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Pathoma & First Aid > Hematology Path > Flashcards

Hematology Path Flashcards

1
Q

Explain the process of maturation of T cells and NK cells.

What receptors are expressed by them?

A

Both have a common precursor.

Hint: All receptors expressed by T cells are below 10.

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2
Q

Explain where B cell mature and where naive B cells develop into plasma cells.

A
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4
Q

Where does the Ig rearrangement and Ig rearranged somatic mutation takes place?

A

Ig rearrangement takes place during B cell maturation which happens in the bone marrow whereas somatic mutation takes place in the presence of an antigen in the lymph nodes.

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5
Q

Explain the structure of a lymph node.

A

Paracortex consists of T cells, cortex contains B cells.

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6
Q

Enumerate common CD markers for different hematopoietic cell lines

A
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7
Q

Enumerate the function of the red pulp and white pulp of the spleen.

A

Spleen consists of white pulp and red pulp areas, white pulp has a function similar to lymph nodes as it contains B and T cells with germinal centers and mantle zone.

Red pulp has stromal cords and vascular sinuses so it allows the spleen to perform its blood filtering function by bringing the RBCs in close proximity with macrophages. Older erythrocytes are phagocytozed here.

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9
Q

Explain the process of immunoglobulin gene rearrangement in B lymphocyte development.

How can we detect if a B cell has undergone Ig gene rearrangement? What is its significance?

A
  1. ‘Ig Somatic Mutation’ occurs in antigenically stimulated B-cells in both heavy and light chain hypervariable regions.
  2. Cells with increased affinity for antigen survive.
  3. Cells with decreased affinity for antigen removed through apoptosis

We can detect this by amplification and sequencing of V region which can then be compared with known germline V genes (which have not undergoine Ig somatic mutation).

This is important for treating some B cell neoplasms

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11
Q
A
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15
Q

Define hypersplenism and list causes of splenomegaly

A

Enlargement of spleen, could be due

  1. Infections and inflammatory conditions Infectious mononucleosis, malaria, typhoid fever, leishmaniasis, rheumatoid arthritis, SLE
  2. Congestive – expansion of red pulp
  3. Portal hypertension, splenic or portal vein thrombosis, cardiac failure
  4. Infiltrative Amyloidosis, hemolytic anemia, immune thrombocytopenia, storage diseases, neoplasms
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16
Q

List important causes of thymic hyperplasia

A

It is due to follicular hyperplasia. This can be for several reasons such as:

  1. Increased B-lymphocytes
  2. Myasthenia gravis
  3. SLE
  4. Graves disease and other autoimmune disorders
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17
Q

List important paraneoplastic syndromes observed with thymic neoplasms.

A

Myasthenia Gravis and Pure Red Cell Aplasia are 2 common paraneoplastic manifestations of thymic neoplasms.

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18
Q

What are some of the important things to remember from this hematologic lineage flow chart?

A
  1. All the recognizable precursors end with ‘blast’
  2. Cell division only occurs in multipotent stem cells, committed stem cells and recognizable precursors i.e ‘in the top half of the chart’
  3. These actively dividing cells are morphologically identical, only maturing and mature myeloid cells can be recognized based on their appearence.
  4. All the myeloid stem cells have limited life span, whereas the lymphoid cells can survive for many years and they can divide at any phase of cell cycle, even during the mature phase.
  5. All hematologic neoplasms originate from dividing cells, hence the cells in the top half of the chart.
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19
Q

What are the different growth factors involved in cell maturation and development?

A
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20
Q

What are the sites of hematopoiesis from prenatal life to adulthood?

A

Yolk sac: 3 weeks

Mesoderm of intraembryonic aorta, gonads, mesonephros region: 3 weeks to 3 months

Liver: 3 months to birth

Bone marrow: 4 month to death

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24
Q

How does hematopoiesis change with age?

A

Shifts to flat bones of axial skeleton, most common location to do a bone marrow biopsy is from the iliac crest of an adult or sometimes it can be done at the sternum

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25
Q

What is extramedullary hematopoiesis?

A

When the demand of hematopoiesis is high and the bone marrow can not keep up there is reactivation of hematopoiesis outside the bone marrow such as in liver, spleen, lymph nodes etc

The most common reason for this is hemolytic anemia or neoplasm

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26
Q

Explain the steps of Neutrophil development starting from Myeloblast.

A

Don’t need to know the names but it is important to know the morphological changes that occur during different stages of development

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27
Q

Explain the steps of erythroid maturation starting from Proerythroblast.

How does RBCs get rid of their nucleus?

A

Via pyknosis and ‘removal’ of the remaining nucleus

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28
Q

What are the different components of blood?

A
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29
Q

Explain the phenomena of left shift.

What is the significance of toxic granulation and Dohle bodies?

A
  1. Left shift refers to increased circulation of band neutrophils or even further stages of immature neutrophils that can be seen on a blood smear.
  2. Left shift is almost always induced by an inflammatory process
  3. Toxic granulations and Dohle bodies are morphological changes that are seen on neutrophils in left shift
  4. Presence of toxic granulations and Dohle bodies signifies the fact that the increase in neutrophils is due to an inflammatory etiology instead of a neoplastic etiology
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30
Q

What are the different components of bone marrow?

A

Sinusoids, hematopoietic cells and fat.

It is important to know that the blood is not continuous with the hematopoietic space.

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31
Q

What is the myeloid:erythrocyte normal ratio in the bone marrow?

A

3:1 in favor of Myeloid cells, which makes sense as myeloid cells like neutrophils have a life span max of 5 days, so there is a greater turnover

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32
Q

What cells are classified as granulocytes?

A

Neutrophils, basophils and eosinophils, primary function of these cells is phagocytosis

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33
Q

What is the function of basophils?

What does their granules contain?

A

IgE mediated allergic reactions.

Granule contain histamine, chondroitin sulfate and tryptase

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34
Q

What is the function of monocytes?

What do they look like?

A
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39
Q

Define Leukemoid reaction.

A
  1. Leukemoid reaction – marked granulocytosis and left shift, resembling chronic myeloid leukemia (CML)
  2. Reactive morphology (toxic granulation and Döhle bodies are seen)
  3. To rule out CML we have to genetically look for Philedelphia chromosome
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40
Q

Define Leukoerythroblastocytosis.

A

Defined by left shift and circulating nucleated red blood cells (remember that the only RBCs in circulation are reticulocytes and mature RBCs, both lack a nucleus).

This signifies:

  1. Bone marrow fibrosis
  2. Bone marrow infiltration - can be infectious or neoplastic
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41
Q

What are the functions of eosinophils?

What does their granules contain?

A

Anti parasitic function, allergic reactions and chronic inflammation.

Granules contain

  1. Peroxidase
  2. Major basic protein
  3. Eosinophilic cationic protein
  4. Eosinophil derived neurotoxin

Last 3 are cytotoxic for helminths and protozoas

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42
Q

Define neutropenia and agranulocytosis and list important causes for each.

A

Neutropenia is defined as absolute neutrophils count (ANC) of less than 1800/microliters. Agranulocytosis is defined as ANC less than 500.

It can be due inadequate production or ineffective production:

  1. Suppression of hematopoietic stem cells - Aplastic anemia, radiation
  2. Suppression of committed granulocytic precursors
    1. Drugs
      1. Dose dependent –alkylating agents, antimetabolites. This is often reversible.
      2. Idiosyncratic –chloramphenicol, aminopyrine, sulfonamides, chlorpromazine, phenylbutazone, thiouracil. This is often non reversible.
    2. Large granular lymphocyte leukemia
  3. Congenital
  4. Ineffective hematopoiesis - Megaloblastic anemia, myelodysplastic syndromes

Or it can be due to increased destruction:

  1. Immune mediated - idiopathic, drug-induced.
  2. Splenic sequestration
  3. Increased margination
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43
Q

Define neutrophilia and list important causes for it

A

Absolute neutrophil count (ANC) >7000/μL

Increased granulopoiesis:

  1. Infections –primarily bacterial Immunological inflammatory
  2. Neoplasia Myeloproliferative neoplasms Paraneoplastic
  3. Drugs –colony stimulating factors

Increased release from marrow stores

  1. Endotoxemia
  2. Infection
  3. Hypoxia
  4. Decreased margination
    1. Exercise
    2. Catecholamines
  5. Decreased extravasation into tissues
    1. Glucocorticoids
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44
Q

Discuss the pathophysiology of leukocyte adhesion deficiency, chronic granulomatous disease, Chediak-Higashi syndrome, and myeloperoxidase deficiency

A
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46
Q

Enumerate the three main histologic types of lymph node hyperplasia with examples

A
  1. Follicular hyperplasia
  2. Paracortical (interfollicular) hyperplasia
  3. Sinus histiocytosis
  4. Mixed pattern of hyperplasia
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47
Q

Discuss the pathologic features of lymphadenopathy related to toxoplasmosis

A

We see a mixed pattern of hyperplasia, there is marked follicular hyperplasia, epitheloid granulomas and sinusoidal dilation with monocytoid B cells.

