Pbl Exam 10 Case 2-2

Front 1

1. What are the symptoms of splenomegaly?

Back 1

When sufficiently enlarged, the spleen causes a dragging sensation in the left upper quadrant and, through pressure on the stomach, discomfort after eating. In addition, its enlargement can lead to sequestration of blood elements. This gives rise to hypersplenism.

Front 2

2. What is the clinical triad of hypersplenism?

Back 2

1. Splenomegaly
2. Anemia, leukopenia, thrombocytopenia, or any combo of these, in association w/hyperplasia of the marrow precursors of the deficient cell type
3. Correction of the blood cytopenias by splenectomy

Front 3

3. What is nonspecific acute splenitis?

Back 3

Enlargement of the spleen occurs in any blood-borne infection. The nonspecific splenic reaction in these infections is caused by both the microbiologic agents themselves and by cytokines that are released as part of the immune response.

Front 4

4. What is the morphology of nonspecific acute splenitis?

Back 4

The spleen is enlarged (up to 200-400 g) and soft. The splenic substance is often diffluent and can be so soft that it literally flows out from the cut surface.

Microscopically, the major change is acute congestion of the red pulp, which can encroach on and sometimes virtually efface the lymphoid follicles. Neutrophils, plasma cells, and occasionally eosinophils are usually present throughout the white and red pulp. At times, there is acute necrosis of the centers of the splenic follicles, particularly when the causative agent is a hemolytic streptococcus.

Front 5

5. What is congestive splenomegaly?

When is it encountered?

Back 5

Chronic venous congestion can cause a form of splenic enlargement referred to as congestive splenomegaly. All of these disorders ultimately lead to portal or splenic vein hypertension. Systemic, or central, venous congestion is encountered in cardiac decompensation involving the right side of the heart, or following left-sided heart failure. Systemic passive congestion produces only moderate enlargement of the spleen that rarely exceeds 500 gm in weight.

Front 6

6. What are the only common causes of striking congestive splenomegaly?

Back 6

The various forms of cirrhosis of the liver. The "pipe-stem" hepatic fibrosis of schitosomiasis causes particularly severe congestive splenomegaly, while the diffuse fibrous scarring of alcoholic cirrhosis and pigment cirrhosis also evokes profound enlargements.

Front 7

7. What else can cause congestive splenomegaly?

Back 7

Congestive splenomegaly is also caused by obstruction of the extrahepatic portal vein or splenic vein. This can stem from spontaneous portal vein thrombosis, which is usually associated w/some intrahepatic obstructive disease, or inflammation of the portal vein (pylephlebitis), such as follows intraperitoneal infections.

Front 8

8. What is the morphology of congestive splenomegaly?

Back 8

Long standing congestion produces marked enlargement of the spleen. The organ is firm and becomes increasingly so the longer the congestion lasts. The weight can reach 5 kg. The capsule is usually thickened and fibrous. The cut surface has a meaty appearance and varies from gray-red to deep red, depending on the amt of fibrosis.

Microscopically, the red pulp is congested in early chronic congestion but becomes increasingly more fibrous and cellular w/time.

Foci of recent or old hemorrhage are often present. **Organization of these focal hemorrhages gives rise to Gandy-Gamma nodules: foci of fibrosis containing iron and calcium salts deposited on connective tissue and elastic fibers.

Front 9

9. What causes splenic infarcts?

Back 9

Chuck norris.

Splenic infarcts are common lesions. Caused by occlusion of the major splenic artery or any of its branches, in normal sized spleens they are most often due to emboli that arise from thrombi in the heart.

The resulting infarcts can be small or large, single or multiple, or can even involve the entire organ.

Front 10

10. What is the morphology of splenic infarcts?

Back 10

Bland infarcts are characteristically pale and wedge-shaped, w/their bases at the periphery, where the overlying capsule is often covered w/fibrin.

In septic infarcts, this appearance is modified by the development of suppurative necrosis.

In the course of healing of splenic infarcts, large, depressed scars often develop.

Front 11

11. Although rare, what are the neoplasms involving the spleen?

Back 11

Neoplastic involvement of the spleen is rare except in tumors of the lymphohematopoietic system. When present, they induce splenomegaly.

Fibromas, osteomas, chrondromas, *lymphangiomas, and *hemangiomas may arise in the spleen.

*Most common and are often cavernous in type.

Front 12

12. Complete absence of the spleen...?

Back 12

Completely absence of the spleen is rare and is usually associated w/other congenital abnormalities such as situs inversus and cardiac malformations.

Hypoplasia is a more common finding.

Front 13

13. What are spleniculi?

Why are they clinically significant?

Back 13

Accessory spleens (spleniculi) are common and have been encountered singly or multiply.

They are small, spherical structures that are histologically and functionally identical to the normal spleen, reacting to various stimuli in the same manner.

They are generally situated in the gastrosplenic ligament or the tail of the pancreas but are sometimes located in the omentum or mesenteries of the small or large intestine.

*They are clinically significant in that accessory spleens may be left in the body by the surgeon when splenectomy is indicated for treatment.

Front 14

14. What causes splenic rupture?

Back 14

Splenic rupture is usually precipitated by a crushing injury or severe blow. Spontaneous ruptures are associated w/infectious mononucleosis, malaria, typhoid fever, and lymphoid neoplasms. These diverse entities can all cause rapid splenic enlargement, producing a thin, tense splenic capsule that is susceptible to rupture.

*Spontaneous rupture of chronically enlarged spleens is less likely b/c of reactive fibrosis that toughens the capsule and pulp.

Front 15

15.What is thymic hypoplasia, and in what condition is it usually seen?

Back 15

Thymic hypoplasia is seen in DiGeorge syndrome, accompanied by PTH developmental failures. This condition is marked by severe deficits in cell-mediated immunity and variable hypoparathyroidism.

DiGeorge syndrome is often associated w/other developmental defects as art of the 22q11 deletion syndrome.

Front 16

16. What are isolated thymic cysts?

Back 16

Isolated thymic cysts are uncommon lesions that are usually discovered incidentally postmortem or during surgery. They rarely exceed 4 cm in diameter, can be spherical or arborizing, and are lined by stratified to columnar epithelium. The fluid contents can be serous or mucinous and are often modified by hemorrhage.

While they are not clinically, significant, neoplastic thymic masses are often associated w/cysts that presumably develop b/c of distortion and compression of adjacent normal thymus.

Front 17

17. What is thymic hyperplasia?

When is it most frequently encountered?

Back 17

AKA thymic follicular hyperplasia.

Although follicular hyperplasia can occur in a number of chronic inflammatory and immunologic states, it is most freq encountered in myasthenia gravis, being present in 65-75% of cases.

Similar thymic changes are sometimes encountered in Graves disease, SLE, scleroderma, and RA as well as other autoimmune disorders.

Front 18

18. What are thymomas?

What are the two main types?

Back 18

This is a tumor of thymic epithelial cells. Thymomas have been classified according to the following categories:
1. Benign or encapsulated thymoma: cytologically and biologically benign
2. Malignant thymoma
a. Type I; also called invasive thymoma: cytologically benign but biologically aggressive and capable of local invasion and, rarely, distant spread
b. Type II, also called "thymic carcinoma"; cytologically malignant with all of the biologic features of cancer

Front 19

19. What is the prevalence of thymomas?

Back 19

All categoies of thymomas are tumors of adults, usually older than 40 years of age, and are rare in children. Males and females are affected equally. Most arise in the anterior superior mediastinum, but sometimes they occur in the neck, thyroid, pulmonary hilus, or elsewhere.

Front 20

20. What is the morphology of a generic thymoma?

Back 20

Macroscopically, thymomas are lobulated, firm, gray-white masses up to 15-20 cm in the longest dimension. They sometimes have areas of cystic necrosis and calcification even in tumors that later prove to be benign. The majority are encapsulated, but 20-25% of the tumors penetrate the capsule and infiltrate perithymic tissues and structures.

*Thymomas typically consist of jigsaw puzzle-type lobules separated by fibrous bands. Microscopically, virtually all are made up of a mixture of epithelial cells and a variable infiltrate of non-neoplastic thymocytes.

Front 21

21. What is the morphology of benign thymomoas?

Back 21

Benign thymomas are most often composed of medullary type epithelial cells or a mixture of medullary and cortical type epithelial cells. In medullary type thymomas, the epithelial cells are elongated or spindle shaped.

In mixed thymomas, there is an admixture of plumper, rounder, cortical type epithelial cells and a denser infiltrate of thymocytes.

*Hassall corpuscles are rarely present w/either pattern and, when found, often are poorly formed.

Front 22

22. What is the morphology of malignant thymoma type I?

Back 22

This refers to a tumor that, although cytologically benign, is locally invasive and has the capaicty for metastasis.

The epithelial cells are most commonly of the cortical variety, w/abundant cytoplasm and rounded vesicular nuclei, and are usually accompanied by immature thymocytes expressing TdT.

Palisading of epithelial cells about blood vessels is sometimes seen.

Front 23

23. What is the critical feature of malignant thymoma type I?

Back 23

The critical feature of malignant thymoma type I is penetration of the capsule and invasion into surrounding structures.

Front 24

24. What is the morphology of malignant thymoma type II?

Back 24

AKA "thymic carcinoma", this represents about 5% of thymomas. In contrast to Type I, these are cytologically malignant, having all the anaplastic features seen in other CAs.

Macroscopically, they are usually fleshy, obviously invasive masses sometimes accompanied by metastases to such sites as the lungs.

*Microscopically, most are squamous cell CAs, either well or poorly differentiated.

Front 25

25. What is lymphoepithleioma-like carcinoma?

Back 25

The next most common thymoma variant is the lymphoepithelioma-like carcinoma, a tumor composed of sheets of cells w/indistinct borders that bears a close histologic resemblance to nasopharyngeal CA.

About 50% of lymphoepithelioma-like carcinomas contain monoclonal EBV genomes, suggesting a role for this virus in their pathogenesis.

Front 26

26. What is the difference between malignant and benign thymic neoplasms?

Back 26

Thymic carcinomas tend to express CD5, a molecule that is normally restricted to T cells and a small subset of B cells, whereas cytologically benign thymomas and other carcinomas do not.

Front 27

27. What is the clinical course of thymomas?

Back 27

About 40% of thymomas present b/c of symptoms stemming from impingement on mediastinal structures, and another 30-50% present due to their association w/myasthenia gravis.

In addition to myasthenia gravis, other paraneoplastic syndromes, such as acquired hypogammaglobulinemia, pure red cell aplasia, Graves disease, pernicious anemia, dematomyositis-polymyositis, and Cushing syndrome, can be seen.

Front 28

28. What is the basis for the association of thymomas with autoimmune disorders?

Back 28

The thymocytes that arise within thymomas give rise to long lived CD4+ and CD8+ cells, and cortical thymomas rich in thymocytes are more likely to be associated w/autoimmune disease. Hence, it is possible that abnormalities in the selection or "education" of T cells w/in the disturbed environment of the neoplasm contribute to the development of autoimmune disorders.

Front 29

29. How does one estimate the hematopoietic marrow activity?

Back 29

A reasonable estimate of marrow activity is obtained by examining the ratio of fat cells to hematopoietic elements in bone marrow biopsy samples. In normal adults, this ratio is about 1:1, but with marrow hypoplasia (e.g., aplastic anemia), the proportion of fat cells is greatly increased.

