodies formed either in the distal convoluted tubules or the collecting ducts of the kidney. Since the walls of the tubule act as a mold for cast formation, the width of the tubule determines the width of the cast. Thus, narrow casts are formed in the distal tubules while broad casts are formed in the collecting ducts. The matrix of all casts is thought to be Tamm-Horsfall protein, a glycoprotein secreted by the distal loop of Henle and the distal tubule. This protein entraps cells and granular material of tubular origin. Very few casts are seen in the urine of a person without renal disease, except for hyaline casts, which may be transiently present after strenuous exercise, and during fever, diuretic therapy, and congestive heart failure. A significant number of urinary casts usually indicates the presence of renal disease.

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Waxy Casts

Waxy casts appear as cylinders of smooth, highly refractive material. They are yellow, homogeneous and their ends may be square or broken off. Cracks may occur within the cast, giving it a segmented appearance. Waxy casts are believed by some to be the final stage of degeneration of the fine granules of granular casts. Since the granules need time to degrade, this finding implies localized nephron obstruction. Waxy casts are seen in chronic renal failure, and acute and chronic renal allograft rejection. Unusually broad waxy casts are known as renal failure casts. These very broad casts are created in the dilated tubules seen in end-stage renal disease.

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Fatty Cast

A fourth type of cast is the fatty cast. Fatty casts are clear cylinders containing droplets of fat which are highly refractile. These casts originate from the breakdown of the tubular epithelium containing oval fat bodies. Fatty casts are characteristic of degenerative tubular disease and are frequently seen with heavy proteinuria.

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Tyrosine Crystals

Tyrosine crystals appear as fine silky needles arranged in sheaves or bundles in acid urine. They are rarely present and may appear together with leucine crystals in liver disease. Do not confuse tyrosine with crystals caused by x-ray dye. X-ray dyes will cause the urine specific gravity to be greatly increased (1.040), Tyrosine crystals are soluble in alkali or dilute mineral acid.

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Which of the following pairs of abnormal crystals may appear together?View Page
Cholesterol Crystals

Cholesterol crystals may be seen in renal tubular disease. These crystals look like plates of glass, sometimes with a notch out of one corner. Under polarized light, they exhibit a stained glass effect. These crystals are rarely seen unless the specimen has been refrigerated, because the lipids remain in droplet form. Large amounts of protein, lipid droplets, fatty casts or oval fat bodies should be found along with cholesterol crystals. Cholesterol crystals are found in acid or neutral urine.

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Tuberculosis Awareness for Healthcare Workers
Trends in Tuberculosis

The tuberculosis (TB) incidence rate in 2007 was the lowest recorded since national reporting began in 1953. However, the average annual percentage decline in the TB rate has slowed. Multi-drug resistant tuberculosis cases have increased. There is persistent disparity in the incidence of tuberculosis between different ethnic groups and also between foreign-born persons and US-born persons. Reference: Pratt R, Robison V, Navin T. Trends in tuberculosis. MMWR/57(11);281 - 285; Centers for Disease Control and Prevention: March 21, 2008. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5711a2.htm Accessed on May 23, 2008.

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High Risk Progression Groups

The following persons are at high risk for progression from LTBI to TB disease: Persons infected with HIV Persons infected with Mycobacterium tuberculosis within the past two years Persons with untreated or inadequately treated TB disease Infants and children <4 years of age Persons with chronic medical conditions or immunocompromising conditions

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LTBI Testing Introduction

It is important to identify and treat persons with LTBI to prevent progression to active disease. Currently there are two tests available to identify LTBI.The tuberculin skin test (TST) is performed on the inner arm.The Blood Assay for Mycobacterium tuberculosis (BAMT) is performed on a blood specimen.

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CDC Guidelines

The Centers for Disease Control (CDC) issued Guidelines for Prevention of Tuberculosis in Healthcare Settings in 2005.These guidelines have broader applications than the Guidelines for Prevention of Tuberculosis in Healthcare Facilities issued by CDC in 1994.