Epitheloid granulomas consists of small and large histiocytic aggregates with germinal centers and interfollicular areas.

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48
Q

Explain the possible reasons that can give rise to eosinophilia.

A
  • Allergic disorders
  • Parasitic infections
  • Malignant neoplasms
  • Drugs (IL-2)
  • Collagen vascular disorders
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49
Q

Explain the possible reasons that may give rise to basophilia in a patient.

A
  • Neoplasms - CML
  • Allergic disorders
  • Inflammation
  • Endocrine disorders
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50
Q

Explain the possible reasons that can lead to the development of monocytosis.

A
  • Chronic infections
  • Inflammation
  • Collagen vascular disorders
  • Neoplasms
  • Inflammatory bowel disease
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51
Q

What is the definition of lymphocytosis?

A

Absolute lymphocyte count > 4000/μL (adults) or > 7000/µL (children) or > 9000/µL (infants)

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52
Q

What are atypical lymphocytes?

A

Aka Downey cells, these are seen in viral infections such as EBV. They have a characteristic appearence.

Atypical lymphocytes are clinically seen in a variety of viral illnesses but as far as STEP is concerned it is only associated with EBV.

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53
Q

How can we differentiate between a blast cell and an atypical lymphocyte?

A

Blast cells has a much higher nucelus to cytoplasm ratio as shown.

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54
Q

What are the most common reasons for the development of lymphocytosis in patients?

A
  1. Viral infections
  2. Acute bacterial infection - only with whooping cough
  3. Chronic bacterial infections - only with TB and brucellosis
  4. Lymphoproliferative diseases
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56
Q

Explain follicular hyperplasia.

How does it look like?

A

Increased number of and larger size of secondary follicles

  • Infection Systemic inflammatory disorders
  • Rheumatoid arthritis
  • Drug reaction
  • AIDS
  • Differential diagnosis includes follicular lymphoma
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57
Q

How can we differentiate between follicular lymphoma and follicular hyperplasia?

A

BCL2 gene is overexpressed in follicular lymphoma, making the B cells non apoptotic, we can stain for this protein to differentiate between the 2

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58
Q

Explain paracortical hyperplasia and how does it look like?

A

Aka interfollicular hyperplasia, expansion of paracortex by a heterogeneous reactive cell population

  • Viral infection –CMV, EBV, measles, varicella
  • Immunologic disorders
  • SLE
  • Drug reaction
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59
Q

What is sinus histiocytosis?

A

Increase in macrophages in sinuses In lymph nodes during infection, cancer

Sinus histiocytosis is associated with massive lymphadenopathy

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61
Q

Define lympohocytopenia and explain why does it develop?

A

Absolute lymphocyte count < 1500/μL (adults) or < 3000/µL (children)

Usually due to decrease in CD4+ helper T-cells

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62
Q

Explain the possible etiologies for the development of lymphocytopenia.

A
  1. Decreased production
    1. Congenital and acquired immunodeficiency syndromes
    2. Hodgkin lymphoma
  2. Increased destruction
    1. Radiation, chemotherapy
    2. Antilymphocyte globulin
    3. Steroids, ACTH
    4. AIDS
  3. Increased loss of lymphocytes
    1. Damage to lymphatics and loss of lymph –protein losing enteropathy, Whipple disease, increased central venous pressure
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63
Q

What is another name of

  1. Chronic Lymphocytic Leukemia
  2. Acute Lymphoblastic Leukemia
A
  1. Chronic Lymphocytic Leukemia = Small Lymphocytic Lymphoma
  2. Acute Lymphoblastic Leukemia = Lymphoblastic Lymphoma
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64
Q

Explain ALL.

A
  1. Most frequently occurs in children; less common in adults (worse prognosis).
  2. T-cell ALL can present as mediastinal mass (presenting as Superior Vena Cava-like syndrome).
  3. Associated with Down syndrome.
  4. Peripheral blood and bone marrow have increased lymphoblasts.
  5. TdT+ (marker of pre-T and pre-B cells), CD10+ (marker of pre-B cells).
  6. Most responsive to therapy.
  7. May spread to CNS and testes.
  8. t(12;21) = Žbetter prognosis.
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65
Q

What is the most common malignancy of childhood?

What is its etiology?

A

ALL - Most common malignancy of childhood but incidence also increases after 50 y.

Etiologic associations

  • Ionizing radiation
  • Immunodeficiency states
  • Trisomy 21 (Later than the age of 5…L for ALL)
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66
Q

What kind of precursor cells are more likely to be found that cause ALL?

A

B cell precursors cause ALL by far majority than T cell precursors.

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67
Q

What are ALL clinical features?

What do we see in peripheral smear and bone marrow?

A
  • Anemia
  • Weakness
  • Fatigue
  • Pallor
  • Fever
  • Bone pain
  • Thrombocytopenia - Bleeding
  • Hepatosplenomegaly
  • Lymphadenopathy

In peripheral smaer we see leukoblastocytosis with blasts or normal WBCs with blasts and bone marrow is hypercellular with sheets of blast cells.

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68
Q

What are the immunophenotypic findings in ALL?

A

Precursor B-ALL (85%)

  • CD10+, CD19+, TdT+, sIg-

Precursor T-ALL (15%)

  • CD2+, CD3+, CD5+, CD7+, TdT+
  • May co-express CD4 and CD8
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69
Q

What genetics determine the prognosis of ALL?

A

ALL is rapidly fatal, if untreated. With chemotherapy, 95% remission rate and 75-85% cure rate if favorable prognostic features

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70
Q

What are some of the other clinical features that make ALL prognosis better or worse?

A
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71
Q
A
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72
Q

What are the 2 most common mature B cell neoplasms?

A

Diffuse large B cell lymphoma and Follicular lymphoma

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74
Q

What is the most common leukemia in the US?

A

CLL or SLL

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75
Q

Explain CLL or SLL.

A
  1. Accumulation of naive B cell, CLL is mainly in the bone marrow whereas SLL is confined to lymph nodes.
  2. Age: > 60 years.
  3. Most common adult leukemia.
  4. CD20+, CD5+ B-cell neoplasm.
  5. Often asymptomatic, progresses slowly
  6. Smudge cells B in peripheral blood smear
  7. Complications of SLL/CLL are
    1. Autoimmune hemolytic anemia.
    2. Richter transformation—SLL/CLL transformation into an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL).
    3. Hypogammaglobulinemia, leading to immunosuppressive state
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76
Q

What are the clinical features of CLL/SLL.

A
  1. Assymptomatic
  2. Anemia
  3. Thrombocytopenia
  4. Lymphadenopathy
  5. Immunologic abnormalities - autoimmune hemolytic anemia, thrombocytopenia, hypogammaglobulinemia.
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77
Q

What are the pathological findings of SLL/CLL.

A
  1. Lymphocytosis - we see smudge cells on peripheral smear
  2. In lymph nodes we see diffuse infiltrate of small round lymphocytes.
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78
Q

What cell markers are observed in CLL/SLL.

A

CD19+, CD20+, CD5+, CD10-, sIg+ (clonal)

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79
Q

Explain the genetics involved in CLL/SLL.

A

About half of the SLL/CLL cases involve Ig gene rearrangment but no somatic hypermutation in IgVH.

Mutated CLL/SLL has Ig gene rearrangment with somatic hypermutation.

Other chromosomal abnormalities may involve 13q deletion.

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80
Q

CLL/SLL course and prognosis.

A
  1. Median survival 6 y
    1. Worse for U-CLL/SLL (3 y) than for M-CLL/SLL (>7 y)
  2. Prolymphocytic transformation –15-30%
    1. >10% prolymphocytes
    2. Increased splenomegaly
    3. Mean survival <2 y
  3. Richter transformation –5-10%
    1. Large cell lymphoma
    2. Increased lymphadenopathy
    3. Mean survival <1 y
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81
Q

Explain hairy cell leukemia.

A
  1. Age: Adult males.
  2. Mature B-cell tumor. Cells have lamentous, hair-like projections.
  3. Causes marrow fibrosis, Ždry tap on aspiration.
  4. Patients usually present with massive splenomegaly.
  5. Stains TRAP (tartrate-resistant acid phosphatase) ⊕. TRAP stain largely replaced with flow cytometry.
  6. Treatment: cladribine, pentostatin.
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82
Q

What are the clinical features of hairy cell leukemia?

A

Hairy Cell Leukemia Clinical Features

  • Initially asymptomatic
  • Splenomegaly - May be massive
  • Hepatomegaly
  • Pancytopenia
  • Infections
  • Indolent course
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83
Q

What are the pathological findings of hairy cell leukemia?

Explain immunophenotype, cytochemistry and genetics of this disease

A
  1. We see ‘hairy cells’ - lymphocytes with villous cytoplasmic projections.
  2. Absolute monocytopenia
  3. Bone marrow shows increased reticulin fibrosis
  4. Spleen has enlarged red pulp.