Conversely, fat cells may disappear completely in diseases characterized by increased hematopoiesis (e.g., hemolytic anemias).

Front 30

30. What can cause marrow cells to be inaspirable?

Back 30

Certain disorders such as metastatic CAs and granulomatous diseases induce local marrow fibrosis, rendering the cells inaspirable.

Front 31

31. What are the limitations of biopsies?

Back 31

The limitation of biopsies is that tissue fixation and decalcification alter the appearance of marrow cells, making them less recognizable than in air dried aspirate.

Often tentative identification is based on the company they keep. Thus, a primitive cell found w/in a focus of maturing granulocytes is likely a myeloblast.

Front 32

32. What is the definition of anemia?

Back 32

Anemia is defined as a reduction below normal limits of the total circulating red cell mass.

In routine practice, anemia is defined as a reduction below normal in the volume of packed red cells, as measured by the HCT, or a reduction in the Hb concentration of the blood.

Front 33

33. What is MCV?

MCH?

Back 33

MCV is the mean cell volume; it is the average volume of a RBC

MCH is the mean cell Hb; it is the average content of Hb/RBC

Front 34

34. What is MCHC?

What is RBC distribution width?

Back 34

MCHC is the mean cell hemoglobin concentration; it is the average concentration of Hb in a given volume of packed RBCs.

RBC distribution width is the coefficient of variation of RBC volume.

Front 35

35. What are the common features of anemia?

Back 35

Whatever its cause, anemia leads to certain clinical features when severe. Pts appear pale. Weakness, malaise, and easy fatigability are common problems. The lowered O2 concentration of the circulating blood leads to dyspnea on mild exertion. The nails can become brittle. Anoxia can cause fatty change in the liver, myocardium, and kidney.

If fatty changes are severe enough, cardiac failure can develop and compound the respiratory difficulty caused by reduced oxygen transport. With acute blood loss and shock, oliguria and anuria can develop due to renal hypoperfusion.

Front 36

36. What are the effects of acute blood loss mainly due to?

Back 36

The effects of acute blood loss are mainly due to the loss of intravascular volume, which can lead to cardiovascular collapse, shock, and death.

If the pt survives, the blood volume is rapidly restored by shift of water from the interstitial fluid compartment. The resulting hemodilution lowers the HCT.

Front 37

37. How long does it take for the progeny of the CFU-Es to fully differentiate after blood loss?

Back 37

It takes about 5 days, and the differentiation is marked by the appearance of increased numbers of newly released red cells (reticulocytes) in the peripheral blood.

Front 38

38. What is the earliest change in the peripheral blood immediately after acute blood loss?

Back 38

The earliest change in the peripheral blood immediately after acute blood loss is leukocytosis, due to the mobilization of granulocytes from marginal pools.

Initially, RBCs appear normal in size and color. ***However, as marrow production increases, there is a striking increase in the reticulocyte count, reaching 10-15% after 7 days.***

Front 39

39. Does chronic blood loss induce anemia?

Back 39

Chronic blood loss induces anemia only when the rate of loss exceeds the regenerative capacity of the marrow or when iron reserves are depleted.

Front 40

40. What are 3 shared features of hemolytic anemias?

Back 40

1. A shortened red cell life space; i.e. premature destruction of red cells
2. Elevated erythropoietin levels and increased erythropoiesis in the marrow and other sites, to compensate for the loss of red cells
3. Accumulation of the products of Hb catabolism, due to an increased rate of red cell destruction

Front 41

41. Where does the physiologic destruction of senescent red cells take place?

Back 41

W/in the mononuclear phagocytic cells of the spleen.

In the great majority of hemolytic anemias, the premature destruction of red cells also occurs within the mononuclear phagocyte system (extravascular hemolysis), and causes splenomegaly.

Front 42

42. What causes intravascular hemolysis?

Back 42

Intravascular hemolysis of red cells is caused by mechanical injury, complement fixation, infection by intracellular parasites such as falciparum malaria, or exogenous toxic factors.

Mechanical injury caused by defective cardiac valves, thrombi w/in the microcirculation, or physical trauma can physically lyse red cells.

Complement fixation can occur on antibody-coated cells during transfusion of mismatched blood.

Front 43

43. What are 5 manifestations of intravascular hemolysis?

Back 43

1. Hemoglobinemia
2. Hemoglobinuria
3. Jaundice
4. Hemosiderinuria
5. ***Decreased serum haptoglobin is characteristic of intravascular hemolysis***

Front 44

44. In hemolytic anemias, is the serum bilirubin conjugated or unconjugated?

Back 44

Unconjugated - the level of hyperbilirubinemia depends on the functional capacity of the liver and the rate of hemolysis.

Front 45

45. What is extravascular hemolysis?

Back 45

Extravascular hemolysis takes place whenever red cells are rendered "foreign" or become less deformable.

Since extreme alterations in shape are required for red cells to navigate the splenic sinusoids successfully, reduced deformability makes the passage difficult and leads to sequestration w/in the cords, followed by phagocytosis.

Front 46

46. What are the features of extravascular hemolysis?

Back 46

W/extravascular hemolysis, hemoglobinemia and hemoglobinuria are not observed, and its principal features are anemia and jaundice.

However, some Hb escapes from phagocytes, leading to decreases in plasma haptoglobin.

Front 47

47. What is the morphology of hemolytic anemias?

Back 47

Anemia and lowered tissue oxygen tension stimulate increased production of erythropoietin, which leads to the appearance of increased numbers of erythroid precursors (normoblasts) in the marrow.

If the anemia is severe, extramedullary hematopoiesis can appear in the liver, spleen, and lymph nodes.

The accelerated erythropoiesis leads to a prominent reticulocytosis in the peripheral blood. Elevated biliary excretion of bilirubin promotes cholelithiasis.

Front 48

48. In general, hereditary disorders are due to _____ defects and acquired disorders are due to _____ factors...?

Back 48

In general, hereditary disorders are due to intrinsic defects and acquired disorders are due to extrinsic factors such as autoantibodies.

Front 49

49. What is hereditary spherocytosis?

Back 49

This is an inherited disorder caused by intrinsic defects in the RBC cytoskeletal membrane which renders erythrocytes spheroidal, less deformable, and vulnerable to splenic sequestration and destruction.

An autosomal dominant inheritance pattern is seen in 75% of cases.

Front 50

50. What is the chief protein component of the red cell membrane?

Back 50

Its chief protein component, spectrin, consists of two polypeptide chains, alpha and beta. The head regions of spectrin dimers self associate to form tetramers, while the tails associate w/actin oligomers. Each actin oligomer can bind multiple spectrin tetramers, thus creating a 2D spectrin-actin skeleton that is connected to the cell membrane by two distinct interactions.

Front 51

51. What are these two distinct interactions?

Back 51

1. Involving proteins ankyrin and band 4.2; which binds spectrin to the transmembrane ion transporter, band 3.

2. Protein 4.1; binds the tail of spectrin to another transmembrane protein, glycophorin A.

Front 52

52. What is the most common cause of autosomal dominant HS?

Back 52

The most common cause is a mutation of red cell ankyrin.

Another 20% of autosomal dominant cases are caused by mutations in band 3.

Front 53

53. So what's the problem in HS?

Back 53

Reduced membrane stability leads to loss of membrane fragments during exposure to shear stresses in the circulation. The loss of membrane relative to cytoplasm "forces" the cells to assume the smallest possible diameter for a given volume, namely, a sphere.

The spleen is the villain - red cells must undergo extreme deformation to leave the cords of Billroth and enter the sinusoids. As spherocytes are trapped in the spleen, the already sluggish circulation of the cords stagnates further, producing a progressively more hostile environment. Lactic acid accumulates and the pH falls, inhibiting glycolysis.

Front 54

54. What is the treatment for HS?

Back 54

The role of the spleen in the premature demise of the spherocytes is proved by the beneficial effect of splenectomy. The spherocytes persist, but the anemia is corrected.

Front 55

55. What is the most outstanding morphologic finding in HS?

Back 55

The spherocytes, apparent on smears as abnormally small, dark-staining (hyperchromic) red cells lacking the normal central zone of pallor.

Present also are changes associated w/all hemolytic anemias, including reticulocytosis, marrow hyperplasia due to increased erythropoiesis, hemosiderosis, and mild jaundice. Cholelithiasis occurs in 40-50% of affected adults. Moderate splenic enlargement is characteristic.

Front 56

56. What are the clinical features of HS?

Back 56

Anemia, spenomegaly, and jaundice. In a minority, HS presents at birth w/marked jaundice, requiring exchange transfusion. In 20-30% of pts, the disease is virtually asymptomatic b/c the decreased red cell survival is readily compensated for by increased erythropoiesis. In most, however, the compensatory changes are outpaced, producing a chronic hemolytic anemia.

Front 57

57. What is an aplastic crisis in HS?

Back 57

The generally stable clinical course is sometimes punctuated by an aplastic crisis, usually triggered by an acute parvovirus infection. Parvovirus infects and kills red cell progenitors, causing red cell production to cease until an effective immune response occurs in usually 1-2 weeks.

B/c the lifespan of red cells in HS is shortened to 10-20 days, cessation of erythropoiesis for even short time periods leads to sudden worsening of the anemia accompanied by reticulocytopenia.

Front 58

58. What is a hemolytic crisis in HS?

Back 58

Hemolytic crises are produced by intercurrent events leading to increased splenic destruction of red cells (e.g., infectious mononucleosis); these are clinically less significant than aplastic crises.

Front 59

59. What is osmotic lysis in HS?

Back 59

In 2/3 of pts, the red cells are abnormally sensitive to osmotic lysis. Spherocytes retain most of the cytoplasm they were born with and lose sodium and water during conditioning in the circulation, ***leading to an increased MCHC in most pts.***

Front 60

60. What about abnormalities in the hexose monophosphate shunt?

Back 60

Abnormalities in the hexose monophosphate shunt or glutathione metabolism resulting from deficient or impaired enzyme function reduce the ability of red cells to protect themselves against oxidative injuries, leading to hemolytic disease.

Front 61

61. What are the variants of G6PD?

Back 61

This is an X-linked disorder

Although there are several variants, only two, G6PD A- and G6PD Mediterranean, lead to clinically significant hemolysis.

A- is present in about 10% of American blacks, and is associated with progressive loss of G6PD in older RBCs. B/c the younger cells are not affected, hemolytic episodes are self limited.

In the Mediterranean variant, G6PD levels are much lower and hemolytic episodes are more severe. Ingestion of fava beans can cause hemolysis in G6PD deficiency b/c these legumes generate oxidants.

Front 62

62. How does deficiency in G6PD cause hemolysis?

Back 62

Compared to the most common normal variant, G6PD B, the half-life of G6PD Mediterranean is more markedly abnormal.

Both disease associated mutations result in misfolding of the protein, making it more susceptible to proteolytic degradation. B/c mature red cells do not synthesize new proteins, G6PD A- or G6PD Mediterranean enzyme activities fall quickly as red cells age to levels inadequate to protect against oxidant stress.

Front 63

63. What causes oxidant stress?

Back 63

This can occur due to ingestion of certain drugs or foods, or more commonly exposure to oxidant free radicals generated by leukocytes in the course of infections. Some drugs cause hemolysis only in those with the more severe Mediterranean variant. Many infections can trigger hemolysis; viral hepatitis, pneumonia, and typhoid fever are examples.

