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Block 6: Microbio, ID, Derm, Heme-Onc > Hematology (Week 7) > Flashcards

Hematology (Week 7) Flashcards

1
Q

Blood and blood forming tissues

A

Erythrocytes (RBCs)

Leukocytes (WBCs)

Platelets

Bone marrow

Spleen

Lymph nodes and antibodies

Coagulation

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2
Q

Definition of blood

A

Blood is differentiated cells (generally nondividing) suspended in plasma

Plasma is composed of coagulation proteins in a solution of serum

Serum contains other proteins and solutes (antibodies, albumin)

Blood = cells + plasma + serum

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3
Q

Definition of bone marrow

A

Source of multipotential stem cells and their differentiated progeny

Source of cellular material of the blood

Source of immunologically active cells of the body (reticuloendothelial system)

Source of adherent bed of cells essential to hematopoietic proliferation, immunomodulation and cell survival

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4
Q

Where do you have bone marrow?

A

Everywhere from skull to axial bones to pelvis..

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5
Q

General flow of differentiation of blood cells

A

Hematopoietic stem cell (can self-renew and is pluripotent) –> committed stem cell (younger ones called “blasts”) –> differentiated cells

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6
Q

Pluripotent stem cell

A

Differentiates into myeloid and prelymphoid component, then inductive stimuli from bone marrow stroma cause cells to eventually become committed (neutrophil, basophil, erythrocyte, platelet, T cell, B cell, NK cell, etc)

(NOT embryonic stem cell, but close!)

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7
Q

How do pluripotent stem cells change as they differentiate?

A

As they differentiate, they get smaller

As they differentiate, they move from adherent bone matrix of marrow into marrow more

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8
Q

Where is blood formed in the growing embryo?

A

19 days: blood is formed in yolk sac

6 weeks: blood is formed in the spleen and liver (main site at weeks 9-24)

10-12 weeks: blood is formed in bone marrow (main site at >24 weeks)

2 weeks post-partum: blood formed only in bone marrow

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9
Q

What kind of cells does cord blood have?

A

Hematopoietic stem cells

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10
Q

Percent cells in the bone marrow

A

100 - age is percent cells in the marrow

(25 year old should have 75% cells in marrow and not too much fat)

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11
Q

Normal RBC maturation

A

Pronormoblast (proerythroblast)

Basophilic normoblast

Polychromatophilic normoblast (cytoplasm contains residual RNA that still stains slightly blue)

Orthochromic normoblast

Reticulocyte (no nucleus)

Mature erythrocyte

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12
Q

Why is it important that RBCs don’t have a nucleus?

A

Because whatever proteins/enzymes they have now is all they’ll ever have because they can’t do any more protein synthesis

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13
Q

What happens when RBCs get old and become senescent?

A

Senescent RBCs become rigid, cannot get through small places and are removed by the spleen

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14
Q

What should happen to reticulocyte cound if you’re anemic?

A

It should increase to compensate for the fact that you don’t have enough RBCs!

Note: only if you have hemolytic anemia or acute blood loss (NOT chronic disease, sideroblastic, iron deficiency, B12/folic acid deficiency, aplastic anemia)

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15
Q

Normal RBC count, hemoglobin, hematocrit, reticulocytes

A

RBC count (x 106 mm3): 4.4-5.9 male; 3.8-5.2 female

Hemoglobin (GM%): 13-18 male; 12-16 female

Hematocrit (%): 40-52 male; 35-47 female

Reticulocytes (%): 0.5-1.5

Reticulocyte count (x 106 mm3): 0.025-0.105

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16
Q

Reticulocyte Index

A

Correction to figure out how many reticulocytes are actually in the blood

1) Correct for degree of anemia: multiply reticulocyte % by Hgbpatient/Hgbcontrol
2) IF nucleated RBCs present, correct for 2-day lifespan of reticulocyte: divide number by 2

Note: reticulocytes still have residual ribosomal RNA (even though nucleus is gone!)

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17
Q

If you have anemia, what would you want to reticulocyte percentage to be?

A

Remember it’s usually only 1% and you need to compensate for destruction/decrease in RBCs

Depends on degree of anemia…

2% is not enough to compensate…maybe 3% and higher would be good compensation??

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18
Q

Mean corpuscular volume (MCV)

A

Average volume of RBC

HCT (%) x 10 / RBC count

Normal: 81-100 mm3

If microcytosis, low

If macrocytosis, high

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19
Q

Mean corpuscular hemoglobin concentration (MCHC)

A

Average concentration of hemoglobin per volume of RBCs

Hg x 100 / HCT

Normal 31-36 g/dL

If hypochromia, will be low

If spherocytosis, will be high (cell volume decreased by Hg content the same)

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20
Q

Mean corpuscular hemoglobin (MCH)

A

Average weight of hemoglobin per RBC

Hg x 10 / RBCs

Normal 27-34 pg

Reflects both size and Hg concentration

Usually varies in similar fashion to MCV

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21
Q

RBC terminology

A

Microcytic = RBC small

Macrocytic = RBC large

Hypochromic = less Hg/cell (larger central pallor)

Anisocytosis = variation in size of RBC

Poikylocytosis = variation in shape of RBC

Polycythemia = too many RBCs

Anemia = too few RBCs

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22
Q

Erythropoietin

A

Hormone that controls RBC production

Made in kidney (some in liver)

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23
Q

Anemia

A

Decreased RBC levels (or decreased hemoglobin levels?)

SIgns: weakness, fatigue, shortness of breath, pallor

Due to one of 4 things: decreased production, ineffective production, increased destruction

Diagnosis: reticulocyte count, evaluate blood smear, RBC indices (MCV, MCHC, MCH)

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24
Q

3 general causes of anemia

A

Hypoproliferative: impaired erythropoiesis

Ineffective: intact erythropoiesis but intramedullary hemolysis (die in bone marrow?)

Compensatory (hemolytic): intact erythroid production, egress from marrow but early erythrocyte destruction (exit bone marrow but die in peripheral blood?)