On immunophenotyping we see CD11c+. CD25+, CD103+ and Annexin A1.

Cytochemistry: Tartrate resistant acid phsophatase

Genetics - BRAF mutation.

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84
Q

What do we see on lymph nodes H&E in follicular lymphoma?

Explain the genetics and immunophenotyping of FL.

A

Mantle zone is markedly diminished or absent.

Genetics - t(14;18), overexpression of BCL2 protein prevents apoptosis

Immunophenotyping - CD19+, CD20+, CD10+, CD5-, sIg+ (clonal)

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85
Q

Explain follicular lymphoma.

A
  1. Very common lymphoma in US
  2. Middle aged to older adults
  3. t(14;18)—translocation of heavy-chain Ig (14) and BCL-2 (18). BCL2 inhibits apoptosis
  4. Hepatosplenomegaly
  5. Indolent, chronic course –median survival 7-9 y
  6. Presents with painless “waxing and waning” lymphadenopathy
  7. Follicular architecture: small cleaved cells (grade 1), large cells (grade 3), or mixture (grade 2).
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86
Q

Explain diffuse large B cell lymphoma.

A
  1. Usually older adults, but 20% in children
  2. Lymphadenopathy and hepatosplenomegaly are observed.
  3. Some cases are associated with HHV8 and EBV, although Sketchy specifically said HIV can directly cause diffuse B cell lymphoma.
  4. In lymph nodes we see diffuse infiltrate of large, non cleaved lymphocytes.
  5. Alterations in BCL2 and BCL6
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88
Q

What is the most common lymophoma in the US?

A

Diffuse Large B cell Lymphoma, it is the most common non Hodgekin lymphoma in the US

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89
Q

What does plasma cell neoplasms consist of?

A

Aberrant proliferation of plasma cells, diseases like multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) are examples plasma cell neoplasms.

Important to know MGUS can develop into MM.

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90
Q

Explain MM.

A

Important to know that death by MM is primarily due to infection or renal involvement.

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92
Q

Explain the different types of Burkitt lymphoma/leukemia.

A
  1. Endemic form of Burkitt lymphoma is in Africa, >95% is associated with EBV in, presents as jaw lesions
  2. Sporadic BL is in the US that involves children and adults, only 20% associated with EBV, this does not present as jaw lesion but instead can have extranodal sites in the abdomen/pelvis.
  3. HIV associated BL, 25% associated with EBV.
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93
Q

Explain Mantle Cell lymphoma.

A
  1. Very aggressive, patients typically present with late-stage disease.
  2. Adult males
  3. t(11;14)—translocation of cyclin D1 (11) and heavy-chain Ig (14)
  4. CD19+, CD20+, CD10-, CD5+. sIg+ and Cyclin D1+
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94
Q

Explain Burkitt lymphoma.

A
  1. Rapidly progressive tumor mass but higher cure rates with aggressive chemotherapy, 90% cure rate in children.
  2. Tumor lysis syndrome is common when treatment is initiated
  3. “Starry sky” appearance, sheets of lymphocytes with interspersed “tingible body” macrophages
  4. t(8;14)—translocation of c-myc (8) and heavy-chain Ig (14)
  5. In lymph nodes we see diffuse infilterate of medium-sized, non cleaved lymphocytes
  6. CD19+, CD20+, CD10+, CD5-, sIg+ and TdT-
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95
Q
A

EMZL MALT

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96
Q
A

EMZL MALT

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98
Q

Explain Extranodal Marginal Zone B cell lymphoma of Mucosa Associated lympoid tissue.

A
  1. Can be along anywhere in the GI tract, lung, head & neck, eye, skin.
  2. Association with chronic infection (e.g. H. pylori ) and autoimmune disorders (e.g. Hashimoto thyroiditis, Sjögren syndrome)
  3. Usually early stage, rarely involves the bone marrow
  4. Expanded marginal zone is observed, lymphoepithelial lesions are seen.
  5. t(11:18)
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99
Q

Explain Mycosis Fungoides.

A
  1. Mycosis fungoides aka CTCL presents with skin patches/plaques, characterized by atypical CD4+ cells with “cerebriform” nuclei.
  2. May progress to Sézary syndrome which is lekemia phase of CTCL (T-cell leukemia).
  3. Associated with epidermotropism and Pautrier microabscesses.
  4. Sezary syndrome causes erythroderma.
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100
Q

Explain Adult T Cell Lymphoma.

A
  1. Caused by HTLV (associated with IV drug abuse)
  2. Adults present with cutaneous lesions; especially affects populations in Japan, West Africa, and the Caribbean.
  3. Lytic bone lesions, hypercalcemia.
  4. Generalized lymphadenopathy with skin lesions
  5. Hepatosplenomegaly
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101
Q

Explain Anaplastic Large Cell Lymphoma.

A
  1. Consists of large anaplstic cells positive for CD30+
  2. t(2;5) - rearrangement of ALK gene, this happens in children and younger adults, associated with good prognosis
  3. No ALK rearrangement Anaplastic Large B cell lymhoma happens in older adults, associated with poor prognosis
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103
Q

Compare Hodgkin vs Non Hodgkin lymphoma as compared in First Aid.

A
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104
Q

Compare Hodgkin vs Non-Hodgkin lymphoma as compared in this lecture.

A
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105
Q

What are Reed Sternberg cells?

A
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107
Q

Explain Peripheral T Cell Lymphoma, Unspecified.

A
  1. Proliferation of mature T-cells
  2. Generalized lymphadenopathy
  3. Fever, pruritus, weight loss
  4. Eosinophilia
  5. Generally poor prognosis.
  6. Lymph nodes
    1. Architectural effacement
    2. Vascular proliferation
  7. Immunophenotype CD2+, CD5+, CD3+, TCR-αβ or γδ
  8. Genetics T-cell receptor gene rearrangement
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111
Q

Explain the features of Hodgkin lymphoma.

A
  1. Lymphadenopathy, splenomegaly
  2. Constitutional (“B”) symptoms –fever, night sweats, weight loss
  3. Immune dysfunction
  4. Prognosis –excellent at early stage (90% cure rate)
  5. Risk of second malignancy in long-term survivors
    1. Myelodysplastic syndromes and acute myeloid leukemia
    2. Lung cancer, breast cancer, gastric cancer, sarcoma, melanoma
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112
Q

What are the 2 types of Hodgkin lymphoma?

A

Classical Hodgekin lymphoma and Nodular lymphocyte predominance Hodgekin lymphoma

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113
Q

What are the pathological findings of classical Hodgkin’s lymphoma?

Explain the genetics of this neoplasm.

A

Reed Sternberg cells + polymorphous cellular background.

Important to know that Reed Sternberg cells are CD15+ and CD30+ and they are negative for most B and T cell markers.

Genetics:

  1. Reed-Sternberg cells arise from germinal center B- cells
  2. NF-κB activation
  3. Transformed cells escape from apoptotic pathways to proliferate
  4. Ig gene rearrangements in most cases
  5. No detectable Ig due to
    1. “Crippled” rearrangements
    2. Upstream mutations
    3. Transcriptional inactivation
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114
Q

What are the further divisions of classical Hodgkin lymphoma

A
  • Nodular sclerosis
    • Broad bands of fibrous tissue
    • A special type of reed sternberg cells called lacunar cells are seen
  • Mixed cellularity - Numerous Reed-Sternberg cells in a mixed cellular background
  • Lymphocyte depletion
    • Rare classic Reed-Sternberg cells
    • Scant lymphocytes
  • Lymphocyte rich –rare
115
Q

How long does it take to erythroblasts to fully mature?

A

7 days

116
Q

What is the primary growth factor for erythropoiesis?

A

EPO

117
Q

Explain the terms anisocytosis, poikilocytosis and anisopoikilocytosis.

A

Anisocytosis = varying sizes.

Poikilocytosis = varying shapes.

Anisopoikilocytosis = variation in size and shape.

118
Q

What is RDW and explain its significance.

A

Red Cell Distribution Width, it is a measure of the variation in size of RBCs. Congenital anemias for example have low RDW (they are more consistent in size) whereas acquired anemias such as iron deficiency anemias have high RDWs.

120
Q

What are reticulocytes?

A

Immature RBCs that are released from the bone marrow that eventually mature to form functioning RBCs, they survive in the circulation for 1 day.

In case of increase hematopoiesis the number of reticulocytes increases dramatically which can be seen on peripheral blood smear, this corresponds to an increase in EPO.

121
Q

What is another name of reticulocytes?

A

Polychromatophilic erythrocytes.

122
Q

What are the clinical features of anemia?

A
  1. Pallor of skin, nail beds, buccal mucosa
  2. Fatigue, weakness, malaise
  3. Dyspnea on exertion
  4. Syncope, headache, visual disturbances
  5. Tachycardia
  6. Angina
  7. Cardiac failure
123
Q

Explain the causes of hypoproliferative anemia.

A

It is due to either inadequate or ineffective production (aka ineffecitve hematopoiesis).