Fava beans can also cause hemolysis.

Front 64

64. What is the morphology of G6PD deficiency?

Back 64

In G6PD deficient cells, high levels of oxidants cause oxidation of reactive sulfhydryl groups on globin chains, which become denatured and form membrane bound precipitates, known as Heinz bodies. induce hemoglobin denaturation. The altered Hb precipitates as Heinz bodies, which attach to the inner cell membrane.

These are seen w/in red cells stained w/crystal violet as dark inclusions. Heinz bodies can damage the membrane sufficiently to cause intravasular hemolysis.

Front 65

65. How do Heinz bodies play a role in G6PD deficiency?

Back 65

As inclusion bearing red cells pass thru the splenic cords, macrophages pluck out the Heinz bodies. Due to membrane damage, some of these partially "bit" cells retain an abnormal shape ("bite cells").

Both bite cells and spherocytes are highly prone to trapping in splenic cords and rapid removal via erythrophagocytosis.

Front 66

66. What causes sickle cell disease?

Back 66

This is a hereditary hemoglobinopathy resulting from the substitution of a valine for a glutamic acid at the 6th position of the β-globin chain, transforming normal hemoglobin A into the mutant hemoglobin S.

Front 67

67. What are the common types of sickle cell disease?

Back 67

About 8% of black Americans are heterozygous for HbS. If an individual is homozygous for the sickle mutation, almost all the Hb in the red cell is HbS.

In heterozygotes, only about 40% of the Hb is HbS, the remainder being normal hemoglobins.

Where malaria is endemic in Africa, as many as 30% of the native population is heterozygous.

Front 68

68. What happens to HbS molecules when they are deoxygenated?

Back 68

When dexoygenated, HbS molecules undergo aggregation and polymerizaiton. Initially, the red cell cytosol converts from a freely flowing liquid to a viscous gel as HbS aggregates form. With continued deoxygenation, aggregated HbS molecules assemble into long needle-like fibers w/in red cells, producing a distorted sickle or holly-leaf shape.

Front 69

69. What happens w/repeated episodes of sickling?

Back 69

W/repeated episodes of sickling, membrane damage occurs and cells become irreversibly sickled, retaining their abnormal shape even when fully oxygenated.

The precipitation of HbS fibers also causes oxidant damage, not only in irreversibly sickled cells but also in normal appearing cells.

Front 70

70. How does calcium play a role in sickled cells?

Back 70

With membrane injury, red cells become loaded w/calcium, which is normally excluded rigorously.

Calcium ions activate a potassium ion channel, leading to the efflux of potassium and water, intracellular dehydration, and an increase in the MCHC.

Front 71

71. What is the most important factor in HbS?

Back 71

The most important factor is the amount of HbS and its interaction w/the other Hb chains in the cell.

Front 72

72. What is a sickle cell trait?

Back 72

Both the low concentraiton of HbS and the presence of interfering HbA act to prevent efficient HbS aggregation and polymerization, and thus red cells in hetero pts do not sickle except under conditions of severe hypoxia.

Such individuals have sickle cell trait, and asymptomatic carrier state.

In contrast, homozygous HbS individuals have full blown sickle cell anemia

Front 73

73. How does HbF affect HbS?

Back 73

Fetal Hb (HbF) inhibits the polymerization of HbS, and hence newborns do not manifest the disease until they are 5-6 mos of age, when the amt of HbF in the cells falls close to adult levels.

Front 74

74. How does HbC affect HbS?

Back 74

HbC, which has a point mutation in the β-globin chain leading to a substitution of lysine for glutamate at position 6.

HbC has a greater tendency to form aggregates w/deoxygenated HbS than HbA.

As a result, individuals with HbS and HbC have a symptomatic sickling disorder (HbSC) disease) that is generally milder than sickle cell anemia.

Front 75

75. The rate of HbS polymerization is strongly dependent upon...?

Back 75

The rate of HbS polymerization is strongly dependent upon the Hb concentration per cells, that is the MCHC.

Higher HbS concentrations increase the probability that aggregation and polymerization will occur during any given period of deoxygenation. ***Thus, intracellular dehydration which increases teh MCHC, facilitates sickling and vascular occlusion.***

Conversely, conditions that decrease the MCHC (α-thalassemia) reduce disease severity.

Front 76

76. How does pH affect sickling?

Back 76

A decrease in pH reduces the oxygen affinity of Hb, thereby increasing the fraction of deoxygenated HbS at any given oxygen tension and augmenting the tendency for sickling.

Front 77

77. How is the length of time red cells are exposed to low oxygen tension important?

What 2 factors play a role in this matter?

Back 77

Sickling of red cells is confined to microvascular beds where blood flow is sluggish. This is normally the case in the spleen and the bone marrow, which are affected by sickle cell disease.

Two factors play important roles in this matter: (1) inflammation, and (2) increased red cell adhesion.

As a result, inflamed vascular beds have longer red cell transit times and are prone to induce clinically significant sickling.

Front 78

78. What are the 2 main clinical manifestations of sickle cell disease?

Back 78

1. Chronic hemolysis
2. Ischemic tissue damage resulting from microvascular occlusions

Front 79

79. The red cell survival correlates with...?

Back 79

The red cell survival correlates with the percentage of irreversibly sickled cells in the circulation, supporting the concept that the hemolytic anemia results primarily from premature removal of irreversibly sickled cells.

Front 80

80. How is NO related to microvascular occlusions?

Back 80

It is thought that in pts with sickle cell anemia, plasma Hb (released from lysed RBC) binds to an inactivates NO.

Such reduction in bioavailable NO predisposes to increased vascular tone (narrowing) and platelet aggregation. These finding provide rationale for NO therapy in sickle cell disease.

Front 81

81. What is the morphology of the bone marrow in sickle cell disease?

Back 81

The bone marrow is hyperplastic b/c of a compensatory hyperplasia of eythroid progenitors. Expansion of the marrow leads to bone resporption and secondary new bone formation, resutling in prominent cheekbones and changes in the skill that resemble a crew cut appearance on xray.

Extramedullary hematopoiesis can also appear.

Front 82

82. What is the morphology of the spleen in sickle cell disease?

Back 82

The spleen is commonly enlarged. On histo exam, there is marked congestion of the red pulp, mainly due to the trapping of sickled red cells in the splenic cords and sinuses. This erythrostasis in the spleen leads to marked tissue hypoxia, thrombosis, infarction, and fibrosis.

Continued scarring causes progressive shrinkage of the spleen so that by adolescence or early adulthood only a small nubbin of fibrous tissue is left (autosplenectomy).

Front 83

83. What are some other morphologic features to know about sickle cell disease?

Back 83

Infarction secondary to vascular occlusions and anoxia can occu rin other tissues as well, including the bones, brain, kidney, liver, retina, and pulmonary vessels, the latter sometimes producing cor pulmonale.

Vascular stagnation in subcutaneous tissues often leads to leg ulcers in adult pts.

Gallstones can develop as well as jaundice.

Front 84

84. What are the three clinical problems in sickle cell disease?

Back 84

1. Severe anemia
2. Vaso-occlusive complications
3. Chronic hyperbilirubinemia

Front 85

85. Are those with sickle cell disease susceptible to infections?

Back 85

Increased susceptibility to infection with encapsulated organsism has two causes:

1. Splenic function is impaired
2. Defects in the alternative complement pathway impair opsonization of encapsulated bacteria such as penumococci and H. influenzae. Septicemia and meningitis caused by these two organisms are the most common causes of death in children with sickle cell anemia.

Front 86

86. What are vaso-occlusive crises (aka pain crises)?

Back 86

These represent episodes of hypoxic injury and infarction associated w/severe pain in the affected region. Although infection, dehydration and acidosis sometimes act as triggers, in most instance no causes are identified.

The most commonly involved sites are the bones, lungs, liver, brain, spleen, and penis. *In children, painful bone crises are common and often difficult to distinguish from acute osteomyelitis. They frequently manifest as the hand-foot syndrome, a dactylitis of the bones of the hands or feet or both.

Particularly dangerous are the crises involving the lungs, which typically present with fever, cough, chest pain, and pulmonary infiltrate (acute chest syndrome).

Front 87

87. What are sequestration crises?

Back 87

Sequestration crises occur in children w/intact spleens. Massive sequestration of sickled red cells leads to rapid splenic enlargement, hypovolemia, and sometimes shock.

Front 88

88. What are aplastic crises?

Back 88

In aplastic crises, there is a transient cessation of bone marrow erythropoiesis due to an acute infection of erythroid progenitor cells by parvovirus B19.

Reticulocytes disappear from the peripheral blood, causing a sudden and rapid worsening of anemia.

Front 89

89. What is one possible treatment for sickle cell anemia?

Back 89

Hydroxyurea acts as an anti-inflammatory agent by inhibiting the production of white cells, which may reduce inflammation-related red cell stasis and sickling.

Also, hydroxyurea increases the mean red cell volume and thereby decreases the concentration of HbS.

Lastly, hydroxyurea can be oxidized by heme groups to produce NO.

Front 90

90. What is the abnormality common to all β-thalassemias?

Back 90

Diminished synthesis of structurally normal β-globin chains, coupled with unimpaired synthesis of α-chains.

Front 91

91. What are the two categories of β-thalassemia?

Back 91

1. β⁰-thalassemia, associated w/total absence of the β-globin chains in the homozygous state
2. β⁺-thalassemia, characterized by reduced (but detectable) β-globin synthesis in the homozygous state.

*Most are point mutations - gene deletions are uncommon in β-thalassemia.

Front 92

92. What are the 3 mechanisms of mutations in β-thalassemia?

Which is most common?

Back 92

1. Promoter region mutations - produces β⁺-thalassemia
2. Chain terminator mutations - produces β⁰-thalassemia
3. Splicing mutations *MOST COMMON FORM* - produces β⁰ or β⁺ forms

Front 93

93. What are the two mechanisms by which impaired β-globin synthesis results in anemia?

Back 93

1. Deficit in HbA synthesis produces "under-Hb", hypochromic, microcytic red cells w/subnormal oxygen transport capacity.

2. Diminished survival or red cells and their precursors, resulting from the imbalance in the alpha and beta chain synthesis. Thus, free α-chains precipitate w/in the normoblasts, forming insolubule inclusions.

Front 94

94. What is the proximal cause of most red cell pathology in β-thalassemia?

Back 94

Cell membrane damage is the proximal cause of most red cell pathology. Many developing normoblasts in the marrow succumb to these membrane lesions, undergoing apoptosis.

In severe β-thalassemia, about 70-85% of normoblasts suffer this fate, leading to ineffective erythropoiesis. Also, the inclusion bearing red cells deprived from precursors escaping intramedullary death are prone to splenic sequestration and destruction.

Front 95

95. In β-thalassemia, marked anemia produced by ineffective erythropoiesis and hemolysis leads to what other problems?

Back 95

Erythropoietin secretion in the setting of severe uncompensated anemia leads to massive erythroid hyperplasia in the marrow and sites of extramedullary hematopoiesis.

Extramedullary hematopoiesis involves the liver, spleen, and lymph nodes, and in extreme cases, produces extraosseous masses in the thorax, abdomen,a nd pelvis.