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25
Q

Hypoproliferative anemia

A

Most common type of anemia

Reticulocytopenia

Low or normal MCV

Impaired production of intact hemoglobin or impaired regulation of hematopoiesis

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26
Q

Specific causes of hypoproliferative anemia

A

Disorders of:

Erythrocyte production: congenital, acquired (deficiency of erythropoietin, chronic renal insufficiency, pure erythrocyte aplasia)

Production of mature hemoglobin: disorder of iron (deficiency, sequestration (anemia of chronic disease/inflammation; sideroblastic anemia)), disorder of heme (thalassemia, lead intoxication, hemoglobin E, sideroblastic anemia)

Hematopoietic stem cell

Bone marrow microenvironment

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27
Q

How is iron lost from the body?

A

No active secretion of iron

Iron lost only when cells lost (urine, skin, gut, menstruation)

Regulation mainly by absorption

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28
Q

Iron turnover

A

20-30 mg per day is turned over between RBC destruction and production

However, remember that only small amounts (1mg per day) are lost in gut, sweat urine that must be renewed by diet

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29
Q

What happens if you have iron deficiency?

A

O2 transport messed up

Electron transport messed up

Anemia

Muscle weakness

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30
Q

What happens if you have iron overload?

A

Oxidant damage affects:

Heart

Liver

Endocrine

Joints

Infection

Note: more of a problem in men because women at least have menstruation to get rid of some iron every month

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31
Q

Iron deficiency anemia

A

Cannot produce mature hemoglobin

Hypoproliferative anemia

Most common cause of anemia worldwide

Get microcytic, hypochromic RBCs, targets, anisocytosis, poikylocytosis

Negative iron stain (with Prussian blue) of marrow

Can be due to chronic blood loss (infancy, lactation, pregnancy, GI ulcer)

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32
Q

Mechanisms of iron deficiency

A

GI blood loss

Menstruation

Blood loss in pregnancy and lactation

Urinary blood loss

Less common: dietary deficiency (in baby on formula), intestinal malabsorption, atransferrinemia

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33
Q

Clinical manifestations of iron deficiency

A

Anemia (hypoproliferative, reticulocytopenia, microcytic)

Epithelial changes (koilonychia, depapillated tongue, esophageal webs and strictures)

Skeletal changes (growth retardation, skull changes)

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34
Q

Anemia of chronic disease (inflammation)

A

Cannot produce mature hemoglobin

Iron is sequestered in macrophages and have erythropoietin dysfunction

Lab: low serum iron, low TIBC, high ferritin, normal serum transferrin receptor

Iron necessary for microorganism growth and division but host binds iron with ovoalbumin, transferrin, lactoferrin and ferritin –> inflammation from disease leads to cytokine release (IL-1, TNF, IL-6) –> macrophages increase lactoferrin receptors to internalize more lactoferrin-bound iron, increase ferritin synthesis and decrease iron output from the macrophage –> overall iron sequestered in macrophages and withheld from both microorganisms and RBCs

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35
Q

Ineffective disorders of hematopoiesis

A

Nuclear-cytoplasmic dissociation (nucleus doesn’t mature normally and keeps cell very big so cannot get out into blood and is destroyed in bone marrow!)

Intramedullary maturation arrest and hemolysis

Reticulocytopenia (bc reticulocytes never get out of bone marrow!) with macrocytosis

May not be restricted to hematopoiesis

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36
Q

Folate deficiency

A

Causes megaloblastic anemia

Get mucosal changes

Measure low folate in serum and RBCs

Get folate deficiency if: poor diet, cancer, hemolysis, alcoholism, during pregnancy and lactation (increased demand), drugs, malabsorption

Folic acid does not need cofactor to be absorbed, is depleted in 5 months (“nutritional” megaloblastic anemia)

Folic acid does 1 carbon transfers to make thymidilate to make pyramidines and purines (for DNA synthesis)

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37
Q

Vitamin B12 (cyanocobalamin) deficiency

A

Causes megaloblastic anemia

Get neurologic symptoms (paresthesias in hands and feet, decreased vibration/position sense, ataxia, psychoses), mucosal changes

Measure low B12 blood levels

Get B12 deficiency if: deficiency in intrinsic factor activity (pernicious anemia), gastric resection/neoplasm, ileal resection/enteritis, fish tapeworm competition, diverticulosis, strict vegans

Get vitamin B12 from meat, dairy

Need intrinsic factor (secreted by parietal cells in stomach) to absorb B12 in terminal ileum

Takes years to deplete B12, so don’t just get nutritional deficiency!

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38
Q

Marrow and blood smear of megaloblastic anemia

A

Marrow shows young nuclei that are large and have no clumping of chromatin

Blood smear shows big RBCs with low hemoglobin (macrocytic and hypochromic?)

Blood smear also shows hypersegmentation of neutrophils

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39
Q

Hemolysis

A

Premature destruction of erythrocytes:

Intravascular vs. extravascular

Intracorpuscular vs. extracorpuscular

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40
Q

Lab evaluation of hemolysis

A

Reticulocytosis (trying to make up for RBC loss/lysis) with any MCV

Polychromatophilia of RBCs

Erythroid hyperplasia of bone marrow –> increased indirect bilirubin, increased urinary and fecal urobilinogen, increased endogenous carbon monoxide production

Depleted unbound haptoglobin (because lots of free hemoblobin to bind haptoglobin)

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41
Q

Findings in a patient with hemolysis

A

Increased indirect bilirubin

Scleral icterus

Serum is yellow from indirect bilirubin

Peripheral blood smear used to determine cause of hemolysis

Erythrocyte features: fragmentation, spherocytosis, distinct erythrocyte morphology, erythrocyte inclusion

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42
Q

Autoimmune hemolytic anemia

A

IgG eats up membrane of RBC

On peripheral blood smear, see spherocytes

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43
Q

Different kinds of hemolytic anemia

A

Trauma to RBC: heart valve shears RBCs –> fragmented RBCs on smear

Chronic liver or kidney disease: RBC membrane becomes pickled due to abnormal distribution of membrane lipids