  1. Bone marrow failure due to
    1. Aplastic anemia
    2. Pure red cell aplasia
    3. Iatrogenic
  2. Bone marrow infiltration/replacement (myelophthisis)
  3. Nutritional deficiency
    1. Iron deficiency (microcytic)
    2. Megaloblastic anemia (macrocytic)
  4. Anemia of chronic disease (microcytic)
  5. Myelodysplastic syndromes (macrocytic)
124
Q
A

Aplastic anemia

125
Q

Explain aplastic anemia.

A

Caused by failure or destruction of myeloid stem cells due to:

  1. Radiation and drugs (benzene, chloramphenicol, alkylating agents, antimetabolites)
  2. Viral agents (parvovirus B19, EBV, HIV, hepatitis viruses)
  3. Fanconi anemia (DNA repair defect causing bone marrow failure); also short stature, incidence of tumors/leukemia, café-au-lait spots, thumb/radial defects
  4. Telomerase defects, acquired stem cell defects, potential for acquiring further mutations and tranforming into AML
  5. Idiopathic (immune mediated, 1° stem cell defect); may follow acute hepatitis

Findings:

  1. Decrease in reticulocyte count, there are high levels of EPO.
  2. Pancytopenia characterized by severe anemia, leukopenia, and thrombocytopenia. Normal cell morphology, but hypocellular bone marrow with fatty infiltration (dry bone marrow tap).

Symptoms: fatigue, malaise, pallor, purpura, mucosal bleeding, petechiae, infection.

Treatment: withdrawal of offending agent, immunosuppressive regimens (eg, antithymocyte globulin, cyclosporine), bone marrow allograft, RBC/platelet transfusion, bone marrow stimulation (eg, GM-CSF).

126
Q
A

Parvovirus inclusion bodies.

128
Q

Explain Pure Red Cell Aplasia.

A
  1. Disorder of erythroid progenitor cell causing decreased erythropoiesis
  2. Incidence –very rare
  3. Clinical features: Anemia – pallor, weakness, fatigue

Pathogenesis and etiology

  1. Highly associated with Thymoma (paraneoplastic syndrome)
  2. Viral infections (parvovirus B19)
  3. Drugs
  4. Autoimmune disorders

Pathology:

  1. Normochromic, normocytic anemia, no poikilocytes
  2. There are markedly decreased erythroid precursors in the bone marrow
  3. Intranuclear inclusions in erythroblasts in parvovirus B19 infection

Treatment: androgens, plasmapheresis, thymectomy, supportive - transfusions.

130
Q

Explain myelophthisic anemia.

A

Decreased erythropoiesis due to bone marrow infiltration or replacement

Clinical features

  1. Anemia –pallor, weakness, fatigue
  2. Features of underlying disease

Pathogenesis and etiology

  1. Metastatic cancer
  2. Fibrosis (primary myelofibrosis or following treatment)
  3. Hematopoietic neoplasms

Pathology

  1. Normochromic, normocytic anemia
  2. Teardrop shaped erythrocytes (poikilocytes)
  3. Circulating nucleated red blood cells
  4. Granulocytic left shift (leukoerythroblastosis)
  5. Replacement of normal bone marrow elements is seen on H&E
131
Q

Explain iron metabolism in the body.

A
  1. Daily intake – 10-20 mg, poorly absorbed in duodenum (10- 15%)
  2. Daily loss – 1-2 mg
  3. Total body iron – 6 g (♂); 2.5 g (♀)
  4. Functional – Hgb, myoglobin, enzymes
  5. Storage – ferritin, hemosiderin
  6. There is constant recycling
  7. Hepcidin inhibits iron uptake from enterocytes to serum
    1. Inappropriately low in hereditary hemochromatosis
    2. Inappropriately high in anemia of chronic disease
133
Q
A

Iron deficiency anemia

134
Q

Explain iron deficiency anemia.

A

Clinical features

  1. Pallor, fatigue, weakness
  2. Pica
  3. Atrophic glossitis, angular stomatitis, koilonychia
  4. Plummer-Vinson syndrome (Paterson-Brown-Kelly syndrome) that consist of
    1. Iron deficiency anemia
    2. Atrophic glossitis
    3. Esophageal webs

Pathology

  1. Hypochromic, microcytic anemia
  2. Anisocytosis
  3. No increase in reticulocytes
  4. Decreased serum iron
  5. Decreased ferritin
  6. Increased transferrin and soluble transferrin receptor
  7. Absent storage iron in bone marrow
136
Q

Explain anemia of chronic disease.

A
  1. InfammationŽ -> increase in hepcidin due to inflammatory mediators such as IL-6 (released by liver, binds ferroportin on intestinal mucosal cells and macrophages, thus inhibiting iron transport) -> decreasesŽ release of iron from macrophages and iron absorption from gut.
  2. Associated with conditions such as rheumatoid arthritis, SLE, neoplastic disorders, and chronic kidney disease.
  3. Decreased iron, decreased TIBC, increased ferritin (this is what differentiates it from iron deficiency anemia).
  4. Normocytic, but can become microcytic.
  5. Treatment: EPO (chronic kidney disease only).
137
Q

What is the principle etiology behind megaloblastic anemia?

What are its associated findings?

A
  1. Its associated findings are hypersegmented neutrophils and macrocytic RBCs
  2. Folate is required for DNA synthesis to transfer one carbon groups for purine synthesis, impaired DNA synthesis leads to delayed Žmaturation of nuclei of precursor cells in bone marrow relative to maturation of cytoplasm.
138
Q

How is vitamin B12 absorbed in the gut.

A
  1. Hepatocorrin is released in the saliva which binds to vitamin B12 initially.
  2. Intrinsic factor is released in the stomach by parietal cells, B12 dissociates from heptocorrin in the duodenum in the presence of proteases and eventially binds to intrinsic factor.
  3. B12 bound to intrinsic factor is eventually absorbed in the gut by ileal cells.
139
Q

Explain how does folate deficiency leads to megaloblastic anemia and what are its associated findings?

A

Folate deficiency:

  1. Causes include malnutrition (eg, alcoholics), malabsorption, drugs (eg, methotrexate, trimethoprim, phenytoin), increased requirement (eg, hemolytic anemia, pregnancy).
  2. Increased homocysteine, normal methylmalonic acid. No neurologic symptoms (vs B12 deficiency).
140
Q

What changes do we see in the CNS in vitamin B12 deficiency.

A

Periventricular white matter degeneration in the brain and posterior column degeneration in the spinal cord

141
Q

What are the findings on peripheral blood smear and in bone marrow of megaloblastic anemia?

A
142
Q

Explain how does B12 deficiency leads to megaloblastic anemia and what are its associated findings?

A

Vitamin B12 deficiency (Cobalamin):

Causes: insuficient intake (eg, veganism), malabsorption (eg, Crohn disease), pernicious anemia, Diphyllobothrium latum (fish tapeworm), gastrectomy.

Findings:

  1. Increased homocysteine, increased methylmalonic acid.
  2. Neurologic symptoms: subacute combined degeneration (due to involvement of B12 in fatty acid pathways and myelin synthesis, deficiency leads to demyelination): spinocerebellar tract, lateral corticospinal tract, dorsal column dysfunction.
  3. Historically diagnosed with the Schilling test, a 4-stage test that determines if the cause is dietary insufficiency vs malabsorption.
143
Q
A

D

145
Q

Explain pernicious anemia.

A

Chronic atrophic gastritis due to autoantibodies against parietal cells. This leads to megaloblastic anemia.

148
Q

What are the changes observed in anemia of blood loss?

A
  1. Acute blood loss
  2. Hypovolemic shock
  3. No immediate change in hemoglobin level
  4. Slow fluid shift from interstitial space to intravascular space leads to low hemoglobin
  5. Normochromic, normocytic anemia
  6. Reactive leukocytosis and thrombocytosis may occur
149
Q

What does intrinsic and extrinsic anemia refer to?

A

Intrinsic anemia refers to the cause of anemia lies within RBC - hemoglobin, enzyme deficiency, membrane defect etc.

Extrinsic anemia refers to external factors like antibodies, trauma.

150
Q

Compare and contrast extravascular and intravascular hemolysis.

A

Main thing to note: in extravascular hemolysis, the RBCs are being destroyed outside of the blood vessels, so there will be no Hb in the blood or urine.

152
Q

What are the clinical features of hemolytic anemia.

A

Clinical features –depend on etiology, severity, and course

  1. Anemia (usually normochromic, normocytic)
  2. Extramedullary hematopoiesis
  3. Jaundice
  4. Splenomegaly –if extravascular and persistent
  5. Gallstones
  6. Hemosiderosis
153
Q

Explain the terms hemoglobinopathy and thalessemia.

A

Hemoglobinopathy:

  • Structurally abnormal hemoglobin due to mutation in α or β globin gene
  • Sickle cell disease

Thalassemia:

  • Decreased production of α or βglobin chains due to mutations
  • α-thalassemia
  • β-thalassemia
154
Q

Explain sickle cell anemia.