***Also another disastrous complication seen in severe β-thalassemia is excessive absorption of dietary iron. This can sometimes induce secondary hemochromatosis.

Front 96

96. What is β-thalassemia major?

Back 96

In general, individuals homozygous for β-thalassemia genes β⁺β⁺ or β⁰β⁰) have a severe, transfusion-dependent anemia called β-thalassemia major.

Front 97

97. What is β-thalassemia minor or β-thalassemia trait?

Back 97

Heterozygotes with one β-thalassemia gene and one normal gene usually have a mild microcytic anemia that causes no symptoms. This conditionon is referred to as β-thalassemia minor or β-thalassemia trait

Front 98

98. What is β-thalassemia intermedia?

Back 98

β-thalassemia intermedia is of intermediate severity and is genetically heterogeneous. This category includes milder variants of β⁺β⁺ or β⁺β⁰-thalassemia and unusually severe variants of heterozygous β-thalassemia.

Front 99

99. What about individuals with β-thalassemia and α-thalassemia gene defects?

Back 99

Ironically, the presence of an α-thalassemia gene defect often decreases the severity of β-thalassemia major, since the imbalance in α and β chain synthesis is lessened; this combination can also result in a clinical phenotype resembling β-thalassemia intermidia.

Front 100

100. What are the features of thalassemia major?

Back 100

β-thalassemia is most common in Mediterranean countries and parts of Africa and Southeast Asia.

In this type, the anemia manifests 6-9 mos after birth, as Hb synthesis switches from HbF to HbA.

The peripheral blood smear shows severe red cell morphologic abnormalities, including marked anisocytosis and poikilocytosis, microcytosis, and hypochromia.

Inclusions of aggregated alpha chains are efficiently removed by the spleen and not easily found in peripheral blood smears.

*HbF is markedly increased and indeed constitutes the major red cell hemoglobin.

Front 101

101. What is the morphology of the β-thalassemias?

Back 101

In the untransfused pt, there is striking expansion of hematopoietically active marrow, particularly in facial bones. This erodes existing cortical bone and induces new bone formation, giving rise to a crew cut appearance on X-rays.

Both mononuclear phagocytic cell hyperplasia and extramedullary hematopoiesis contribute to enlargement of the spleen.

*Iron deposition often causes damage to several organs, most notably the heart, liver, and pancreas.

Front 102

102. What is the clinical course of β-thalassemia major?

Back 102

The clinical course of β-thalassemia major is brief unless blood transfusions are given. untreated children suffer from growth retardation and die at an early age from the profound effects of anemia. Blood transfusions not only improve the anemia but also suppress secondary features related to excessive erythropoiesis.

Cardiac disease resulting from progressive iron overload and secondary hemochromatosis is an important cause of death. Administration of iron chelators can forestall this complication.


Bone marrow transplantation from an HLA-identical sibling is currently the only therapy offering a cure.

Front 103

103. What is the clinical course in β-thalassemia minor?

Back 103

Thalassemia minor is much more common than thalassemia major and effects the same ethnic groups. Most pts are heterozygous carriers. Thalassemia trait may offer resistance against faciparum amlaria, accounting for its prevalence in parts of the world where malaria is endemic. This pts are usually asymptomatic, and anemia is mild if present.

Hb electrophresis characteristically reveals an increase in HbA₂, to 4-8% of the total Hb (normal = 2.5%). HbF levels can be normal or slightly increased.

Front 104

104. Why is recognition of β-thalassemia trait important?

Back 104

1. Differentiation from the hypochromic microcytic anemia of iron deficiency
2. Genetic counseling

Front 105

105. What are the α-thalassemias?

Back 105

The α-thalassemias are characterized by reduced or absent synthesis of α-globin chains.

The anemia that results stems from both lack of adequate Hb and the effects of excess unpaired non-α chains (β,γ,δ).

Front 106

106. What are the pathologic mechanisms in α-thalassemia?

Back 106

In the newborn with α-thalassemia, excess unpaired γ-globin forms γ4-tetramers known as hemoglobin Barts, whereas in adults excess β-globin chains form β4-tetramers known as HbH.

Since free β and γ chains are more soluble than free α chains and form fairly stable homotetramers, hemolysis and ineffective erythropoiesis are less severe than in β-thalassemias.

Front 107

107. What are the most common causes of reduced α-chain synthesis in α-thalassemia?

Back 107

Deletion of α-globin genes.

Thalassemia syndromes stem from combos of deletions that remove 1-4 α-globin gene copies. The severity of the syndrome is related to the number of missing α-globin genes.

Front 108

108. What is the silent carrier state of α-thalassemia?

Back 108

This occurs if a single α-globin gene is deleted. These individuals are completely asymptomatic.

Front 109

109. What is the α-thalassemia trait?

Back 109

This is caused by a deletion of two α-globin genes.

The two involved genes can be from the same chromosome (α/α -/-) or one α-globin gene can be deleted from each of the two chromosomes (α/- α/-).

Both genotypes produce similar deficiencies of α-globin chains and are clinically identical.

***Only matings involving individuals with the (α/α -/-) genotype are at risk for producing offspring with hydrops fetalis.***

Front 110

110. What is Hemoglobin H disease?

Back 110

This is caused by deletion of three α-globin genes.

With only one normal α-globin gene, the synthesis of α chains is markedly reduced and tetramers of excess β-glboin, called HbH, form. HbH has extremely high affinity for oxygen and therefore is not useful for oxygen exchange, leading to tissue hypoxia disproportionate to the level of hemoglobin.

*The instability of HbH is a major cause of anemia, as precipitates of oxidized HbH form in older red cells, which are then removed by splenic macrophages. This produces a moderately severe anemia resembling β-thalassemia intermedia.

Front 111

111.What is hydrops fetalis?

Back 111

This most severe form of α-thalassemia is caused by deletion of all four α-globin genes.

Signs of fetal distress usually become evident by the third trimester of pregnancy. The fetus shows severe pallor, generalized edema, and massive hepatosplenomegaly similar to that seen in erythroblastosis fetalis.

Front 112

112. What is paroxysmal nocturnal hemoglobinuria?

Back 112

This is the only hemolytic anemia caused by an acquired intrinsic defect in the cell membrane.

PNH results from acquired mutations in phosphatidylinositol glycan A (PIGA), which is essential for the synthesis of the GPI anchor.

Only the active PIGA gene needs to be mutated to produce a functional deficiency; all its clonal progeny (red cells, white cells, and platelets) are deficient in proteins attached to the cell membrane via GPI. ***Several GPI-linked proteins inactivate complements; this absence in PNH renders blood cells unusually sensitive to lysis by complement.***

Front 113

113. What are the 3 GPI-linked proteins that regulate complement?

Back 113

1. Decay accelerating factors (CD55)
2. Membrane inhibitor of reactive lysis (CD59)
3. C8 binding protein

*All of these are deficient in PNH.

Front 114

114. Which GPI-linked protein is the most important in PNH?

Back 114

CD59. It is a potent inhibitor of C3 convertase, and thereby prevents spontaneous activation of the alternative complement pathway in vivo.

Front 115

115. What is the hemolysis like in PNH?

Back 115

The intravascular hemolysis is actually paroxysmal and nocturnal in only 25% of cases. Chronic hemolysis w/o dramatic hemoglobinuria is more common.

During the disease course, hemosiderinuria eventually leads to iron deficiency. Episodic venous thrombosis, often involving the hepatic, portal, or cerebral veins can sometimes manifest in some cases and be fatal.

Front 116

116. PNH often arises in which settings?

Back 116

PNH often arises in the setting of primary bone marrow failure (aplastic anemia), which can be caused by immune-mediated destruction or suppression of marrow stem cells.

PNH pts are also at increased risk for developing acute myelogenous leukemia.

Front 117

117. The Dx of immunohemolytic anemias requires what tests?

Back 117

The Dx of immunohemolytic anemias require the detection of antibodies and/or complement on pt red cells. This is done using the direct Coombs antiglobulin test. In this test, pt red cells are mixed with antisera specific for human Igs or complement. if either is present, red cells are crosslinked causing clumping or agglutination.

The indirect Coombs antiglobulin test, in which pt serum is tested for its ability to agglutinate defined test red cells, can then be used to characterize the target of the autoantibody. *Also, the temperature dependence of this reaction helps to define the type of antibody responsible.

Front 118

118. What is warm antibody immunohemolytic anemia?

Back 118

This is the most common form of immune hemolytic anemia. About half of cases are idiopathic (primary); the remainder arise secondarily in the setting of a predisposing condition or drug exposure.

Most causative antibodies are of the IgG class; sometimes IgA are present.

Front 119

119. What is the hemolysis like in warm antibody immunohemolytic anemia?

Back 119

Most red cell destruction in this form is extravascular. IgG coated red cells bind Fc receptors on monocytes and splenic macrophages, which results in loss of red cell membrane during "partial" phagocytosis.

*Moderate splenomegaly is characteristic of this form of anemia*

In many cases, the antibodies are directed against the Rh blood group antigens.

Front 120

120. What is cold antibody immunohemolytic anemia?

Back 120

This form is caused by so called cold agglutinins, IgM antibodies that bind and agglutinate red cells avidly at low temps. It is less common than warm antibody immunohemolytic anemia.

Such antibodies appear acutely durign the recovery phase of certain infectious disorders, such as mycoplasma pneumonia and IM. Other agents associated with this form of anemia include CMS, influenza virus, and HIV.

Front 121

121. What is the pathophysiology behind cold antibody immunohemolytic anemia?

Back 121

These symptoms result form binding of IgM to red cells at sites such as exposed fingers, toes, and ears where the temp is cold. IgM binding agglutinates red cells and rapidly fixes complement on their surface. As the blood recirculates and warms, IgM is rapidly released, usually before complement mediated hemolysis can occur. However, the transient interaction w/IgM is sufficient to deposit sublytic quantities of C3b, leading to rapid removal of affected red cells in the liver and spleen.

Front 122

122. What are the clinical symptoms of cold antibody immunohemolytic anemia?

Back 122

The hemolysis is of variable severity. Vascular obstruction caused by red cell agglutinates results in pallor, cyanosis of the body parts exposed to cold temps, and Raynaud phenomenon.

Front 123

123. What is cold hemolysin hemolytic anemia?

Back 123

This anemia occurs in paroxysmal cold hemoglobinuria, manifesting as acute intermittent massive intravascular hemolysis after exposure to cold.

Autoantibodies are IgG directed against the P blood group antigen.

They attach to the RBCs and fix complement at low temps; when the temp is elevated, hemolysis occurs.

Most cases follow infections such as mycoplasma pneumonia, measles, mumps, and ill-defined viral and flu syndromes.

Front 124

124. What are Donath-Landsteiner antibodies?

Back 124

The autoantibodies in cold hemolysin hemolytic anemia (IgG directed against the P blood group antigen) are also known as Donath-Landsteiner antibodies. This was first recognized in associated with syphilis.

Front 125

125. What are the hemolytic anemias caused by trauma?

Back 125

Hemolytic anemias caused by cardiac valve prostheses, or narrowing or obstruction of the microvasculature, are most important clinically.

Severe traumatic hemolytic anemia is more frequently associated with artificial mechanical valves than bioprosthetic porcine valves.