Infection: Plasmodium falciparum infects RBCs and causes RBC lysis

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44
Q

Different sites of erythrocyte injury

A

Splenic consumption

Vasculature

Plasma

Erythrocyte membrane

Cytoplasm

Hemoglobin

Erythrocyte enzymatic machinery

Infection

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45
Q

Spleen

A

Normal spleen 200-300 cc/minute (4-5% cardiac output)

Half cells capable of phagocytosis

White and red pulp, marginal zone and germinal centers

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46
Q

Differential diagnosis of splenomegaly

A

Portal HTN

Infiltrative disorders of spleen (lymphoma)

Cardiomyopathy

Autoimmune disease

Subcapsular hemorrhage

Hematologic disorders (hemolysis, hemoglobinopathy, neoplastic)

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47
Q

Vascular disorders causing hemolytic anemia

A

Macroangiopathic hemolytic anemias (heart valve shearing RBCs)

Microangiopathic hemolytic anemias (DIC, malignant hypertension, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome)

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48
Q

Plasma disorders causing hemolytic anemia

A

Membrane lysins

Toxins and envenomations (clostridial sepsis, spider bites, snake bites, chemical lysins)

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49
Q

Membraneopathies causing hemolytic anemia

A

Congenital: hereditary spherocytosis, elliptocytosis, stomatocytosis, acanthocytosis

Acquired: immunohemolytic anemias, immune hemolysis, Rh incompatibility, autoimmune hemolytic anemia, drug-induced hemolytic anemia

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50
Q

Hemoglobinopathies

A

Change in AA can give new characteristics to hemoglobin and lead to:

Sickle cell hemoglobin (HbS): increased hemoglobin precipitation

Unstable hemoglobin

Methemoglobins: inability to keep iron in reduced form within hemoglobin molecule

High/low affinity molecules: altered O2 affinity of hemoglobin molecule

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51
Q

Hemoglobin genes

A

Alpha on chromosome 16 (4 genes total)

Betas on chromosome 11 (2 genes total)

Also, gamma and delta on chromosome 11

Note: easier to develop beta thalassemia because only 2 beta genes!

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52
Q

Normal hemoglobins

A

HgA: alpha2beta2 = major adult Hg (>95%)

HgA2: alpha2delta2 = minor adult Hg (<3%)

HgF: alpha2gamma2 = major Hg in fetus (<2% in adults)

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53
Q

Sickle cell disease (HgSS)

A

Qualitative problem

Point mutation at 6th AA position of beta globulin gene from hydrophilic glutamic acid to hydrophobic valine –> when hemoglobin deoxygenated, beta globulins interact with each other so hemoglobins form polymers within RBC –> rigid, sickled RBC

10% of American Blacks have S gene

Age of onset is variable (6 months - 2 years)

Lab: low grade anemia, erythroid hyperplasia, extravascular hemolysis (in the spleen? indirect hyperbilirubinemia)

Symptoms: pain, bone infarcts, lungs, CNS, heart, renal, autosplenectomy, infections

Treatment: analgesia, fluid if dehydrated, alkalinization if acidotic, antibiotics if infected, transfusions, hydroxyurea (only FDA approved), bone marrow transplant (?)

85% survive to age 20; 60% survive to age 50

Cause of death in kids is infection (spleen infarcted –> encapsulated bacterial infection); cause of death in adolescents/adults is acute chest syndrome or infection

Carrier state (HgAS usually asymptomatic and resistant to Malaria)

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54
Q

Thalassemias

A

Quantitative problem

Decrease in synthesis of a globin chain (globin gene missing!) resulting in unbalanced synthesis of globin chains and decreased hemoglobin production

Microcytic, hypochromic RBCs

Beta Thalassemia Major: homozygous; severe anemia, hepatosplenomegaly, hypercellular marrow, bone changes, iron overload (due to transfusions AND hemolysis of bad RBCs), infections, HgA 0; Hg 2-6

Beta Thalassemia Minor: heterozygous; mild anemia or asymptomatic, may worsen with infections or pregnancy; Hg >9

Hydrops fetalis: missing all 4 alpha genes; fetus has “Barts Hg” (gamma 4 tetramers) and dies

Hemoglobin H disease: missing 3 alpha genes so get HgH which is tetramer of beta chains only; intra-erythrocytic inclusions because they precipitate; hemolytic anemia, microcytic, hypochromic target cells

Alpha Thalassemia Minor: missing 2 alpha genes; mild microcytic, hypochromic anemia or asymptomatic

Silent carrier: missing 1 alpha gene; asypmtomatic

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55
Q

Enzymopathies that can cause hemolytic anemia

A

G6PD deficiency

Pyruvate kinase deficiency

Hemolytic anemias caused by other derangement of Embden-Meyerhoff pathway (glycolysis)

Abnormalities of nucleotide metabolism

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56
Q

Erythrocyte infections that can cause hemolytic anemia

A

Malaria

Babesiolsis

Other protozoal infections

Bartonellosis

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57
Q

If absolute neutrophil count (ANC) is <500, what are patients at risk for?

A

Bacterial infection

Hyphal fungal infection

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58
Q

3 types of WBC disorders

A

1) Too many WBCs (leukocytosis): reactive (infection) vs. neoplastic (leukemias, lymphomas)
2) WBC dysfunction: congenital, toxic, neoplastic
3) Too few WBCs (leukopenia): decreased production, increased destruction, or splenic sequestration

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59
Q

Aplastic anemia

A

Decreased marrow production of (usually) all blood cells

Get pancytopenia (decreased erythroid, myeloid and megakaryocytic cell lines); only cells that remain are ones that live a long time (plasma cells and lymphocytes)

Bone marrow is hypocellular

Symptoms: weakness, fevers, infections (bc low WBC), bleeding (bc low platelets)

Signs: peticheae, hemorrhage, pallor, fever

Causes: idiopathic, drugs/toxins (benzene, chloramphenicol), infection, radiation, immune mediated, paroxysmal nocturnal hemoglobinuria

Treatment: transfusion, antibiotics, immune suppression (ATG = horse serum), hematopoietic stem cell transplantation

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60
Q

Lymphoproliferative disorders

A

Abnormal production or accumulation of lymphoid cells with clinical behavior reminiscent of ontogeny of the cells

Note: you can only get cancer in dividing cells so there is no such thing as neutrophilic leukemia because neutrophils can’t divide

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61
Q

Suffixes for decreased and increased numbers of cells

A

Decreased: cytopenias

Increased: cythemias, or cytoses

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62
Q

Two different reasons why you may have leukocytosis

A

1) Primary marrow abnormality (neoplastic or preneoplastic)
2) Secondary (appropriate marrow response to external signals, like infection!)