A
  1. HbS point mutation (SNP), causing a single amino acid replacement in β chain (substitution of glutamic acid with valine).
  2. Causes extravascular and intravascular hemolysis.
  3. Pathogenesis: low O2, high altitude, or acidosis precipitates sickling (deoxygenated HbS polymerizes)Ž leads to anemia and vaso-occlusive disease.
  4. Newborns are initially asymptomatic because of increase HbF and decrease in HbS.
  5. Heterozygotes (sickle cell trait) also have resistance to malaria.
  6. 8% of African Americans carry an HbS allele. Sickle cells are crescent-shaped RBCs A .
  7. “Crew cut” on skull x-ray due to marrow expansion from erythropoiesis (also seen in thalassemias)
  8. Coexistence of HbA, HbF prevents sickling
  9. Coexistence of HbC allows sickling
155
Q

What are the complications associated with Sickle cell disease.

A

Complications in sickle cell disease:

  1. Aplastic crisis (due to parvovirus B19).
  2. Autosplenectomy (Howell-Jolly bodies), increased risk of infection by encapsulated organisms (eg, S pneumoniae).
  3. Splenic infarct/sequestration crisis.
  4. Salmonella osteomyelitis.
  5. Painful crises (vaso-occlusive): Dactylitis (painful swelling of hands/feet), priapism, acute chest syndrome, avascular necrosis, stroke.
  6. Renal papillary necrosis (decreased PO2 in papilla) and microhematuria (medullary infarcts).
156
Q

How is the diagnosis of sickle cell disease made?

A

Via hemaglobin electrophoresis.

157
Q

What is the treatment of sickle cell disease.

A

Blood transfusion

Hydroxyurea, leads to increased HbF, hydration also helps.

Hematopoietic stem cell transplant is potentially curative

158
Q

Explain β thalessemia.

A

Point mutations in splice sites and promoter sequences , leads to decreased β-globin synthesis. Prevalent in Mediterranean populations.

β thalassemia minor (heterozygote):

  1. β chain is underproduced.
  2. Usually asymptomatic.
  3. Diagnosis confirmed by increased HbA2 (> 3.5%) on electrophoresis.

β thalassemia major (homozygote):

  1. β chain is absentŽ leads to severe microcytic, hypochromic anemia with target cells and increased anisopoikilocytosis requiring blood transfusion. (2° hemochromatosis).
  2. Marrow expansion (“crew cut” on skull x-ray)Žskeletal deformities.
  3. “Chipmunk” facies.
  4. Extramedullary hematopoiesisŽ leading to hepatosplenomegaly.
  5. Risk of parvovirus B19–induced aplastic crisis.
  6. Increased HbF (α2γ2). HbF is protective in the infant and disease becomes symptomatic only after 6 months, when fetal hemoglobin declines.
  7. HbS/β thalassemia heterozygote: mild to moderate sickle cell disease depending on amount of β-globin production.
159
Q
A

Crew cut sign, in this case it is due to beta thalessemia.

160
Q

What is the crew cut sign observed on X ray in RBC disorder?

A

Crew cut sign is observed in X ray due to expansion of facial and cranial bones due to increased hematopoiesis in sickle cell disease and thalessemia.

162
Q

Explain alpha thalessemia.

What is HbH disease?

A
  1. Defect: α-globin gene deletions, leads to decreased Žα-globin synthesis.
  2. cis deletion (both deletions occur on same chromosome) prevalent in Asian populations; trans deletion (deletions occur on separate chromosomes) prevalent in African populations.
  3. 4 allele deletion: No α-globin. Excess γ-globin forms γ4 (Hb Barts). Incompatible with life (causes hydrops fetalis).
  4. 3 allele deletion: inheritance of chromosome with cis deletion + a chromosome with 1 allele deleted leads tŽo HbH disease. Very little α-globin. Excess β-globin forms β4 (HbH).
  5. 2 allele deletion: less clinically severe anemia.
  6. 1 allele deletion: no anemia (clinically silent).
163
Q

What are the concequences of having imbalance of alpha, beta or gamma chains in Hb?

A
  1. An imbalance of Hb chains leads to apoptosis of RBCs and its precursors in bone marrow so there is decreased hematopoiesis.
  2. There is also increased destruction of RBCs in spleen leading to extravascular hemolysis.
164
Q

What pathology is seen in alpha thalessemia in blood smear?

A
  1. Hypochromic microcytic anemia
  2. Target cells
  3. Variable reticulocyte count
  4. HbH disease (3-gene deletion) - Elevated HbH (β 4 )
  5. HbBarts disease (4-gene deletion)
    1. Elevated HbBarts (γ 4 )
    2. Severe anemia
    3. Intrauterine death (hydrops fetalis) without intrauterine transfusions
165
Q
A

Heinz bodies and bite cells, seen in G6PD deficiency

166
Q

Explain hereditary spherocytosis.

A
  1. Autosomal dominant
  2. Extravascular hemolysis due to defect in ankyrin, band 3, protein 4.2, spectrin).
  3. Loss of biconcave shape (spherocytes) and an increase in membrane rigidity.
  4. Results in small, round RBCs with less surface area and no central pallor (increased MCHC), this leads to premature removal by spleen.
  5. Splenomegaly, aplastic crisis (parvovirus B19 infection).
  6. Labs: osmotic fragility test ⊕. Normal to decreased MCV with abundance of cells.
  7. Treatment: splenectomy.
167
Q

What is the treatment of thalessemias?

A
  1. Blood transfusion with iron chelation to avoid development of secondary hemachromatosis.
  2. Bone marrow transplant is potentially curative.
168
Q
A

A

169
Q

Explain G6PD deficiency anemia.

A
  1. X-linked recessive..
  2. Causes extravascular and intravascular hemolysis.
  3. Defect in G6PD, leads a decrease in NADPH production and subsequently a decrease in ability to reduce glutathione. There is an increase in RBC susceptibility to oxidant stress.
  4. Hemolytic anemia follows oxidant stress (eg, sulfa drugs, antimalarials, infections, fava beans).
  5. Back pain, hemoglobinuria a few days after oxidant stress.
  6. Labs: blood smear shows RBCs with Heinz bodies (denatured Hemoglobin) and bite cells.
172
Q

What are the clinical features and pathology observed in hereditary spherocytosis?

A
  1. Variable anemia
  2. Spherocytosis
  3. Increased MCHC
  4. Splenomegaly
  5. Gallstones
  6. Negative direct antiglobulin (Coombs) test
173
Q

Explain paroxysmal nocturnal hemaglobinuria.

A
  1. Complement-mediated intravascular RBC lysis (impaired synthesis of GPI (phosphotidylinositol glycan complementation group A) anchor for decay-accelerating factor that protects RBC membrane from complement).
  2. Acquired mutation in a hematopoietic stem cell.
  3. Increased incidence of acute leukemias.
  4. Triad: Coombs ⊝ hemolytic anemia, pancytopenia, and venous thrombosis.
  5. Labs: CD55/59 ⊝ RBCs on flow cytometry.
  6. Treatment: eculizumab (terminal complement inhibitor).
174
Q

What are CD55 and CD59

A

CD 55 = decay accelerating factor

CD59 = C3 convertase inhibitor

175
Q

Pathology and clinical features of PNH?

A

Clinical features

  1. Anemia
  2. Hematuria –typical nocturnal hematuria in 25% of cases
  3. Venous thrombosis
  4. Transformation to acute myeloid leukemia

Pathology

  1. Normochromic normocytic anemia
  2. Positive urinary hemoglobin and hemosiderin I
  3. Iron deficiency
  4. Flow cytometric evidence of deficiency of CD55 and CD59 on RBCs and leukocytes
176
Q

What is the MOA of eculizumab?

A

It blocks the conversion of C5 to C5a

177
Q

What is potentially curative treatment of PNH?

A

Hematopoietic stem cell transplant.

178
Q

Explain direct and indirect Coombs test.

A

Direct Coombs test—anti-Ig antibody (Coombs reagent) added to patient’s blood. RBCs agglutinate if RBCs are coated with Ig.

Indirect Coombs test—normal RBCs added to patient’s serum. If serum has anti-RBC surface Ig, RBCs agglutinate when Coombs reagent added.

179
Q

Explain autoimmune hemolytic anemia.

A
  1. Warm (IgG)—chronic anemia seen in SLE and CLL and with certain drugs (eg, α-methyldopa) (“warm weather is Great”).
  2. Cold (IgM and complement)—acute
  3. anemia triggered by cold; seen in CLL, Mycoplasma pneumonia infections, and infectious Mononucleosis (“cold weather is MMMiserable”).
  4. RBC agglutinates, may cause painful, blue fingers and toes with cold exposure.
  5. Many warm and cold AIHAs are idiopathic in etiology.
  6. Autoimmune hemolytic anemias are Coombs test +ve.
181
Q

How can we differentiate warm AHA from cold AHA on peripheral smear?