Front 126

126. What is microangiopathic hemolytic anemia?

Back 126

Microangiopathic hemolytic anemia occurs when red cells are forced to squeeze thru abnormally narrowed small vessels. Narrowing is most often caused by fibrin deposition in association with DIC.

Front 127

127. What is the common feature among all hemolytic anemias caused by trauma?

Back 127

A microvascular lesion that causes mechanical injury to circulating red cells. This damage is evident in peripheral blood smears in the form of red cell fragments (schistocytes), "burr cells", "helmet cells", and "triangle cells").

Front 128

128. What is the main problem that causes megaloblastic anemias?

Back 128

The magaloblastic anemias constitute a diverse group of entities, having in common impaired DNA synthesis and distinctive morphologic changes in the blood and bone marrow.

Erythroid precursors and red cells are abnormally large due to defective cell maturation and division.

Front 129

129. How does vitamin B12 and folic acid cause megaloblastic anemia?

Back 129

Vitamin B12 and folic acid are coenzymes required for synthesis of thymidine, one of the four bases found in DNA.

A deficiency of these vitamins or impairment in their metabolism results in defective nuclear maturation due to deranged or inadequate DNA synthesis with an attendant delay or block in cell division.

Front 130

130. What does the peripheral blood exam show in megaloblastic anemias?

Back 130

It reveals pancytopenia, as all myeloid lineages are affected. There is marked variation in the size and shape of red cells (anisocytosis), which nonetheless are normochromic.

*Many red cells are macrocytic and oval, with MCV above 100 fl. The MCHC is not elevated.

*Neutrophils are also larger than normal and hypersegmented; that is, they have 5-6 or more nuclear lobules. The marrow is usually marked hypercellular.

Front 131

131. In what cells is megaloblastic change detected?

Back 131

In all stages of red cell development. The most primitive cells (promegaloblasts) are large, with a deeply basophilic cytoplasm, prominent nucleoli, and a distinctive fine nuclear pattern. As these cells differentiate and begin to accumulate Hb, the nucleus retains its finely distributed chromatin, and thus fails to undergo the chromatin clumping typical of the normoblast.

B/c DNA synthesis is impaired in all proliferation cells, granulocytic precursors also display nuclear cytoplasmic asynchrony in the form of giant metamyelocytes and band forms.

Front 132

132. What about the marrow in megaloblastic anemia?

Back 132

The marrow hyperplasia usually seen in megaloblastic anemias is a response to increased levels of growth factors such as erythropoietin. However, due to the derangement in DNA synthesis, most myeloid precursors undergo apoptosis in the marrow, leading to pancytopenia.

The anemia is further exacerbated by increased hemolytic destruction of red cells in the periphery.

Front 133

133. What is pernicious anemia?

Back 133

Pernicious anemia is a specific form of megaloblastic anemia caused by atrophic gastritis and an attendant failure of intrinsic factor production that leads to vitamin B12 deficiency.

Absorption of vitamin B12 requires intrinsic factor, which is secreted by the parietal cells of the fundic mucosa.

Front 134

134. What is the fundamental cause of impaired DNA synthesis in vitamin B12 deficiency?

Back 134

The fundamental cause of impaired DNA synthesis is the reduced availability of FH4, most of which is trapped as N5-methyl FH4.

Whatever the mechanism, lack of folate is the proximate cause of anemia in vitamin B12 deficiency, as the anemia inevitably improves w/admin of folic acid.

Front 135

135. A deficiency in vitamin B12 leads to increased levels of what...?

Back 135

Leads to increased plasma and urine levels of methylmalonic acid. interruption of the succinyl pathway and consequent build-up of methylmalonate and propionate could lead to the formation and incorporation fo abnormal fatty acids into neuronal lipids.

*It has been suggested that this biochemical abnormality predisposes to myelin breakdown and thereby produces the neurologic complications of vitamin B12 deficiency.

Front 136

136. What are 7 things that can cause vitamin B12 deficiency?

Back 136

Can result from impaired absorption, which has several causes:
1. Achlorhydria, which impairs viatamin B12 release from teh R protein bound form
2. Gastrectomy, which leads to the loss of intrinsic factor
3. Pernicious anemias
4. Resection of the distal ileum, which prevents absorption of intrinsic factor-B12 complex
5. Malabsorption syndromes
6. Increased requirements (i.e. pregnancy)
7. Inadequate diet (very uncommon)

Front 137

137. What are the causes of pernicious anemia?

Back 137

Pernicious anemia is believed to result form immunologically mediated, possibly autoimmune, destruction of gastric mucosa.

The resultant chronic atropic gastritis is marked by a loss of parietal cells, a prominent infiltrate of lymphocytes and plasma cells, and megaloblastic changes in mucosal cells similar to those found in erythroid precursors.

Front 138

138. What are the three types of antibodies that are present in many but not all with pernicious anemia?

Back 138

1. Type I antibody that blocks binding of vitamin B12 to intrinsic factor (75%)
2. Type II antibodies prevent IF or IF-B12 complex from binding to the ileal receptor
3. Antibodies against the gastric proton pump bind to parietal cells and affect acid secretion (85-90%).

-Type III antibodies are not specific for pernicious anemia or other autoimmune diseases.

Front 139

139. What type of immune response is generated by these autoantibodies?

Back 139

It is believed that an autoreactive T-cell (CD4+ T cells) response initiates gastric mucosa injury, triggering the formation of autoantibodies, which may exacerbate epithelial injury.

When the mass of intrinsic factor-secreting cells falls below a threshold, anemia develops.

Front 140

140. What is the morphology of the GI system in pernicious anemia?

Back 140

Abnormalities are found in the tongue and stomach. The tongue is beefy, shiny and glazed (atrophic glossitis). The changes in the stomach are those of atrophic gastritis.

*The most characteristic histologic alteration is the atrophy of the fundic glands, affecting both chief cells and parietal cells, the latter being virtually absent. The glandular lining epithelium is replaced by mucus-secreting goblet cells that resemble those lining the large intestine, a form of metaplasia referred to as intestinalization.*

Front 141

141. Patients w/pernicious anemia have an increased risk of...?

Back 141

Gastric cancer. The gastric atrophic and metaplastic changes are due to autoimmunity and not B12 deficiency; hence, parenteral admin of B12 corrects the bone marrow changes, but gastric atrophy and achlorhydria persist.

Front 142

142. What are the morphologic changes in the CNS in pernicious anemia?

Back 142

The principal alterations involve the spinal cord, where there is degeneration of myelin in the dorsal and lateral tracts, sometimes followed by loss of axons.

These changes give rise to spastic paraparesis, sensory ataxia, and severe paresthesias in the lower limbs. Less freq, degenerative changes occur in the ganglia of the posterior roots and in peripheral nerves.

Front 143

143. What are the 10 diagnostic features in pernicious anemia?

Back 143

1. A moderate to severe megaloblastic anemia
2. Leukopenia with hypersegmented granulocytes
3. Mild to moderate thrombocytopenia
4. Mild jaundice due to ineffective erythropoiesis and peripheral hemolysis of red cells
5. Neurologic changes related to involvement of the posterolateral spinal tracts
6. Achlorhydria even after histamine stimulation
7. Inability to absorb an oral dose of cobalamin (Schilling test)
8. Low serum levels of B12
9. Elevated levels of homocysteine and methylmalonic acid in the serum
10. A striking reticulocytic response and improvement in HCT levels beginning about 5 days after admin of B12.

****Serum antibodies to intrinsic factor are highly specific for pernicious anemia.

Front 144

144. Can high dose vitamin B12 treat pernicious anemia?

Back 144

With parenteral or high dose oral vitamin B12, the anemia can be cured and the peripheral neurologic changes reversed, or at least halted in their progression, but the changes in the gastric mucosa are unaffected.

Overall longevity can be restored virtually to normal.

Front 145

145. What is anemia of folate deficiency?

Back 145

A deficiency of folic acid, more properly pteroylmonoglutamic acid, results in a megaloblastic anemia having the same characteristics as that caused by vitamin B12 deficiency. However, the neurologic changes seen in vitamin B12 deficiency do not occur.

Front 146

146. Again, what is the common problem in folate deficiency?

Back 146

Suppressed synthesis of DNA is the immediate cause of megaloblastosis.

This is the same denominator in vitamin B12 deficiency, and thus it is essential to exclude vitamin B12 deficiency in megaloblastic anemia before initiating therapy with folate.

Front 147

147. If folic acid is common in normal diets in adequate amts, how can a deficiency occur?

Back 147

The folic acid in these foods is largely in the form of folylpolyglutamates. Despite their abundance in raw foods, polyglutamates are sensitive to heat; boiling, steaming, or frying of foods for 5-10 minutes destroys up to 95% of the folate content.

Front 148

148. What are the 4 major causes of folic acid deficiency?

Back 148

1. Inadequate intake, usually in those living on marginal diets (i.e.chronic alcoholics, elderly, and the indigent)
2. Malabsorption syndromes (e.g., tropical and nontropical sprue)
3. Increased demand (pregnancy, infancy, hemolytic anemias, or disseminated CA)
4. Admin of folate antagonists such as methotrexate, a chemotherapeutic agent.

Front 149

149. How is the Dx of megaloblastic anemia resulting from a deficiency of folic acid made?

Back 149

Induces a megaloblastic anemia clinically and hematologically indistinguishable from that seen in vitamin B12 deficiency.

*Dx can be made only by demonstration of decreased folate levels in the serum or red cells. As in vitamin B12 deficiency, serum homocysteine levels are also increased.

Front 150

150. What maintains the body's iron balance?

Where is iron found in the body?

Back 150

Iron balance is maintained largely by regulated the absorption of dietary iron.

Approx 80% of the functional iron is found in Hb; myoglobin and iron containing enzymes such as catalase and cytochromes contain the rest. The storage pool represented by hemosiderin and ferritin contains approx 15-20% of the total body iron.

Front 151

151. Serum levels of _______ correlate well with body iron stores...?

Back 151

Plasma ferritin is derived largely from the storage pool of body iron and thus its levels correlate well with body iron stores.

Front 152

152. Where is most iron absorbed in the GI tract?

Back 152

Most is absorbed in the duodenum via the DMT1 transporter.

The HFE gene, which encodes and HLA-like transmembrane protein, is also clearly involved in regulation of iron absorption.

Front 153

153. What is hepcidin?

Back 153

An excellent candidate for a negative "iron metabolism regulatory hormone" is hepcidin, a small, liver-derived plasma peptide.

Hepcidin inhibits iron uptake in the duodenum and iron release from macrophages. The concentration of hepcidin falls as iron stores become depleted, and hepcidin knockout mice develop hemochromatosis. Conversely, overexpression of hepcidin in transgenic mice causes an iron defcieincy anemia.

***These findings suggest the existence of a hepcidin receptor on duodenal enterocytes.

Front 154

154. What are 4 causes of iron deficiency?

Back 154

1. Low dietary intake (rarely the cause of iron deficiency by itself in the US b/c the avg daily intake is more than enough for men and adequate for most women) malabsorption, excessive demand, and chronic blood loss.

2. Malabsorption caused by sprue and celiac disease or after gastrectomy

3. Increased demands (pregnancy, menstruating women)

4. Chronic blood loss; this is the most common cause of iron deficiency in the western world.

Front 155

155. A deficiency in iron in adult men and postmenopausal women must be attributed to...?

Back 155

Must be attributed to GI blood loss (cancer, ulceration, lesion) until proven otherwise.