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63
Q

Leukemia vs. lymphoma

A

Leukemia: abnormal cells in blood and marrow

Lymphoma: abnormal cells in lymph nodes, thymus, spleen, or other lymphoid tissues (Peyer’s patches)

Note: this is a relative difference, not aboslute–they overlap obviously

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64
Q

Leukemias where you have too many lymphocytes (lymphocytosis)

A

Chronic lymphocytic leukemia (CLL)

Acute lymphocytic leukemia (ALL)

65
Q

How can you tell if lymphocytosis is neoplastic or infectious?

A

Neoplastic will be clonal: all lymphocytes have either kappa or lambda light chain but not both

Infectious will be polyclonal because lots of different cells fighting infection

66
Q

Chronic lymphocytic leukemia (CLL)

A

Lymphoproliferative disorder

Lymphocytosis, lymphadenopathy, hepatosplenomegaly, infections, immunologic abnormalities (hypogammaglobulinemia, immune cytopenias, paraproteinemias), secondary malignancies

Usually monoclonal mature B-cells, but rarely T cells, NK, Prolymphocytic, or Hairy Cell)

30% of all leukemias in US

Cytogenetic abnormalities: deletion 13q14.3, trisomy 12

Lab: coexpression of CD5 (usually T cell marker) with CD19 and 20 (B cell markers), anemia, thrombocytopenia

Treatment: only treat if symptomatic (alkylators, fludarabine, chemo, steroids to induce apoptosis of lymphocytes, Mab therapy, blood or marrow transplant in younger pts)

67
Q

Staging of CLL

A

Stage 0: lymphocytosis of blood and marrow

Stage I: lymphocytosis + lymphadenopathy

Stage II: lymphocytosis + splenomegaly and/or hepatomegaly

Stage III: lymphocytosis + anemia (Hg<11)

Stage IV: lymphocytosis + thrombocytopenia (plt<100,000)

68
Q

Why do people with CLL get frequent infections if too many immune cells?

A

Body tries to control B cell clone but actually ends up controling normal clones and neoplastic cells still grow

(reason why patients develop hypogammaglobulinemia?)

CLL patients get encapsulated bacteria infections

69
Q

Hairy cell leukemia

A

Lymphoproliferative disorder

Blood and marrow lymphocytes with fine filamentous “hairy” projections

Usually B cells

Stain for tartrate resistant acid phosphatase (trap), monoclonal surface immunoglobulin and Fc receptors

Pancytopenia, splenomegaly, infections, immune abnormalities

Responsive to deoxycoformycin, alpha-interferon, splenectomy

1 week of nucleoside analog can produce 10 year remission!

70
Q

Chronic T cell leukemias/lymphomas

A

Mycosis fungoides/Sezary’s syndrome: CD4+ lymphoma which produces cutaneous infiltrates, lymphadenopathy and can transform to erythrodermatous phase with circulating Sezary cells

Large granular lymphocytosis syndrome: T cell/NK cell disorder (CD8+), severe neutropenia, pancytopenia, rheumatoid arthritis, splenomegaly

Adult T cell leukemia/lymphoma: associated with HTLV-1, have lymphocytosis, lymphadenopathy, hypercalcemia, lytic bone lesions

71
Q

Three stages in thrombus formation

A

1) Vasoconstriction (if have vascular disease and hardened vessel, can’t constrict and pt will bleed!)
2) Primary hemostasis: platelets
3) Secondary hemostasis: fibrin

72
Q

What initiates primary hemostasis (platelet plug formation)?

A

Endothelium is damaged and exposes subendothelium below

von Wildebrand Factor (vWF) binds subendothelium

Platelets then bind vWF via GpIb receptor

73
Q

Platelet adhesion vs. platelet activation

A

Platelet adhesion: unactivated platelets bind ??

Platelet activation: activated platelets expose adhesion molecules and adhere to subendothelium?

74
Q

Steps in primary hemostasis

A

1) Adhesion
2) Activation and secretion
3) Aggregation
4) Procoagulant activity (assembly of factors in secondary hemostasis)

75
Q

What prevents us from clotting all the time?

A

1) Endotheluim: covers subendothelium because as soon as subendothelium exposed, we clot
2) Fast flow of blood: things zipping by so fast that they can’t find each other (need high enough concentration to make clotting happen)

76
Q

Basics of intrinsic and extrinsic pathways

A

Intrinsic pathway: 9 needs 8 as cofactor to activate 10 –> 10 needs 5 as cofactor to activate 2 (thrombin) –> thrombin turns fibrinogen to fibrin

Extrinsic pathway: 7 activates 10 –> 10 needs 5 as cofactor to activate 2 (thrombin) –> thrombin turns fibrinogen to fibrin

77
Q

Which 4 enzymes are Vitamin K (Ca2+) dependent?

A

7, 9, 10, 2 (thrombin)

These trigger the clotting cascade

Serine proteases, synthesized in liver

These zymogens (proenzymes) need to be carboxylated by carboxylase, but carboxylase needs Vitamin K as cofactor –> once carboxylated, can bind Ca2+ which they need in order to become active

78
Q

Coumadin (warfarin)

A

Coumadin inhibits carboxylase reaction on 7, 9, 10, 2 so that these clotting enzymes cannot become active

79
Q

How low can enzyme/co-factor level get before coagulation is impaired?