What is the reason behind this difference in pathology?

A

We see spherocytes in warm AHA, as opposed to cold AHA where we just see agglutinated RBCs.

RBCs agglutinate due to pentavalent nature of IgM in cold AHA.

183
Q

Treatment of AHA?

A

Splenectomy, steroids and rituximab.

184
Q
A

Traumatic hemolytic anemia

186
Q
A

C

187
Q

Explain paroxysmal cold hemaglobinuria.

A

Paroxysmal Cold Hemoglobinuria

  1. IgG antibodies against RBC membrane P blood group antigen (Donath-Landsteiner antibody)
  2. Intravascular, extrinsic, acquired

Pathogenesis

  1. Antibodies bind below 37C in extremities
  2. IgG coated RBCs fix complement at 37C in central circulation
  3. Complement coated RBCs lyse in circulation (massive intravascular hemolysis)
  4. Clearance of hemoglobin in urine (hemoglobinuria)

Clinical features

  • Episodic anemia and hemoglobinuria following cold exposure
  • Hemolysis only when incubation at 4 C followed by incubation at 37 C
188
Q

Explain traumatic hemolytic anemia.

A

Traumatic Hemolytic Anemia

  1. RBC destruction by trauma
  2. Intravascular, extrinsic, acquired
  3. Etiology and pathogenesis
    1. Macroangiopathic –in large vessels Mechanical heart valves
    2. Microangiopathic –in small capillaries
      1. Disseminated intravascular coagulation
      2. Thrombotic thrombocytopenic purpura
      3. Hemolytic uremic syndrome

An important lab finding here is the presence of schistocytes.

190
Q

What are the clinical symptoms of polycythemia?

A

Leads to hyperviscosity syndrome which can cause visual dysfunction such as blurred vision and neurological deficits such as headache, dizziness, deafness, stupor.

It can physiologic such as due to lung disease, heart disease, high altitude or it can pathologic such as due to local kidney hypoxia or EPO secreting tumors.

191
Q

Define the following terms

  1. Purpura
  2. Petechia
  3. Ecchymosis
  4. Hematoma
  5. Hemarthrosis
A
  1. Purpura : bleeding within skin or mucous membranes
  2. Petechia : pin point bleeding of skin or mucous membranes (a type of purpura)
  3. Ecchymosis : large confluent area of bleeding within skin, larger than petechiae (a type of purpura)
  4. Hematoma : a collection of blood in an organ, space, or tissue
  5. Hemarthrosis : bleeding into the joint space
192
Q

What is the clinical significance of petechiae and skeletal muscle hematoma/hemarthrosis?

A

Petechia are seen in vascular and platelet disorders whereas hematoma/hemarthrosis are seen in coagulation disorder

193
Q

Explain hereditary hemorrhagic telangiectasia.

A
  1. Autosomal dominant
  2. Aka Osler-Weber-Rendu syndrome.
  3. Inherited disorder of blood vessels, weak venules lead to recurrent bleeding.
  4. Caused by mutation in endoglin gene or activin- receptor-like kinase 1 gene
  5. Thickened smooth muscle layer and absent elastin fibers in venule wall
  6. Findings: branching skin lesions (telangiectasias), recurrent epistaxis, skin discolorations, arteriovenous malformations (AVMs), GI bleeding, hematuria.
194
Q

Explain Henoch-Schonlein Purpura.

A

Henoch-Schonlein Purpura

  1. Most common childhood systemic vasculitis.
  2. Acquired disorder, often follows URI, viral infection or drugs.
  3. Classic triad:
    1. Skin: palpable purpura on buttocks/legs
    2. Arthralgias
    3. GI: abdominal pain
  4. Vasculitis 2° to IgA immune complex deposition.
  5. Associated with IgA nephropathy (Berger disease).
  6. Fibrinoid necrosis of vessel walls.
195
Q

Explain immune thrombocytopenia purpura.

A
  1. Anti-Gp2b-3a antibodiesŽ, leads to splenic macrophage consumption of platelet-antibody complex.
  2. Commonly due to viral illness. Can also be due to SLE or lymphoma
  3. Excessive bleeding, skin, muscosa, there can be even intracranial bleeding.
  4. Increased megakaryocytes on bone marrow biopsy.
  5. Treatment: steroids, IVIG, Rituximab, splenectomy (for refractory ITP).
197
Q

Explain thrombotic thrombocytopenic purpura.

A
  1. Inhibition or deficiency of ADAMTS 13 (vWF metalloprotease), leads to decrease in degradation of vWF multimers.
  2. Pathogenesis: increased large vWF multimersŽ platelet, leads to increased platelet adhesionŽ, aggregation and thrombosis.
  3. Labs:
    1. Schistocytes,
    2. Increased serum LDH
    3. Hyaline microthrombi are seen within the arterioles and capillaries (this is the cause of renal failure in this disease)
  4. Classic pentad:
    1. Micrangiopathic hemolytic anemia
    2. Thrombocytopenia
    3. Fever
    4. Neurologic deficits
    5. Renal failure
  5. Treatment: plasmapheresis, Rituximab, steroids.
199
Q

What are qualitative platelet disorders that are associated with platelet receptor defects?

A

Qualitative Platelet Disorders –Inherited Platelet Receptor Defects

Bernard-Soulier Syndrome

  1. GP Ib/V/IX deficiency
  2. Defective platelet adhesion
  3. Diagnosed by platelet aggregation testing
  4. No platelet aggregation response to ristocetin

Glanzmann thrombasthenia

  1. GP IIb/IIIa deficiency
  2. Defective platelet aggregation
  3. Diagnosed by platelet aggregation testing
  4. No platelet aggregation response to epinephrine, ADP, collagen, arachidonic acid, thrombin
  5. Normal platelet aggregation response to ristocetin
201
Q
A

C

202
Q

What is a common feature of platelet disorders?

A

All of them result in an increase in bleeding time and a decrease in platelet count - thrombocytopenia

204
Q

Explain hemolytic uremic syndrome.

A
  1. Characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure.
  2. Typical HUS is seen in children, accompanied by diarrhea and commonly caused by Shiga toxin-producing E coli (STEC) (eg, O157:H7).
  3. HUS in adults does not present with diarrhea; STEC infection not required.
  4. Same spectrum as thrombotic thrombocytopenic purpura (TTP), with a similar clinical presentation and same initial treatment of plasmapheresis.
    1. Hyaline mircothrombi
    2. Schistocytosis
    3. Elevated serum LDH
    4. Thrombocytopenia
    5. NO neurologic symptoms!
206
Q

What are qualitative platelet disorders that are associated with platelet granule defects?

A

Qualitative Platelet Disorders –Inherited Platelet Granule Defects

Alpha Storage Pool Disease

  1. Deficiency of alpha granules (protein-rich)
  2. Defective platelet aggregation
  3. Bleeding is mild to moderate in severity
  4. Diagnosed by electron microscopy

Delta Storage Pool Disease

  1. Decreased or defective delta granules (ADP-rich)
  2. Defective platelet aggregation
  3. Bleeding is mild to moderate in severity
  4. Diagnosed by platelet aggregation testing
207
Q

What are the different tests employed to check for coagulation disorders?

A
  1. PT — tests function of common and extrinsic pathway (factors I, II, V, VII, and X). Defect leads to increased ŽPT.
  2. INR (international normalized ratio) — calculated from PT. 1 = normal, > 1 = prolonged. Most common test used to follow patients on warfarin.
  3. PTT—tests function of common and intrinsic pathway (all factors except VII and XIII). Defect leads to increased PTT.
208
Q

Explain hemophilia.

A
  1. Hemophilia is defined as intrinsic pathway coagulation defect.
    1. A: deficiency of factor VIII ; X-linked recessive.
    2. B: deficiency of factor IXŽ; X-linked recessive.
    3. C: deficiency of factor XIŽ; autosomal recessive.
  2. PTT is increased
  3. Platelet count and bleeding time is normal in all hemophilia
  4. Macrohemorrhage in hemophilia—hemarthroses (bleeding into joints, such as knee), easy bruising, bleeding after trauma or surgery (eg, dental procedures).
  5. Treatment: desmopressin + factor VIII concentrate (A); factor IX concentrate (B); factor XI concentrate (C).
209
Q

What are the different types of Hemophilia A?

A
  1. Severe (50%), moderate (10%) and mild (40%)
  2. In severe there is spontaneous bleeding, mainly due to the development of FVIII inhibitor.
  3. Moderate and mild only result from factor VIII deficiency, there is prolong bleeding only after trauma or surgery.
  4. Hence blood transfusion will help mild and moderate hemophilia A but not severe.
  5. Treatment for severe hemophilia A consists of recombinant FVIII and recombinant FVIIa
211
Q

Explain Von Willebrand Disease.