Front 156

156. What are the clinical features of iron deficiency?

Back 156

***Induces a hypochromic, microcytic anemia.***

Also, depletion of iron enzymes in cells throughout the body can cause koilonychia, alopecia, atrophic changes in the tongue and gastric mucosa, and intestinal malabsorption.

Front 157

157. What is the Plummer-Vinson triad?

Back 157

1. Microcytic hypochromic anemia
2. Atrophic glossitis
3. Esophageal webs

Front 158

158. What is a diagnostically significant finding in iron deficiency in the bone marrow?

Back 158

The disappearance of stainable iron from mononuclear phagocytic cells in the bone marrow, which is assessed by performing Prussian blue stains on aspirated or sections bone marrow.

Poikilocytosis (abnormal shapes) in the form of small, elongated red cells (pencil cells) is also characteristic.

Front 159

159. What are the serum iron and ferritin levels and the TIBC in iron deficiency anemia?

Back 159

The serum iron and ferritin levels are low, and the TIBC is high.

Low serum iron with increased TIBC results in a reduction of transferrin saturation levels to below 15%.

Front 160

160. What are three groups of anemia of chronic disease?

Back 160

1. Chronic microbial infections, such as osteomyelitis, bacterial endocarditis, and lung abscess
2. Chronic immune disorders, such as RA and regional enteritis
3. Neoplasms, such as Hodgkin lymphoma and carcinomas of the lung and breast

Front 161

161. What are the common features characterizing anemia in these chronic diseases?

Back 161

There is low serum ion and reduced TIBC in association with abundant stored iron in the mononuclear phagocytic cells.

This combo suggests some impediment in the transfer of iron from the storage pool to the erythroid precursors.

Front 162

162. Why do marrow erythroid progenitors NOT proliferate adequately in anemia of chronic disease?

Back 162

This is b/c erythropoietin levels are inappropriately low for the degree of anemia.

The reduction in renal erythropoietin generation is caused by IL-1, TNF, and IFN-y, secretion of which is triggered by the underlying chronic inflammatory or neoplastic disease.

These cytokines also stimulate hepcidin synthesis in the liver, which in turn inhibits the release of iron from the storage pool.

Front 163

163. What is aplastic anemia?

Back 163

Characterized by a failure or suppression or disappearance of multipotent myeloid stem cells; neutropenia, anemia, and thrombocytopenia (pancytopenia) result.

Most cases of aplastic anemia of known etiology follow exposure to chemical and drugs.

Front 164

164. What are the 4 known causes of aplastic anemia?

Back 164

Idiopathic in 60% of cases

Known causes are:
1. Myelotoxic drugs or chemicals (6-MP, vincristine, and busulfan)
2. Total body irradiation
3. Infections (viral hepatitis of non-A, non-B, non-C, and non-G types)
4. Inherited diseases (e.g. Fanconi anemia)

Front 165

165. What is Fanconi anemia?

Back 165

Fanconi anemia is a rare autosomal recessive disorder caused by defects in a component of a multiprotein complex required for DNA repair.

Marrow hypofunction in Fanconi anemia becomes evident early in life and is accompanied by multiple congenital anomalies, such as hypoplasia of the kidney and spleen and hypoplastic anomalies of bone, often involving the thumbs or radii.

Front 166

166. What is the pathogenesis of aplastic anemia?

Back 166

Stem cell alterations may be due to environmental insults, drug exposure, or infections. In idiopathic cases, stem cell failure may be due to:

1. Primary defect in the number or function of stem cells; in some case due to mutagen exposure. Occasionally, genetically damaged stem cells can transform to acute leukemias.

2. Suppression of antigenically altered stem cells by T cell mediated immune mechanisms.

Front 167

167. What is the morphology of aplastic anemia?

Back 167

The markedly hypocellualr bone marrow is largely devoid of hematopoietic cells; often only fat cells, fibrous stroma, and scattered or clustered foci of lymphocytes and plasma cells remain. A marrow aspirate often yields little material (a "dry tap").

Front 168

168. What is the clinical course of aplastic anemia?

Back 168

The onset is usually insidious. Initial manifestations depend on which cell line is affected. Anemia can cause progressive weakness, pallor, and dyspnea. Petechiae and ecchymoses can herald thrombocytopenia. Granulocytopenia can manifest as frequent and persistent minor infections or the sudden onset of chills, fever, and prostrations.

***Splenomegaly is characteristically absent; if present, the Dx of aplastic anemia should be seriously questioned.***

Front 169

169. How does one distinguish aplastic anemia from other causes of pancytopenia, such as myelodysplastic syndromes?

Back 169

In aplastic anemia, the marrow is hypocellular, whereas myeloid neoplasms are associated with hypercellular marrow filled with abnormal myeloid progenitors.

Front 170

170. What is pure red cell aplasia?

Back 170

Pure red cell aplasia is a form of marrow failure characterized by a marked hypoplasia of marrow erythroid elements in the setting of normal granulopoiesis and thrombopoiesis.

Pure red cell can be primary, or they can arise secondarily to neoplasms, particularly thymic tumors (thymomas) and large granular lymphocytic leukemia. due to the absence of RBC precursors.

Front 171

171. What is myelophthisic anemia?

Back 171

Space occupying lesions that destroy or distort the marrow architecture depress productive capacity.

Associated w/pancytopenia and frequently w/the appearance of white and red blood cell precursors in the peripheral blood.

Most common cause is metastatic cancer, most often carcinomas arising in the breast, lung, and prostate.

Front 172

172. What are 2 other conditions that can be associated with anemia?

Back 172

Diffuse liver disease and chronic renal failure.

Front 173

173. Diffuse liver disease (toxic, infectious or cirrhotic) and anemia

Back 173

The anemia is primarily due to bone marrow failure; often exacerbated by variceal bleeding or folate deficiency

Front 174

174. Chronic renal failure and anemia

Back 174

Chronic renal failure is almost always associated w/anemia.

The basis is multifactorial, but inadequate erythropoietin production is most important.

Treatment w/recombinant erythropoietin usually yields significant improvement.

Front 175

175. What is polycythemia?

Back 175

Polycythemia, or erythrocytosis, denotes an abnormally high concentration of RBCs, usually w/a corresponding increase in Hb level.

The increase in red cells can be relative, when there is hemoconcentration due to decreased plasma volume, or absolute when there is an increase in total red cell mass.

Front 176

176. What is relative polycythemia?

Back 176

Relative polycytemia results from any cause of dehydration, such as deprivation of water, prolonged vomiting, diarrhea, or excessive use of diuretics.

Front 177

177. What is Gaisbock syndrome?

Back 177

Relative polycythemia is also associated with an obscure condition of unknown etiology called stress polycythemia, or Gaisbock syndrome. Affected individuals are usually hypertensive, obese, and anxious.

Front 178

178. What is absolute polycythemia?

Back 178

Absolute polycythemia is primary when it results from an intrinsic abnormality of the myeloid stem cells and secondary when the red cell progenitors are responding to increased levels of erythropoietin.

Primary polycythemia (polycythemia vera) is one of several neoplasms originating from myeloid stem cells.

Front 179

179. What is congenital polycythemia?

Back 179

Another much less common form of primary polycythemia results from mutations in the erythropoietin receptor that cause hyperresponsiveness to erythropoietin. Affected individuals have congenital polycythemia.

Front 180

180. What can cause secondary polycythemia?

Back 180

Secondary polycythemias can be caused by an increase in erythropoietin secretion that is physiologically appropriate (e.g., chronic hypoxia) or inappropritate (pathologic).

Front 181

181. Excessive bleeding can result form what 4 things...?

Back 181

1. Increased fragility of vessels
2. Platelet deficiency or dysfunction
3. Derangement of coagulation
4. Combination of these

Front 182

182. What are bleeding time tests?

Back 182

This measures the time taken for a standardized skin puncture to stop bleeding and provides and in vivo assessment of platelet response to limited vascualr injury.

The reference range depends on the method and varies from 2-9 minutes. Prolongation generally indicates a defect in platelet numbers or function.

Front 183

183. How are platelet counts evaluated?

Back 183

Platelet counts are obtained on anticoagulated blood using an electronic particle counter. The reference range is from 150-300 x 10^3 /uL.

Counts well outside this range need to be confirmed by a visual inspection of a peripheral blood smear, as clumping of platelets can cause spurious thrombocytopenia during automated counting, and high counts may be indicative of a myeloproliferative disorder.

Front 184

184. What is PT?

Back 184

Prothrombin time assay tests the extrinsic and common coagulation pathways. The clotting of plasma after addition of an exogenous source of tissue thromboplastin and calcium ions is measured in seconds.

*A prolonged PT can result from deficiency or dysfunction of factor 5, 7, 10, prothrombin, or fibrinogen.

Front 185

185. What is PTT?

Back 185

Partial thromboplastin time assay tests the intrinsic and common clotting pathways. The clotting of plasma after addition of kaolin, cephalin, and calicum ions is measured in seconds. Kaolin serves to activate the contact-dependent factor 12, and cephalin substitutes for platelet phospholipids.

Prolongation of the PTT can be due to deficiency or dysfunction of factor 5, 8, 9, 10, 11, or 12, prothrombin, or fibrinogen.

Front 186

186. What are the infectious that can induce petechial and purpuric hemorrhages?

Back 186

Many infections do this, but especially implicated are meningococcemia, other forms of septicemia, infective endocarditis, and several of the rickettsioses.

The involved mechanism is presumably microbial damage to the microvasculature (vasculitis) or DIC.

Front 187

187. What 3 things are associated with microvascular bleeding resulting from impaired formation of collagens needed for support of vessel walls?

Back 187

1. Scurvy
2. Ehlers-Danlos syndrome
3. Cushing syndrome

Front 188

188. What is Henoch-Schonlein purpura?

Back 188

Systemic hypersensitivity reaction of unknown cause characterized by purpuric rash, abdominal pain, polyarthralgia, and acute glomerulonephritis

Associated with vascular and glomerular mesangial deposition of immune complexes.

Front 189

189. What is hereditary hemorrhagic telangiectasia?

Back 189

Hereditary hemorrhagic telangiectasia is an autosomal dominant disorder characterized by dilated, tortuous blood vessels with thin walls that bleed readily.

Bleeding can occur anywhere in the body but is most common under the mucous membranes of the nose (epistaxis), tongue, mouth, and eyes and throughout the GI tract.

Front 190

190. What about systemic amyloidosis and bleeding disorders?

Back 190

Amyloid infiltration of blood vessels can by due to systemic amyloidosis., which is associated with perivascular deposition fo amyloid and consequent weakening of blood vessel wall.

This is most commonly observed in plasma cell dyscrasias and is manifested as mucocutaneous petechiae.

Front 191

191. What is thrombocytopenia?

Back 191

A platelet count below 100,000/uL is generally considered to constitute thrombocytopenia. However, spontaneous bleeding does not become evident until the count falls below 20,000/uL. Bleeding resulting from thrombocytopenia alone is associated with a prolonged bleeding time a normal PT and PTT.

Spontaneous bleeding associated with thrombocytpenia most often involves small vessels. The common sites of such hemorrhage are the skin and mucous membranes of the GI and GU tracts.