A

Since enzymes/co-factors are not consumed in reaction, levels can get very low (<30%) before coagulation is impaired (recessive or X-linked mutations)

Mild bleeding: 30-5% activity of factors

Moderate bleeding: 5-1% activity of factors

Severe bleeding: <1% activity

Note: fibrinogen and vWF ARE consumed in reaction, so lower levels of those show anti-coagulation phenotype easily (autosomal dominant mutations)

80
Q

Clinical findings of platelet defects

A

Petechiae and purpura (usually symmetric; small bleeds)

History of easy or spontaneous bruising

Mild to moderate mucosal membrane bleeding (gingival, menorrhagia, epistaxis)

81
Q

Platelet disorders

A

Thrombocythemia (primary or secondary)

Thrombocytopenia (decreased production or increased destruction)

Loss of platelet function (congenital or aquired)

82
Q

Primary thrombocythemia

A

Myeloproliferative disease (CML, PV, ET)

Platelets can have normal or abnormal function

83
Q

Secondary thrombocythemia

A

Increased release of platelets from bone marrow

Due to steroids or stress, or cute phase reactant, iron deficiency, acute blood loss, post splenectomy, epinephrine, chronic infections

Platelets have normal function

84
Q

Thrombocytopenia due to decreased production

A

Marrow replacement (space taken up by fibrosis)

Aplastic anemia

Viral infection

Drugs (chemical wiped out progenitors)

Congenital disorders (rare)

85
Q

Thrombocytopenia due to increased destruction

A

Prosthetic valves

Hypersplenism

Immune mediated disseminated intravascular coagulation (DIC)

Medications (heparin, antibiotics, H2 blockers)

86
Q

Causes of immune thrombocytopenia

A

Autoimmune (ITP) acute or chronic

Alloantibodies (neonatal or transfusion)

Drug induced (ie heparin) by creating new epitope

Disease association (make antibodies you shouldn’t): other autoimmune, lymphoproliferative, myeloproliferative, solid tumors, infection

87
Q

Acute vs. chronic ITP (immune thrombocytopenia)

A

Acute: children 2-9 years; abrupt onset, after infection, <20,000 platelets (very dangerous!); lasts 2-6 weeks but then 80% spontaneous remission (don’t need tx other than support); variable response to immunosuppression or splenectomy

Chronic: adults 20-40 years; more female; gradual onset; no clear antecedent; 20-100,000 platelets still; lasts years and spontaneous remission is rare; usually respond to immunosuppression or splenectomy

88
Q

What causes loss of platelet function?

A

Uremia (not clear why)

Liver disease

Prosthetic valves

Aspirin or NSAIDs (or other drugs)

Essential thrombocythemia

Congenital (vWD, intrinsic platelet defects)

89
Q

Lab tests to assess platelet-type bleeds

A

Platelet count

Bone marrow (look for megakaryocytes to determine production vs. destruction)

Bleeding time (only if platelets >100,000)

Platelet aggregation assays

90
Q

Risk of bleeding with thrombocytopenia

A

Normal platelet count: 150-350,000

Risk of excess bleeding with surgery: <50,000

Risk of spontaneous bleeding: <20,000

Imminent risk of GI or cerebral hemorrhage: <5,000

91
Q

When would you use bleeding time as a screening test?

A

Very archaic, only used if you think there is a vascular problem (can’t test that with other lab tests!)

Normal bleeding time 10 minutes

Only do this if patient has >100,000 platelets and no liver disease, uremia, collagen vascular disease, prosthetic valves, etc because of course bleeding time will be increased!

92
Q

Coagulation disorders (hemorrhagic)

A

Decreased factor production: acquired (liver disease, Vitamin K deficiency), congenital (hemophilia)

Increased factor consumption: acquired (DIC), congenital (rare: alpha2-anti-plasmin)

93
Q

Congenital bleeding disorders

A

Von Willebrand’s Disease (autosomal dominant)

Hemophilia A (factor 8; X-linked)

Hemophilia B (factor 9; X-linked)

Other factors (autosomal recessive)

Fibrinogen (dominant or recessive)

94
Q

Von Willebrand’s Factor (vWF)

A

Made in endothelial cells

Glues platelets down to exposed collagen to start primary hemostasis

Consumed in reaction so mutation is autosomal dominant (unlike enzymes!)

Also stabilizes factor 8, so can affect secondary hemostasis –> larger bleeds

95
Q

Clinical findings in coagulation factor deficiencies

A

Common: bleeding in major muscles and joints, large bruises

Rare: mucosal hemorrhage, intracranial bleeds, bleeding from minor cuts and abrasions

96
Q

Regulators of coagulation

A

Plasmin: degrades fibrin (degrades clot)

Protein C: serine protease (like 7, 9, 10, 2) with co-factor Protein S that degrades other co-factors 8 and 5; has shortest half-life

Anti-thrombin III: serine protease inhibitor; in presence of heparin, inhibits 2, 9, 10 (not 7 because doesn’t fit)

97
Q

Heparin

A

Potentiates anti-thrombin III to inhibit factors 2, 9, 10

Starts working immediately!

98
Q

If someone is clotting too much, which drug do you give first?

A

Give heparin first because starts anti-coagulating immediately (works to inhibit factors 2, 9, 10 by potentiating anti-thrombin III)

Give coumadin a few days later because coumadin only works on NEWLY synthesized factors (prevents carboxylation/inhibits protein C first to get slight clotting which you don’t wait–then prevents carboxylation/inhibits factor 7, 9, 10, 2 to anti-coagulate); coumadin will KEEP factors 7, 9, 10, 2 from working long-term

99
Q

Coagulation disorders (thrombotic)

A

Note: clotting disorders are all autosomal dominant with incomplete penetrance (most symptomatic patients have >1 mutation and other contributing factors); homozygous mutation is incompatible with life!