A
  1. Intrinsic pathway coagulation defect: decreased vWF leads to increased ŽPTT (vWF acts to carry/protect factor VIII).
  2. Defect in platelet plug formation: decreased vWF leads to Ždefect in platelet-to-vWF adhesion.
  3. Autosomal dominant.
  4. Petechiae are observed.
  5. Mild but most common inherited bleeding disorder.
  6. Platelet count is normal, bleeding time is increased, PT is normal, PTT is increased.
  7. No platelet aggregation with ristocetin cofactor assay.
212
Q

Explain FXIII deficiency.

A

Factor XIII Deficiency

  1. Rare autosomal recessive bleeding disorder
  2. Causes defective fibrin cross-linking and an unstable fibrin clot
  3. Manifested by bleeding and delayed wound healing
  4. Normal PT, normal PTT, normal bleeding time
  5. Abnormal urea solubility test (blood clot dissolves in urea, a denaturing agent)
214
Q

How is vWF treated?

A

Von Willebrand Disease -Treatment

  1. Humate P (VWF concentrate)
  2. Cryoprecipitate -good source of VWF
  3. Desmopressin (anti-diuretic hormone) -stimulates endothelial cells to release remaining VWF stores
215
Q

What are some of the other acquired coagulation disorders?

A
216
Q

What are some of the acquired fibrinolytic protein deficiency disorders?

A
217
Q
A

E

218
Q

Explain acquired factor VIII inhibitor disease.

A

Acquired Factor VIII Inhibitor

  1. Pathogenesis
    1. Idiopathic (elderly)
    2. Secondary (autoimmune disease: SLE, rheumatoid arthritis, postpartum, hemophilia A)
    3. specificity against factor VIII
  2. Clinical features - mild to severe bleeding, spontaneous resolution or chronic
  3. PTT is increased, PT is normal
  4. Treatment is immunosuppressive drugs, recombinant FVIIa
219
Q

Explain DIC.

A

Defined as an acquired hemorrhagic and/or thrombotic disorder caused by excessive release of tissue factor into the blood, leading to over activation of the coagulation system and secondary fibrinolysis.

  1. Pathogenesis
    1. release of tissue factor into the blood
    2. risk factors: bacterial sepsis, massive trauma, acute promyelocytic leukemia, carcinoma, placental abruption, retained dead fetus
    3. excess thrombin and plasmin generation
    4. clotting factor and platelet consumption
  2. Clinical features
    1. bleeding (venipuncture sites, etc.)
    2. thrombosis (arterial and venous; brain, heart, lung, kidney, adrenal gland, spleen, liver, etc.)
    3. syndromes (Waterhouse-Friderichsen, Kasabach-Merritt)
  3. Pathologic features
    1. hyaline microthrombi of microvessels
    2. platelet and fibrin rich thrombi
    3. thrombocytopenia
    4. prolonged PT and/or PTT
    5. decreased fibrinogen
    6. elevated D-dimer
    7. microangiopathic hemolysis (schistocytes on blood smear
220
Q

Explain Virchows triad.

A

Hypercoagulability

Venous stasis

Vessel damage

221
Q

What factors predisoposes a patient for greatest risk of DVT?

A

Major surgery/trauma and history of thrombosis

222
Q

What are the symptoms of DVT and what test can be done to confirm the dx?

A

Unilateral leg pain, swelling and non specific symptoms

Compression ultrasound can be done to confirm the diagnosis. Additionally venography of proximal leg veins can also be done.

223
Q

What are the symptoms of PE?

What diagnosis testing can be done?

A

Pulmonary Embolism Clinical Features

  1. Dyspnea
  2. Wheezing
  3. Chest pain (pleuritic -infarction)
  4. Hemoptysis (infarction with bleeding into airway)
  5. Right sided heart failure; cor pulmonale (hypotension, syncope, coma)
  6. Hypoxemia
  7. These features are nonspecific; objective testing required for diagnosis

Diagnostic testing may involve spiral CT that has a high positive predictive value and D dimer test that has a high negative predictive value.

Additionally ventilation perfusion scan or pulmonary angiography can also be done.

224
Q

Explain Factor V Leiden mutation.

A
  1. Production of mutant factor V (G ->ŽA, DNA point mutationŽ near the cleavage site, Arginine to Glutamine) that is resistant to degradation by activated protein C.
  2. Most common cause of inherited hypercoagulability in Caucasians.
  3. Complications include DVT, cerebral vein thromboses, recurrent pregnancy loss.
  4. Heterozygotes also have increased risk

Diagnosis:

  1. Activated Protein C (APC) resistance test is used as a screening test. APC causes prolonged PTT in normal individuals, there is less PTT prolongation in people with Factor V Leiden mutation.
  2. Mutation analysis PCR can then be done as a confirmatory test.
225
Q

Explain the function of Protein C.

A

Protein C and Protein S are vitamin K dependent proteins that play a role in anticoagulation pathway.

226
Q
A

E

227
Q

Explain the origin of heparin, thrombomodulin, anti thrombin III, Protein C and Protein S.

Explain their MOA and their effects on coagulation cascade.

A

Heparin and thrombomodulin is expressed on the surface of endothelial cells whereas antithrombin, Protein C and Protein S are made by the liver and are found in plasma.

Heparin binds to antithrombin, causes a conformational change such that antithrombin then inhibits several coagulation factors, most of the anticoagulent effect of heparin comes from inhibition of thrombin (FII).

Protein C and Protein S together inactivates FV and FVIII so they have an anticoagulent effect.

228
Q

Explain prothrombin gene mutation disease.

A

Mutation in 3′ untranslated region leading to increased stability of prothrombin mRNA, leads to increased Žproduction of prothrombinŽ, causes increased plasma levels and venous clots.

High prevalence in Caucasians.

Diagnosis is made by checking for mutation via PCR.

229
Q

Explain Protein C and Protein S deficiency disease.

A
  1. Decreased ability to inactivate factors Va and VIIIa.
  2. Leads to increased risk of thrombotic skin necrosis with hemorrhage after administration of warfarin. If this occurs, think protein C deficiency.
  3. Patients have a high risk of DVT
  4. Those who are homozygous for the mutation can express this as neonates that have skin thrombosis and necrosis at birth, disease called Neonatal Purpura Fulminans
  5. There are decreased levels of Protein C (or Protein S) in the plasma so mutation analysis is not required, other causes of protein C or S deficiency can be warfarin, liver disease, vitamin K deficiency and DIC
230
Q

Explain Anti thrombin III deficiency.

A
  1. Inherited deficiency of antithrombin: has no direct effect on the PT, PTT, or thrombin time but diminishes the increase in PTT following heparin administration.
  2. Can also be acquired: renal failure/nephrotic syndromeŽ, leads to antithrombin loss in urine, as a result there is a decrease in Žinhibition of factors IIa and Xa.
  3. Hallmark of this disease is that there is resistance to heparin therapy, PTT doesn’t increase when heparin is administered.
  4. There is decreased plasma levels of anti thrombin III, could be due to other factors such as liver disease, nephrotic syndrome, DIC
231
Q

Explain antiphospholipid syndrome.

A
  1. APS is an acquired disease characterized by the acquisition of one or more thrombosis-promoting autoantibodies called antiphospholipid antibodies.
  2. Can be primary or secondary due to lupus
  3. Primary antigen is β2 glycoprotein.
  4. Diagnose based on clinical criteria including history of thrombosis (arterial or venous)or spontaneous abortion along with laboratory findings of
    1. Lupus anticoagulant
    2. Anticardiolipin
    3. Anti-β2 glycoprotein antibodies.
  5. Treatment is systemic anticoagulation and immunosuppression.
  6. Anticardiolipin antibodies and lupus anticoagulant can cause false-positive VDRL/RPR (syphilis test) and prolonged PTT.
  7. Viral infections can give a false positive, must give a positive test on 2 occasions 12 weeks apart.
232
Q

Explain lupus induced APS.

A
  • Causes a prolonged PTT with a noncorrected 1:1 mixed study
  • Must perform two tests to confirm the diagnosis:
    • dilute Russell Viper venom time
    • hexagonal phase phospholipid neutralization test
  • Lupus anticoagulant is diagnosed if either test is positive
  • Must show positive test on 2 occasions, 12 weeks apart, to exclude transient lupus anticoagulant due to infection
233
Q

Explain HIT.

A

Heparin Induced Thrombocytopenia

Definition: A drug induced thrombotic disorder caused by antibodies directed against the heparin-platelet factor 4 complex

234
Q

HIT clinical features.

A
235
Q

HIT diagonsis and treatment.

A
236
Q
A

B

237
Q

What are the basis of dividing some of the hematologic neoplasms?

A

They can be divided into myeloid and lymphoid neoplasms, they can be further divided by the types of genetic mutations and chromosomal abnormalities and their respective concequences.

238
Q

What is the difference between leukemia and lymphoma?

A
241
Q

What are myeloproliferative disorders?

A

Neoplasms of hematopoietic stem cells with proliferation of one or two myeloid lineages.

  1. CML
  2. Polycythemia vera
  3. Primary myelofibrosis
  4. Essential thrombocytopenia
  5. Mastocytosis

Hallmark of these diseases is constitutively activated tyrosine kinase.