Front 192

192. What are the 4 main categories of thrombocytpenia?

Back 192

1. Decreased production of platelets
2. Decreased platelet survival
3. Sequestration
4. Dilutional

Front 193

193. Decreased production of platelets can be due to...?

Back 193

This can accompany generalized diseases of bone marrow such as aplastic anemia and leukemias or result from diseases that affect the megakaryocytes somewhat selectively. In vitamin B12 or folic acid deficiency, there is poor development and accelerated destruction of megakaryocytes w/in the bone marrow b/c DNA synthesis is impaired.

Front 194

194. Decreased platelet survival can be due to?

Back 194

This can be due to immunologic or nonimmunologic causes. In the immune conditions, platelet destruction is caused by circulating antiplatelet antibodies or immune complexes. The antiplatelet antibodies can be directed against self antigen on the platelets or against platelet antigens that differ among individuals.

Front 195

195. What are common antigenic targets of both autoantibodies and alloantibodies?

Back 195

The platelet membrane glycoprotein complexes IIb-IIIa and Ib-IX

Autoimmune thrombocytopenias include ITP, certain drug induced thrombocytopenias, and HIV.

Alloimmune thrombocytopenias arise when an individual is exposed to platelets from another person as may occur after blood transfusion or during pregnancy.

Front 196

196. What about sequestions?

Back 196

Thrombocytopenia, usually moderate in severity, may develop in any pt with marked splenomegaly. When necessary hypersplenic thrombocytopenia can be ameliorated by splenectomy.

Front 197

197. What about dilutional thrombocytopenias?

Back 197

Massive transfusions can produce a dilutional thrombocytopenia.

Blood stored for longer than 24 hours contains virtually no viable platelets; thus, plasma volume and red cell mass are reconstituted by transfusion, but the number of circulating platelets is relatively reduced.

Front 198

198. What are the two clinical subtypes of primary ITP?

Back 198

Acute and chronic; both are autoimmune disorders in which platelet destruction results from the formation of antiplatelet autoantibodies.

Front 199

199. Immunologically mediated destruction of platelets occurs in what settings?

Back 199

SLE, AIDS, after viral infections, and as a complication of drug therapy.

These secondary forms of immune thrombocytopenia can sometimes mimic the idiopathic autoimmune variety, and this Dx should be made only after exclusion of other known causes of thrombocytpenia.

***SLE is a very important cause***

Front 200

200. What causes chronic ITP?

Back 200

Chronic ITP is caused by the formation of autoantibodies against platelet membrane glycoproteins, most often IIb-IIIa, or Ib-IX in 80% of pts. In the majority of cases, the antiplatelet antibodies are of the IgG class.

Front 201

201. How do these autoantibodies cause chronic ITP?

Back 201

Opsonized platelets are rendered susceptible to phagocytosis by the cells of the mononuclear phagocyte system. Splenectomy is helpful, since the spleen is the major site of removal of sensitized platelets.

There is some evidence that megakaryocytes may be damaged by autoantibodies, leading to impairment of platelet production.

Front 202

202. What are the principal morphological lesions of thrombocytopenic purpura?

Back 202

They are found in the spleen and bone marrow but they are not diagnostic. The spleen is normal in size. There is congestion of the sinusoids and hyperactivity and enlargement of the splenic follicles, manifested by the formation of prominent germinal centers. In many instances, scattered megakaryocytes are found w/in the sinuses and sinusoidal walls. This may represent a very mild form of extramedullary hematopoiesis driven by elevated levels of thrombopoietin.

Front 203

203. What is the importance of the bone marrow exam in thrombocytopenia?

Back 203

Bone marrow reveals a modestrly increased number of megakaryocytes. Some of apparently immature, w/large, nonlobulated single nuclei.

The improtance of the bone marrow exam is to rule out thrombocytopenias resulting from bone marrow failure. *A decrease in the number of megakaryocytes argues against the Dx of ITP.

Front 204

204. What are the clinical features of chronic ITP?

Back 204

Chronic ITP occurs most commonly in adult women younger than 40. The female to male ratio is 3:1. This disorder is often insidious in onset and is characterized by bleeding into the skin and mucosal surfaces.

Cutaneous bleeding is seen in the form of pinpoint hemorrhages (petechiae), especially prominent in the dependent areas where the capillary pressure is higher. Petechiae can beceom confluent, giving rise to ecchymoses. Often, there is a history of easy bruising, nosebleeds, beleding from the gums, and hemorrhages into soft tissues w/minor trauma.

The disease may manifest first w/melena, hematuria, or excessive menstrual flow. *Subarachnoid hemorrhage and IC hemorrhage are serous consequences.

Front 205

205. What supports the destruction of platelets being the cause of thrombocytopenia?

Back 205

The findings of a low platelet count and normal or increased megakaryocytes in the bone marrow. The bleeding time is prolonged, but PT and PTT are normal. Therefore, a Dx of ITP should be made only after other causes of platelet deficiencies have been ruled out.

Front 206

206. What is acute immune thrombocytopenic purpura?

Back 206

Like chronic ITP, this condition is caused by antiplatelet autoantibodies, but its clinical features are course are distinct.

Acute ITP is a disease of childhood. The onset of thrombocytopenia is abrupt and is preceded in many cases by a viral illness. Unlike the adult chronic form, the childhood disease is self-limited. Steroid therapy is indicated only if thrombocytopenia is severe.

Front 207

207. What is drug induced thrombocytopenia?

Back 207

The drugs most commonly involved are quinine, quinidine, sulfonamide antibiotics, and heparin. Heparin induced thrombocytopenia is important b/c this anticoagulant is sued widely.

*Most develop so-called type I thrombocytopenia, which occurs rapidly after onset of therapy, is modest in severity and clinically insignificant, and may resolve despite continuation of heparin therapy. It most likely results from a direct platelet-aggregating effect of heparin.

Front 208

208. What is type II thrombocytopenia?

Back 208

More severe; usually occurs 5-14 days after commencement of therapy and can, paradoxically, lead to life-threatening venous and arterial thrombosis.

It is caused by an immune reaction directed against a complex of heparin and platelet factor 4. It appears that heparin binding modifies the conformation of platelet factor 4, making it susceptible to immune recognition. Binding of antibody to platelet factor 4 produces immune complexes that activate platelets, promoting thrombosis even in the setting of marked thrombocytopenia.

Front 209

209. What is HIV-associated thrombocytopenia?

Back 209

This is the most common hematologic manifestation of HIV infection. Both impaired platelet production and decreased destruction are responsible. CD4 has also been demonstrated on megakaryocytes; infected megakaryocytes are prone to apoptosis and are impaired in terms of platelet production.

HIV infection also causes hyperplasia and dysregulation of B cells, which predispose to the development of immune-mediated thrombocytopenia.

Also, antibodies directed against platelet membrane glycoprotein IIb-III complexes are detected in some pts, which sometimes cross-react with HIV-associated gp120, and act as opsonins.

Front 210

210. What is the pentad of TTP?

Back 210

1. Fever
2. Thrombocytopenia
3. Microangiopathic hemolytic anemia
4. Transient neurologic deficits
5. Renal failure

Front 211

211. What is HUS?

Back 211

HUS is also associated with microangiopathic hemolytic anemia and thrombocytopenia but is distinguished from TTP by the absence of neurologic symptoms, the prominence of acute renal failure, and frequent affliction of children.

Front 212

212. What are the common fundamental features in TTP and HUS?

Back 212

Widespread formation of hyaline thrombi, comprised primarily of platelet aggregates, in the microcirculation.

Consumption of platelets leads to thrombocytopenia, and the intravascular thrombi provide a likely mechanism for the microangiopathic hemolytic anemia and widespread organ dysfunction.

PT and PTT are usually normal.

Front 213

213. What enzyme is often deficient in TTP?

Back 213

ADAMTS 13. This enzyme is designated "vWF metalloprotease" and it normally degrades very high molecular weight multimers of vWF.

In the absence of this enzyme, high molecular weight multimers of vWF accumulate in plasma and sometimes promote platelet microaggregate formation throughout the microcirculation, leading to the symptoms of TTP.

Front 214

214. How is a deficiency of ADAMTS 13 acquired?

Back 214

May be inherited or acquired. In many pts an antibody that inhibits vWF metalloprotease is detected. Much less commonly the pts have inherited an inactivating mutation in the gene encoding this enzyme.

*IT is important to consider the possibility of TTP in any pt presenting with thrombocytopenia and microangiopathic hemolytic anemia, as any delay in Dx and Tx can be fatal. Plasma exchange can be life saving b/c it provides the missing enzyme.

Front 215

215. What about pts with HUS?

Back 215

In contrast to TTP, most pts with HUS have normal levels of vWF metalloprotease.

One important cause in children and the elderly is infectious gastroenteritis caused by E. coli 0157:H7. It binds to and damages endothelial cells in the glomerulus and elsewhere, thus initiating platelet activation and aggregation. Affected children prseent with bloody diarrhea, ,and a few days later HUS makes its appearance.

In addition, HUS can also be seen in adults following exposures that damage endothelial cells.

Front 216

216. What are the three classifications of congenital disorders of platelet function?

Back 216

1. Defects of adhesions (Benard-Soulier syndrome)

2. Defects of aggregation (Glanzmann's thrombasthenia)

3. Disorders of platelet secretion (storage pool disorders)

Front 217

217. What is Benard-Soulier syndrome?

Back 217

Bleeding resulting from defective adhesion of platelets to subendothelial matrix is best illustrated by the autosomal recessive disorder Benard-Soulier syndrome, which is caused by an inherited defcieincy of the platelet membrane glycoprotein complex Ib-IX.

This glycoprotein is a receptor for vWF and is essential for normal platelet adhesion to subendothelial matrix.

Front 218

218. What is Glanzmann's thrombasthenia?

Back 218

Bleeding due to defective platelet aggregation is exemplified by Glanzmann's thrombasthenia, which is also transmitted as an autosomal recessive trait.

Thrombasthenic platelets fail to aggregate in response to ADP, collagen, epinephrine, or thrombin owing to deficiency or dysfunction of glycoprotein IIb-IIIa, a protein complex that participates in the formation of "bridges" between platelets by binding fibrinogen and vWF.

Front 219

219. What are the two clinically significant acquired defects of platelet function?

Back 219

1. Ingestion of aspirin and other NSAIDs, which significantly prolong the bleeding time

2. Uremia

Front 220

220. How does the bleeding in factor deficiencies differ from platelet deficiencies?

Back 220

The bleeding in factor deficiencies differs from platelet deficiencies in that spontaneous petechiae or purpura are uncommon. Rather, the bleeding is manifested by large post-traumatic ecchymoses or hematomas, or prolonged bleeding after a laceration or any form of surgical procedure.

Bleeding into the GI and urinary tracts, and particularly into weight bearing joints, is common.

Front 221

221. What about vitamin K deficiency?

Back 221

Vitamin K deficiency results in impaired synthesis of factors 2, 7, 9, and 10 and protein C.

Since the liver makes virtually all the clotting factors, severe parenchymal liver disease can be associated w/a hemorrhagic diathesis.

Front 222

222. What are the causes of hemophilia A and von Willebrand disease?

Back 222

These are caused by qualitative or quantitative defects involving the factor 8-vWF complex.

The two components of factor 8-vWF complex, synthesized separately, come together and circulate in the plasma as a unit that serves to promote clotting as well as platelet-vessel wall interactions necessary to ensure hemostasis.