Antiphospholipid syndrome (often seen in lupus)

Factor V Leiden mutation (resistance to Protein C)

Protein C deficiency

Protein S deficiency

ATIII deficiency

Prothrombin mutation

Homocysteinemia

100
Q

Disseminated intravascular coagulation

A

Result of something else bad going on: major tissue trauma, brain trauma, shock (to treat DIC, fix initial problem; short term treatment has no protocol, either can fix clotting or bleeding)

Generalized intravascular clotting AND fibrinolysis (dissolving clots)

Disseminated microvascular thrombi cause tissue injury

Consumption of coagulation factors and platelets causes hemorrhage

See low platelets, factors, fibrinogen, and high fibrin degradation products

101
Q

Trigger mechanisms in DIC

A

Direct intravascular factor activation by proteases: snake venom, proteases released in acute pancreatitis, crude factor concentrates

Release of cellular procoagulants (tissue factor) causes intravascular cell lysis (hemolysis, leukemia, granulocyte lysis in sepsis), extravascular cell lysis (tumor, trauma, surgery), ascitic or amniotic fluid emboli

Vascular factors: endothelial cell damage by endotoxin, hypotension and stasis (shock), hemangiomas

Note: with shock, coagulation factors going really slowly and can aggregate easier

102
Q

Damage caused by DIC

A

Glomerular capillaries frequently affected because plugged with microthrombi (fibrin-platelet thrombi)

Widespread focal ischemia AND hemorrhage damages kidney, skin, brain, lung, GI, mucous membranes

103
Q

Lab tests to evaluate hemorrhagic and thrombotic disorders

A

Prothrombin time (PT): 9-12 sec

Partial thromboplastin time (PTT): 22-33 sec

Fibrinogen: 200-400 mg/dl

Specific factor/co-factor assays: >50% activity

APC resistance/Factor V Leiden

D-dimer assay: should be negative (measures plasma degraded fibrin)

104
Q

How various diseases/drugs affect PT or PTT

A

Remember, PT measures extrinsic pathway (factor 7) and PTT measures intrinsic pathway (factor 9 and 8)

Mutation in 7 –> prolonged PT

Hemophilia A –> prolonged PTT

Hemophilia B –> prolonged PTT

Mutation in 10 –> both

Liver disease –> both

Vitamin K deficiency –> both

Give heparin –> prolonged PTT (doesn’t affect 7!)

Give coumadin –> prolonged PT (7 has shortest half life!)

105
Q

Part of marrow in normal adult where hematopoiesis occurs

A

Ends of long bones

Iliac crest

106
Q

Nutrients required for RBC production

A

Iron

B-12

Folate

107
Q

Where do reticulocytes mature?

A

2/3 mature in the marrow and then are released into circulation

1/3 are put into circulation and THEN mature in the circulation

108
Q

If a patient is anemic, how high should the reticulocytes be?

A

Depends, but can be up to 10x higher % (normal is 0.5 - 1.5%, so could be 5 - 15%)

109
Q

Proteins in the RBC membrane

A

Spectrin

Ankyrin

Actin

Note: these hold bilayer together and keep RBC in its normal shape; if defect in proteins, form spherocytes

110
Q

Anemias with different RBC morphologies

A

Microcytic: iron deficiency, thalassemia

Macrocytic: folate or B12 deficiency

Normocytic but with abnormal shapes: hereditary spherocytosis, sickle cell disease

111
Q

Clinical presentation in iron deficiency

A

Fatigue, breathlessness

Pica (persistent compulsive desire to ingest certain food or non-edible items like ice, clay, plaster)

Sore mouth, angular stomatitis, palor

112
Q

Megaloblastic anemia

A

B12 and folic acid deficiency

Hypercellular bone marrow with increased megaloblasts

All hematopoetic lineages show nuclear to cytoplasmic dyssynchrony

Hypersegmented neutrophils

Treat with B12 and see increase in reticulocyte count in first week and disappearance of hypersegmented neutrophils in 2-3 weeks

113
Q

Granules of neutrophils

A

Primary granules: MPO, elastase, defensins, cathepsins

Secondary granules: lactoferrin

Tertiary granules: cathepsin, gelatinase

Note: these enzymes play important role in killing microorganisms

114
Q

Absolute neutrophil count (ANC)

A

ANC = WBC x (% bands + % mature neutrophils) x 0.01

115
Q

Clinical presentation and treatment of severe neutropenia

A

Severe neutropenia <500 per mm3

Get infections (chills, fever, weakness), ulcerating, necrotizing oral/pharyngeal lesions with massive growth of bacteria and no granulocyte response

Treatment includes recombinant hematopoietic growth factors (G-CSF)

116
Q

Multiple myeloma

A

Neoplasm of malignant plasma cells

Normal hematopoietic elements replaced by malignant plasma cells

Neoplastic plasma cells secrete paraproteins which cause kidney problems and interfere with normal antibody secretion by plasma cells

Clinical features: CRAB = calcemia, renal failure, anemia, bone lesions (lytic)

Diagnosis: M-protein (paraproteins) in serum or urine, bone marrow with clonal plasma cells or plasmacytoma, CRAB

117
Q

Thrombopoetin

A

Hormone responsible for platelet production

Produced by liver and kidney

118
Q

Normal platelet count but loss of function

A

Uremia (renal failure)

Liver disease

Prosthetic valves

Aspirin or NSAIDs (or other drugs)

Congenital (intrinsic platelet defects): Bernard Soullier syndrome (Gp1b deficiency), Glanzmann’s thrombasthenia

119
Q

What does it mean for a diagnostic test if the prevalence of a disease in a population is low?

A

If prevalence of disease in a population is low, even tests with high specificity or sensitivity will have low positive predictive values

Makes sense because if prevalence is low, more positives will be false positive and more negatives will be truly negative

120
Q

HIV testing is >99% sensitive and specific, is screening the population a good idea?

A

If very low HIV prevalence, positive predictive value (PPV) is very low but NPV is very high –> just have to do confirmatory test on positive results

Note: ELISA used for screening and nucleic acid test used for confirmation (not western blot anymore because that misses patients with early HIV infection)

121
Q

Detuned HIV test

A

Strategy used to diagnose “recent” infection

First test with threshold of 50, see positive result, then test with threshold of 100 and see negative result –> means antibody titer is low which means person was just recently infected with HIV

This strategy “tunes down sensitivity of the test” (increase threshold to call test positive)

122
Q

ABO blood groups

A

ABH antigens are located on transport proteins of the RBC membrane

Antigens differ only with respect to one terminal sugar

O: no terminal sugars (H antigen)

A: N-acetyl-D-galactosamine

B: D-galactose

123
Q

What different blood types can receive

A

Blood type A (has A antigen) can receive RBCs from A, O; plasma from A, AB

Blood type B (has B antigen) can receive RBCs from B, O; plasma from B, AB

Blood type O (no antigens) can receive RBCs from O; plasma from O, A, B, AB

124
Q

Cross matching

A

Add recipient plasma to donor RBC and see if there is a reaction (should be NO reaction if ABO matched!)