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CDC Risk Categories

CDC has identified three risk categories in health-care settings: A low risk healthcare setting is one in which HCWs will most likely not be exposed to persons with TB disease or to clinical specimens that might contain M. tuberculosis. A medium risk healthcare setting is one in which the HCW will or might possibly be exposed to persons with TB disease or to clinical specimens that might contain M. tuberculosis. A potential ongoing transmission healthcare setting is temporarily applied to any setting if there is evidence of person-to-person transmission of M. tuberculosis in the past year.

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Three levels of TB Infection Control

Administrative controls reduce the risk of exposure to persons who might have TB disease.Environmental controls prevent the spread and reduce the concentration of infectious droplet nuclei in ambient air.Respiratory protection controls are for situations that pose a high risk of exposure to further reduce risk of exposure of HCWs to infectious droplet nuclei that have been expelled into the air from a patient with infectious TB disease.

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References

Pratt R, Robison V, Navin T. Trends in tuberculosis. MMWR/57(11);281 - 285; Centers for Disease Control and Prevention: March 21, 2008. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5711a2.htm Last accessed on May 23, 2008.Respiratory Protection in Health-Care Settings Fact Sheet. Available at http://www.cdc.gov/niosh/99-143.html. Last accessed May 23, 2008. Slide set - Guidelines for preventing the transmission of M. Tuberculosis in Healthcare settings, 2005. Available at http://www.cdc.gov/tb/pubs/slidesets/InfectionGuidelines/program.htm Last accessed on May 23, 2008.Tuberculin Skin Testing Fact Sheet. Available at http://www.cdc.gov/TB/pubs/tbfactsheets/skintesting.htm Last accessed on May 23, 2008.

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Biosafety Levels

Laboratory workers who handle infectious materials in the microbiology laboratory should be aware of the work practices, safety equipment, and barriers that will protect them and others in the area from infectious agents. The Centers for Disease Control and Prevention (CDC) and the National Institutes of Health (NIH) created guidelines to assist laboratories in developing safe practices based on the infectious agents that are handled. These guidelines are referred to as Biosafety Levels 1 through 4. Each increasing number represents increased risk, requiring more stringent work practice and increasingly protective safety equipment and barriers. A copy of the Guidelines can be obtained from the CDC or accessed online at:http://www.cdc.gov/OD/ohs/biosfty/bmbl5/bmbl5toc.htm

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Variations in White Cell Morphology - Granulocytes
Importance of Recognition

It is important to be able to recognize the presence of these changes and then identify them for several reasons:If the changes are pathological, their identification may aid the physician in diagnosing a specific condition.If the changes are not pathological, their identification alerts the physician to the fact that the changes are present, thus avoiding a possible misdiagnosis.If reactive, it indicates that although the cells are functioning normally, they are reacting to a stimulus. Indicating the presence of such cells may aid in determining the diagnosis or monitoring the course of disease once a diagnosis has been made.

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Variations in Morphology

Many variations in morphology may be seen when examining Wright's stained peripheral blood smears. One method of classifying these variations in white cell morphology is based on the way the body responds to a stimulus, deficiency, or the presence of an inherited defect. This classification falls into three groups:Pathological: Cells may show abnormalities in appearance and/or function. The body is responding abnormally to a stimulus or inherited defect, resulting in physiological impairment in the patient. Nonpathological: Cells may show variation in morphology but their function is normal. Their presence does not cause physiological impairment. Reactive: Cells show variation in morphology but are functioning normally in response to a specific stimulus, such as a virus or bacteria. There is a disease process in progress to which the cells are responding. Although the morphology has varied from normal and their presence is significant, the body is responding normally to a stimulus.

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White Cell and Platelet Disorders: Peripheral Blood Clues to Nonneoplastic Conditions
A most useful follow-up test to consider when faced with hypersegmented neutrophils and oval macrocytes (see photograph) in a peripheral blood smear is:View Page
A peripheral smear was submitted for morphology/clinical because of the number of monocytes as captured in the upper and lower photographs. This picture is consistent with each of the following conditions except:View Page


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