Front 223

223. What is the role of factor 8?

Back 223

Factor 8 procoagulant protein is an intrinsic pathway component required for activation of factor 10.

***Deficiency of factor 8 gives rise to hemophilia A

Front 224

224. What is the role of vWF?

Back 224

Circulating factor 8 is noncovalently associated with very large vWF multimers.

vWF also interacts w/several other proteins involved in hemostasis, including collagen, heparin, and platelet membrane glycoproteins (Ib-IX and IIb-IIIa).

***Glycoprotein Ib-IX serves as the major receptor for vWF.

*The most important function of vWF in vivo is to promote the adhesion of platelets to subendothelial matrix. vWF multimers also serve as a carrier for factor 8 and are important for its stability. A deficiency of vWF causes von Willebrand disease.

Front 225

225. What is the ristocetin agglutination test?

Back 225

Tests for vWF levels. It measures the ability of ristocetin to promote the interaction between vWF and platelet membrane glycoprotein Ib. Multivalent ristocetin-dependent binding of vWF creates interplatelet "bridges," leading to the formation of platelet clumps (agglutination).

Thus, the degree of ristocetin-dependent platelet agglutination caused by the addition of patient plasma provides a bioassay for vWF.

Front 226

226. What is the major source of vWF?

Back 226

vWF is produced by endothelial cells and megakaryocytes . *Endothelial cells are the major source of subendothelial and plasma vWF.

Front 227

227. What is the major source of factor 8?

Back 227

Factor 8 is made in several tissues; sinusoidal endothelial cells and Kupffer cells in the liver and glomerular and tubular epithelial cells in the kidney appear to be important sites of synthesis.

Front 228

228. What is von Willebrand disease?

Back 228

von Willebrand disease is believed to be one of the most common inherited disorders of bleeding in humans. It is characterized by spontaneous bleeding from mucous membranes, excessive bleeding from wounds, menorrhagia, and a prolonged bleeding time in the presence of a normal platelet count.

In most cases it is transmitted as an autosomal dominant disorder.

Front 229

229. What is type I von Willebrand disease?

Back 229

Both type I and III von Willebrand disease are associated w/a reduced quantity of circulating vWF.

Type I, an autosomal dominant disorder, accounts for approx 70% of all cases and is relatively mild. Reduced penetrance and variable expressivity characterize this type, and hence clinical manifestations are varied.

There is a prolongation of the PTT in type I von Willebrand disease.

Front 230

230. What is type II von Willebrand disease?

Back 230

Type II disease is characterized by qualitative defects in vWF; there are several subtypes, of which type 2A is the most common. It is inherited as an autosomal dominant disorder.

***B/c of missense mutations, the vWF formed is abnormal, leading to defective multimer assembly. Large and intermediate multimers, representing the most active forms of vWF, are missing from plasma.

Type II disease accounts for 25% of all cases and is associated with mild to moderate bleeding.

Front 231

231. What is type III von Willebrand disease?

Back 231

Type III (an autosomal recessive disorder) is associated w/extremely low levels of functional vWF, and the clinical manifestations are correspondingly severe.

B/c a severe deficiency of vWF has a marked affect on the stability of factor 8, some of the bleeding characteristics resemble those seen in hemophilia. There is a prolongation of the PTT.

*Type III disease is associated with deletions or frameshift mutations.

Front 232

232. Pts with von Willebrand disease have what bleeding time characteristics?

Back 232

Pts with von Willebrand disease have a prolonged bleeding time despite a normal platelet count.

The plasma level of active vWF, measured as the ristocetin cofactor activity, is reduced. B/c vWF stabilizes factor 8 by binding to it, a deficiency of vWF gives rise to a secondary decrease in factor 8 levels. This will prolong the PTT time.

Front 233

233. What is hemophilia A?

Back 233

Hemophilia A is the most common hereditary disease associated w/serious bleeding. It is caused by a reduction in the amt or activity of factor 8. This protein serves as a cofactor for factor 9 in the activation of factor 10 in the coagulation cascade.

Hemophilia A is inherited as an X-linked recessive trait, and thus occurs in males and in homozygous females. (Can occur in heterozygous females due to inactivation of the normal X chromosome in most of the cells).

Approx 20% of pts have no family history; their disease is presumably caused by new mutations.

Front 234

234. What are the various stages of clinical symptoms in hemophilia A?

Back 234

Depends on levels of factor 8 activity.

Those w/less than 1% of normal activity develop severe disease; levels betwen 2-5% of normal are associated w/moderate disease; and pts w/6-50% of activity develop mild disease.

The variable degrees of factor 8 deficiency are explained by heterogeneity in the causative mutations?

Front 235

235. Most severe deficiencies in hemophilia A result from what type of mutation?

Back 235

Most severe deficiencies result from an unusual inversion involving the X chromosome that completely abolishes the synthesis of factor 8.

Front 236

236. What are the clinical features of hemophilia A?

Back 236

In all symptomatic cases, there is a tendency toward easy bruising and massive hemorrhage after trauma or operative procedures. In addition, spontaneous hemorrhages freq occur in the regions of the body normally subject to trauma, particularly the joints, where they are known as hemarthroses.

Recurrernt bleeding into the joints leads to progressive deformities that can be crippling.

*Petechiae are characteristically absent.

Front 237

237. Pts with hemophilia A have what bleeding time characteristics?

Back 237

They have a normal bleeding time, platelet count, and PT, and a prolonged PTT.

***These tests point to an abnormality of the intrinsic coagulation pathway.***

Front 238

238. Why do patients bleed when the extrinsic pathway is intact in hemophilia A?

Back 238

It appears that the chief role of the extrinsic pathway in hemostasis is to produce a limited initial burst of thrombin activation upon tissue injury. This is reinforced and amplified by a feedback loop whereby thrombin activates factors 9 and 11 of the intrinsic pathway.

In addition, high levels of thrombin are required to activate thrombin activatable fibrinolysis inhibitor, a factor that augments fibrin deposition by inhibiting fibrinolysis.

Thus, both inadequate coagulation and inappropriate clot removal contribute to the bleeding diathesis in hemophilia.

Front 239

239. What is the treatment of hemophilia A?

Back 239

Involves infusion of recombinant factor 8.

Approx 15% of pts w/low or absent factor 8 develop antibodies that bind to an inhibit factor 8; inhibitors are most likely to develop in pts with severe factor 8 deficiency possibly b/c the protein is perceived as foreign b/c it was never seen before by the immune system.

Front 240

240. What is hemophilia B (AKA Christmas disease or factor 9 deficiency)?

Back 240

Severe factor 9 deficiency produces a disorder clinically indistinguishable from factor 8 deficiency.

Like hemophilia A, the B form is inherited as an X-linked recessive trait and shows variable clinical severity. In about 14% of these pts, factor 9 is present, but nonfunctional. Also, the PTT is prolonged and the PT is normal.

Recombinant factor 9 is used for treatment.

Front 241

241. What is DIC?

Back 241

DIC is an acute, subacute, or chronic thrombohemorrhagic disorder occurring as a secondary complication in a variety of diseases.

It is characterized by activation of the coagulation sequence that leads to the formation of microthrombi throughout the microcirculation of the body, often in an uneven distribution. Sometimes the coagulaopathy is localized to a specific organ or tissue.

***As a consequence of the thrombotic diathesis, there is consumption of platelets, fibrin, and coagulation factors and, secondarily, activation of fibrinolytic mechanisms. These greatly aggregate the hemorrhagic diathesis.

Front 242

242. What is the pathogenesis of DIC?

Back 242

DIC is not a primary disease. It is a coagulopathy that occurs in the course of a variety of clinical conditions, such as obstetric complications, infections, neoplasms, massive tissue injury and misc conditions.

Front 243

243. Clotting can be initiated by what two ways?

Back 243

1. Extrinsic, which is triggered by the release of tissue factor
2. Intrinsic, which involves the activation of factor 12 by surface contact with collagen or other negatively charged substances.

Both pathways, thru a series of intermediate steps, result int the generation of thrombin, which in turn converts fibrinogen to fibrin. Once activated at the site of injury, thrombin further augments local fibrin deposition thru feedback activation of the intrinsic pathway and inhibition of fibrinolysis.

Front 244

244. So what causes DIC again?

Back 244

Could result from pathologic activation of the extrinsic and/or intrinsic pathways of coagulation or impairment of the clotting inhibiting influences.

Front 245

245. What 2 major mechanisms trigger DIC?

Back 245

1. Release of tissue factor or thromboplastic substances into the circulation
-Can be from the placenta in obstetric complications and the granules of leukemic cells in acute promyelocytic leukemia. Also common in gram-negative sepsis due to release of IL-1 and TNF.

2. Widespread injury to the endothelial cells.
-due to TNF in spetic shock, SLE, heat stroke, etc...

Front 246

246. DIC is most likely to follow what disorders?

Back 246

Obstetric complications, malignant neoplasia, sepsis, and major trauma.

Front 247

247. DIC is most likely to occur in what cancers?

Back 247

Acute promeylocytic leukemia and carcinomas of the lung, pancreas, colon, and stomach are most frequently associated with DIC.

These tumors release a variety of thromboplastic substances, including tissue factors, proteolytic enzymes, mucin, and other undefined tumor products.

Front 248

248. What are the 2 major consequences of DIC?

Back 248

1. There is widespread deposition of fibrin w/in the microcirculation, which leads to ischemia of the more severely affected organs and to a hemolytic anemia resulting from fragmentation of red cells.

2. A hemorrhagic diathesis can dominate the clinical picture. This results from consumption of platelets and clotting factors as well as activation of plasminogen. Plasmin can not only cleave fibrin, but also digest factors 5 and 8, thereby reducing their concentration further.

*All these influences lead to the hemostatic failure seen in DIC.

Front 249

249. Where are thrombi most likely to be found in DIC?

Back 249

In decreasing order of freq:
1. Brain
2. Heart
3. Lungs
4. Kidneys
5. Adrenals
6. Spleen
7. Liver

Front 250

250. What is the morphology of DIC in the lungs?

Back 250

Numerous fibrin thrombi may be found in alveolar capillaries, sometimes associated w/pulmonary edema and fibrin exudation, creating "hyaline membranes" reminiscent of ARDS.

Front 251

251. What is the morphology of DIC in the CNS?

Back 251

Fibrin thrombi can cause microinfarcts, occasionally complicated by simultaneous hemorrhage. Such changes are the basis for the bizarre neurologic signs and symptoms sometimes observed in DIC.

Front 252

252. What are two special endocrine conditions that are caused by a form of DIC?

Back 252

1. Waterhouse-Friderichsen syndrome
2. Sheehan postpartum pituitary necrosis.

Front 253

253. What are the clinical features of DIC?

Back 253

The onset can be fulminant, as in endotoxic shock or amniotic fluid embolism, or insidious and chronic, as in cases of carcinomatosis or retention of a dead fetus.

Overall, about 50% of pts with DIC are obstetric pts having complications of pregnancy. In this setting, the disorder tends to be reversible with delivery of the fetus.

Front 254

254. Lastly, how does acute DIC differ from chronic DIC?

Back 254

In general, acute DIC, associated with obstetric complications or major trauma, for example, is dominated by a bleeding diathesis, whereas chronic DIC, such as occurs in CA pts, tends to present initially with thrombotic complications.