Use secondary antibody to Fc region of human antibodies to allow for clumping if the recipient’s antibody did bind to donor’s RBC

125
Q

What does giving one unit of packed RBCs do?

A

1 unit of packed RBCs = 250-300ml

One unit will increase hemoglobin by 1 gm/dL (Hct, 2-3%)

126
Q

How do you decide when to transfuse RBCs?

A

Not based upon numbers, but upon symptoms!

To restore O2 carrying capacity in symptomatic anemia (exertional dyspnea, dyspnea at rest, fatigue, hyperdynamic state, lethargy and confusion, CHF, angina, arrhythmia, MI) or acute bleeding

In general, transfuse high risk patients (acute MI, unstable angina) at Hgb < 10g/dL; low risk patients at Hgb < 7g/dL

Note: if someone anemic (Hg = 6) but doesn’t have symptoms, don’t transfuse them!

127
Q

Acute hemolytic transfusion reaction

A

What we’re most scared of during transfusion!

Occurs within minutes to hours after transfusion

Signs and symptoms: chills, fever, hemoglobinuria, hypotension, renal failure with oliguria, DIC (oozing from IV sites), back pain, pain at infusion site, anxiety

Management: supportive (maintain hydration, analgesics, pressors, hemostasis, follow-up labs), prevention

Incidence = 1:38,000 - 1:70,000

Etiology: clerical error 70% of time

ABO incompatible transfusions are the worst (can also have incompatibilities in other proteins?)

128
Q

Hemolytic disease of the newborn

A

Occurs secondary to anti-D (anti-Rh) antibodies

Mother lacks antigen (Rh-)

Fetus possesses antigen (Rh+)

First baby’s fetal red cells stimulate maternal IgG response during birth (?)

If second baby is Rh+, antibody from mother crosses the placenta and binds/destroys fetal RBCs –> fetal anemia (cardiac failure and edema, hydrops fetalis, jaundice, kernicterus)

Note: mother can be sensitized by transfusion or previous pregnancy (maybe not enough of antibody response to cause anemia in first baby? Maybe just IgM with first baby..?)

129
Q

Rhogam

A

Rho(D) immune globulin (Rhogam) is given to all Rh- mothers at 28 weeks gestation

If baby is Rh+, the Rho(D) immune globulins will coat baby’s RBCs so that mother never “sees” the antigen and never makes Rh antibodies!

When baby is born, can type the baby to see if it’s actually Rh+ –> if baby was Rh+, keep giving mother Rhogam until all baby’s blood out of her system?

130
Q

How do you monitor mother/baby for potential hemolytic disease of the newborn?

A

Take serial titers every 2-4 weeks

Measure Rh antibody in mother

If baseline increase by two dilutions, means baby is at risk for hemolytic disease of newborn (baby is Rh+ and mother is reacting to it!)

Note: you can also look at the paternal genotype to see if he is Rh+

Can also use serial doppler ultrasound to measure peak systolic velocity of fetal MCA (if anemic, lower blood viscosity and increased cardiac output); this is performed at 18 - 35 weeks

131
Q

Intra-uterine transfusion

A

Can do this if baby is anemic

Cord blood obtained by cordocentesis to measure hemoglobin level

Transfuse fresh O and Rh negative blood using umbilical vein

Goal is to suppress fetal red cell production

Do transfusions until birth

132
Q

Transfusion of platelet products

A

Do this if someone has platelet count <10-20,000 (myelosuppression from chemotherapy or primary aplasa (ALL))

Apheresis platelets: platelets in small vol of plasma with minimal RBC/WBC; 150-250 ml/unit; raises platelet count by 30,000

Platelet concentrate (PC): platelets in small vol of plasma with minimal RBC/WBC; 50-70 ml/unit

133
Q

Allergic transfusion reactions

A

Second most common reaction

IgE to donor plasma proteins (FFP > platelets > RBC > cryo)

Signs and symptoms: urticaria, pruritis, flushing

Therapy: stop transfusion, give antihistamine, then can restart transfusion; or give antihistamine prophylactically if know will have this rxn

134
Q

Febrile non-hemolytic transfusion reaction

A

Antibody to donor WBCs, or transfusion of pre-formed cytokines in blood products (platelets most common)

Signs and symptoms: fever, chills, rigors, headaches, possibly changes in BP, HR, dyspnea, nausea

Not life-threatening but uncomfortable

Therapy: antipyretic; use leukocyte-reduced blood products

135
Q

Fresh frozen plasma transfusion

A

FFP contains all coagulation factors, so give to someone who is not clotting well (liver disease, DIC, factor deficiency, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome being treated by plasma replacement, coumadin reversal)

Therapy guided by coag studies (PT, aPTT)

1 unit plasma increases most factors 2.5%; 4 units plasma increases most factors 10%

Contraindications: available specific therapy (factor 8, 9, vitamin K), volume expansion

136
Q

Transfurion-related acute lung injury (TRALI)

A

Causes death more often than any other transfusion reaction (mortality 5-10%)

Leakage of fluid into alveolar space due to diffuse alveolar damage (antibody-mediated or cytokines)

Signs and symptoms: acute respiratory distress, frothy fluid coming from endotracheal tube, tachycardia, fever, hypo/hypertension, cyanosis

Consequences: lung injury and prolonged ventilatory time, predispose to pulmonary infection, death

Therapy: supportive care until recovery; test for WBC antibody (HLA, granulocyte) in donor and recipient

Note: this is a clinical diagnosis (act fast and lab test takes a week!)