242
Q

Epidemiology, key findings and treatment of CML

A
  1. Occurs across the age spectrum with peak incidence 45–85 years, median age at diagnosis 64 years. (disease of older individuals)
  2. Philadelphia chromosome (t[9;22], BCR-ABL)
    1. ​ABL on chromosome 9 goes next to BCR on chromosome 22
    2. Chromosome 22 looks extra short
  3. Marked granulocytosis including all stages of maturation
  4. May accelerate and transform to AML or ALL (“blast crisis”).
  5. Responds to bcr-abl tyrosine kinase inhibitors (eg, imatinib).
243
Q

What are the symptoms of CML?

A

Initially assymptomatic for many years as its a slowly progressing disease, may present with non specific symptoms such as fatigue, fever, malaise, weight loss.

Patients often develop massive splenomegaly (early satiety and LUQ discomfort). There can also be thrombosis and bleeding disorders.

244
Q

What are the pathological findings of CML?

A
  1. On blood smear we can see granulocytes of all stages of maturity
  2. Leukocytosis, defined to be above 20,000/microL.
  3. Basophilia
  4. Bone marrow is markedly hypercellular
  5. Massive splenomegaly due to expanded red pulp that carries out extramedullary hematopoiesis.
245
Q
A

Blast crisis seen in CML.

246
Q

How do we make a definitive diagnosis of CML?

A

Looking for the Philedelphia chromosome.

247
Q

What are the different stages of CML?

What is the treatment for CML?

A
  • Chronic phase, lasts from 2 to 8 years
  • Accelerated phase:
    • Blasts 10-19%
    • Increased basophils
    • Persistent thrombocytopenia or thrombocytosis
    • Increasing splenomegaly and WBC
    • Karyotypic evolution
  • Blast crisis –survival <1 y
    • Blasts ≥20%
    • Can progress to ALL of AML kind of illness

Only bone marrow transplant is curative, Imatinib is not a long term solution since tumor cells develop resistance by changing the ATP binding site of TK receptors.

249
Q

Explain Polycythemia Vera.

A
  1. Disorder of multipotent stem cell with predominant effects in erythroid lineage, leads to 1° polycythemia. Disorder of hematocrit.
  2. May present as intense itching after hot shower. Rare but classic symptom is erythromelalgia (severe, burning pain and red-blue coloration) due to episodic blood clots in vessels of the extremities
  3. Responds to aspirin.
  4. EPO levels are low (vs 2° polycythemia, which presents with endogenous or artifcially high EPO).
250
Q

Explain the genetics of polycythemia vera.

What drug can be used to cure this?

A
  • Point mutation in pseudokinase domain of JAK2, as a result it is constitutively active as there is a loss of autoinhibition.
  • This leads to increases phosphorylation of downstream targets including STAT5.
  • NOT seen in CML or lymphoproliferative disorders.
  • Ruxolitinib can be used to inhibit JAK2, but it is not as widely used to due to higher incidence of toxic effects
251
Q

What are the clinical features of PV?

A

Increased RBC mass, it can cause

  1. Plethora
  2. Dizziness
  3. Angina
  4. Headache
  5. Visual disturbances
  6. Intermittent claudification

Splenomegaly and thrombosis or bleeding can also occur.

Important to know that RBCs are normochromic and normocytic.

252
Q

What are the findings in the spleen and bone marrow in PV?

A

Decreased or absent iron in the bone marrow together with hypercellularity and an increase in red pulp with extramedullary hematopoiesis in spleen.

253
Q

What are the symptoms of Primary myelofibrosis?

What are the pathological findings of the disease?

A
  1. Non specific flu-like symptoms
  2. Hemorrhage
  3. Recurrent infections
  4. Hallmark of this disease is massive splenomegaly

Leukoerythroblastocytosis and tear-drop RBCs are 2 important pathological findings.

254
Q

Explain what is obsered in bone marrow in primary myelofibrosis.

A

Reticulin, collagenous fibrosis and osteosclerosis

255
Q

Explain the course of polycythemia vera.

A

There is a proliferative phase during which the RBC count can get very high, this is followed by Spent consisting of a stable or decrease in RBC count.

Finally the last phase is post polycythemia myelofibrosis, consisting of progressive anemia, splenomegaly, myelofibrosis.

In 2% of the cases patients with PV can develop AML like disease.

256
Q

Explain the disease process of Primary Myelofibrosis.

A
  1. Obliteration of bone marrow with fibrosis due to increase in fibroblast activity. Often associated with massive splenomegaly and “teardrop” RBCs.
  2. Neoplasm of multipotential hematopoietic stem cell with reactive fibrosis
  3. Pro-fibrotic growth factors (PDGF, TGF-β) from megakaryocytes
  4. Leukoerythroblastosis and extramedullary hematopoiesis
  5. Epidemiology Middle aged and older adults
  6. Excludes CML and PCV that progress to fibrosis
257
Q

What genes are associated with primary myelofibrosis?

A

Genetics

  • JAK2 mutation in up to 50% of cases
  • Calreticulin mutations in 35% of cases
  • MPL mutation in 1-5% of cases - this is a thrombopoietin receptor, thrombopoietin is a factor for megakaryocyte growth and development
260
Q

Explain the disease process, epidemiology and genetics of Primary Thrombocytosis.

A
  1. Characterized by massive proliferation of megakaryocytes and platelets.
  2. Symptoms include bleeding and thrombosis.
  3. Blood smear shows markedly increased number of platelets, which may be large or otherwise abnormally formed B . Erythromelalgia may occur.
  4. Epidemiology - middle aged and older adults
  5. Genetics - JAK2, Calreticulin mutations and MPL mutation.
261
Q

Explain mastocytosis.

A

Increased and morphologically abnormal mast cells, these are associated with c-KIT mutation.

It can be localized mastocytosis which is called Urticaria pigmentosa or it can be systemic

262
Q

Explain AML.

A
  1. There is proliferation AND lack of maturation, which requires atleast 2 different mutations. Median onset 65 years.
  2. Auer rods (picture below)
  3. Myeloperoxidase ⊕ cytoplasmic inclusions seen mostly in APL (acute promyelocytic leukemia, formerly M3 AML)
  4. Circulating myeloblasts on peripheral smear.
  5. Risk factors: prior exposure to
    1. alkylating chemotherapy,
    2. topoisomerase II inhibitors
    3. radiation,
    4. myeloproliferative disorders,
    5. Down syndrome.
  6. t(15;17)Ž = APL subtype responds to all-trans retinoic acid (vitamin A), inducing differentiation of promyelocytes.
  7. DIC is a common presentation.
264
Q
A

AML

265
Q

What are the clinical features of AML?

A
  1. Anemia - can lead to fatigue, weakness, pallor.
  2. Thrombocytopenia - bleeding disorders.
  3. Hepatosplenomegaly - 1/3rd of the cases
  4. In the bone marrow we see increased number of blast cells (of lymphoid lineage unlike ALL), we also see Auer bodies
267
Q

What are some of the other organs involvement seen in AML?

A

Leukostasis and granulocytic sarcoma.

268
Q

What is the clinical course and prognosis of AML?

A
269
Q

How do we define Acute Promyeloid Leukemia?

Explain this disease.

A
  1. AML with t(15;17) defines acute promyelocytic leukemia
  2. Disrupts retinoic acid receptor (RAR-α) gene
  3. Abnormal promyelocytes with multiple Auer rods
  4. Frequent association with DIC
  5. All trans retinoic acid (ATRA) used for treatment. However, this is not the cure, these patients still have t(15;17), ATRA only makes these immature cells become mature (neutrophils) and eventually die.
  6. Favorable to intermediate prognosis
270
Q

Explain Langerhan’s Cell Histiocytosis.

A
  • Neoplastic proliferation of Langerhans cells
  • BRAF mutations in 60% of cases
  • Admixed eosinophils, plasma cells, neutrophils
  • Variable clinical presentation
271
Q

What are the different diseases that are classified under Langerhan’s Cell Histiocytosis and seperated by age groups and presentation?

A
272
Q
A

Langerhan Cell Histiocytosis

273
Q

How can we identify Langerhan cells under electronmicroscope?

A

By the presence of Birbeck Granules.

274
Q

What are some of the other AML diseases that have good prognosis?

A
  • t(8;21) - Favorable prognosis
  • inv(16) or t(16;16) - Acute myelomonocytic leukemia with abnormal eosinophils (AML –M4Eo), also favorable prognosis
276
Q

Explain myelodysplastic syndromes.

A
  1. Ineffective hematopoiesis together with peripheral cytopenias + hypercellular marrow
  2. Etiologic associations
    1. Benzene
    2. Alkylating chemotherapeutic drugs
    3. Ionizing radiation
    4. Topoisomerase II inhibitors
  3. Clinical features –related to pancytopenia
    1. Variable course
    2. May smolder for years; some are transfusion dependent
    3. 10-40% transform to AML

Pathoma & First Aid (3 decks)

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