137
Q

Transfusion-associated circulatory overload (TACO)

A

Volume overload temporally associated with transfusion

Signs and symptoms: SOB, increased RR, hypoxemia, cough, tachycardia, JVD, headache

Therapy: upright posture, O2, IV diuretic, transfuse split unit

138
Q

When people donate blood, what do we screen it for?

A

HIV

HepB

HepC

HTLV-1, 2

WNV

Syphilis

CMV (sometimes?)

Chagas (not yet FDA mandated)

139
Q

Hemoglobin

A

Oxygen carrying protein within RBCs

Normal adult HbA contains 4 subunits: 2 alpha chains and 2 beta chains

Each subunit has a globin (polypeptide chain) and a heme (iron-containing prosthetic group)

140
Q

Why do we see alpha gene defects in embryonic development but not beta gene defects?

A

Because alpha is expressed during fetal life and beta is not expressed until after birth

141
Q

Globin gene developmental expression and globin switching

A

Ordered regulation of developmental gene expression

Genes in each cluster arranged in same transcriptional orientation and same sequential order as developmental expression

142
Q

Embryonic and fetal hemoglobin

A

Embryonic hemoglobin: zeta2epsilon2

Fetal hemoglobin (HbF): alpha2gamma2 (predominates 5 weeks gestation to birth; 70% of total Hb at birth; <1% of total Hb in adulthood)

143
Q

Adult hemoglobins

A

HbA: alpha2beta2 (nearly all is HbA by 3 months old)

HbA2: alpha2delta2 (<2% of adult Hb)

144
Q

Thalassemias

A

Relative imbalance (NOT instability!) in relative amounts of alpha and beta chains, due to mutations resulting in decreased synthesis of one or more globin chains

Excess normal chains precipitate in red cell to damage cell membrane and destroy RBCs prematurely

Results in hypochromic microcytic anemia and tissue iron overload

Seen in Mediterraneans

145
Q

Hereditary persistence of fetal hemoglobin (HPFH)

A

Clinically “benign” and not associated with disease

Mutations impair perinatal switch from gamma to beta globin synthesis

At least one gamma gene remains intact

Increased gamma chain production so increased HbF in adult

HPFH heterozygotes have 17-35% HbF

146
Q

Sickle cell anemia

A

Autosomal recessive disorder HbSS

HbS is mutation of 6th codon of beta globin gene turning hydrophilic glutamic acid to hydrophobic valine

When deoxygenated, hemoglobin S interacts with other hemoglobin S to polymerize and cause RBC to be rigid and sickled

Found in “Malaria Belt” but mutation emerged outside of Africa separately too (heterozygote confers resistance to malaria)

147
Q

Clinical features of SS disease

A

Presentation in first 2 years of life

Infections, anemia, failure to thrive, splenomegaly, dactylitis

Vaso-occlusive infarctions: strokes, acute chest syndrome, renal papillary necrosis, autosplenectomy, leg ulcers, priapism, bone aseptic necrosis, visual loss

However as many as 70% of people have no symptoms

Causes of death: progressive renal/cardio-pulmonary failure (in 30s and 40s), parvovirus infections (high risk of life-threatening aplastic anemias, temporary cessation of RBC production)

148
Q

Alpha thalassemias

A

Disorder of alpha globin production

Affects formation of both fetal and adult hemoglobins (can cause intrauterine and postnatal disease)

In absence of alpha globin chains, beta globin tetramers form (gamma4 is Hb Bart’s and beta4 is HbH) which cannot release O2 to tissues normally

Normal = 4 functional alpha genes

Silent carrier = 3 functional alpha genes

Alpha-thal mild = 2 functional alpha genes

Alpha-thal HbH = 1 functional alpha genes

Hydrops fetalis = 0 functional alpha genes

149
Q

Hydrops fetalis due to severe alpha thalassemia

A

High level of Hb Bart’s (gamma4)

Marked intrauterine hypoxia

Seen most commonly in Southeast Asia (high gene frequency, predominant form of alpha thal trait there is –/aa, so have risk of –/– whereas elsewhere it’s -a/-a!)

Note: hydrops fetalis is massive generalized fluid accumulation in utero

150
Q

Milder alpha thalassemia (HbH)

A

Anemia develops because of gradual precipitation of HbH in erythrocytes

151
Q

Beta thalassemia

A

Excess alpha chains

Alpha chains are insoluble, precipitate in RBC precursors and cause RBCs to be destroyed in bone marrow (ineffective erythropoiesis)

Not apparent until a few months after birth

Beta thalassemia minor = heterozygote

Beta thalassemia major = homozygous

152
Q

Beta thalassemia minor

A

Heterozygote (one normal beta globin gene, the other mutated)

Hypochromic, microcytic anemia

May be misdiagnosed as iron deficiency anemia

HbA2 elevation only in these heterozygotes (alpha2delta2)

HbF is also increased (not due to reactivation of gamma globin gene but increased selective survival and possibly increased production of minor population of HbF-containing adult RBCs)

153
Q

What is the mutation in beta thalassemia?

A

There are many different mutations in the beta globin gene that can lead to beta thalassemia!

154
Q

Beta thalassemia major

A

Usually genetic compounds that create homozygote (two genes with mutations in beta globin though)

Severe anemia with phenotype due to combined effects of two alleles

Beta0 thal: no HbA present

Beta+ thal: HbA present

Severe hypochromic anemia

Treatment: blood transfusion and iron chelation; bone marrow transplantation if appropriate match

155
Q

What happens if you have one gene that is beta thal and one that is beta S?

A

If the beta thal gene is beta0: like sickle cell disease

If the beta thal gene is beta+: may be mild phenotype

156
Q

What happens if you have mutations in both alpha and beta loci?

A

Beta thal homozygotes (beta thal major) who also inherit alpha thal allele may have LESS severe beta thalassemia because there is LESS imbalance of alpha vs. beta globins!

157
Q

Some symptoms of iron deficiency anemia

A

Pica (eating ice)

Glossitis (sore tongue)

Dysphagia (esophageal webs)

158
Q

Hereditary spherocytosis

A

Due to defect in membrane skeleton protein of RBC

Intracorpuscular hemolysis

Block 6: Microbio, ID, Derm, Heme-Onc (10 decks)

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