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Heme/Onc > Hematology > Flashcards

Hematology Flashcards

1
Q

Iron deficiency anemia

A

Microcytic hypochromic anemia= reduced hemoglobin, reduced MCV, increased RDW

  • Serum iron= reduced iron, reduced ferritin, increased total iron-binding capacity
  • Reticulocytes= normal to low, lack polychromasia on smear
  • Smear= Microcytic hypochromic RBCs, increased central pallor
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2
Q

Anisocytosis

A

Variation in RBC cell size

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3
Q

Poikilocytosis

A

Variation in RBC cell shape

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4
Q

Polychromasia

A

Increase in reticulocyte count

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5
Q

Spherocytes

A

Smaller, round shaped red blood cells which lack central pallor. Due to:

  • Acquired immune hemolytic anemia
  • Post transfusion
  • Hemolytic anemia due to oxidant drugs
  • Hemolysis due to a large spleen
  • Hereditary spherocytosis
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6
Q

Elliptocyte

A

AKA ovalocyte: An elongated red blood cell with blunt end; Shape varies from slightly oval or egg-shaped to long pencil-like. due to:

  • Hereditary elliptocytosis
  • Smaller number can be seen in iron deficiency, thalassemia, hemoglobinopathy, and other anemia.
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7
Q

Microangiopathic hemolytic anemia

A
  • Include thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulation (DIC), hemolytic uremic syndrome, uremia with hypertension, sickle cell anemia with pulmonary emboli.
  • Red blood cells are fragmented by intravascular fibrin deposit in TTP and DIC
  • Red cell morphology includes helmet, burr, acanthocyte, spur, spiculated, fragmented, pinched etc.
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8
Q

Lab testing for multiple myeloma/immune secretory disorders

A
  • Serum immunoglobulin and free light chain quantitation
  • Serum and urine protein electrophoresis
  • Immunofixation
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9
Q

RBC

A

Red blood cell count (total)

  • Cells/liter of blood
  • Male= 4.5-6 x 10^12/L
  • Female= 4-5.5 x 10^12/L
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10
Q

Hemoglobin

A

Concentration of blood (grams of cells/dL blood)

  • Anemia= decreased Hb
  • Polycythemia= increased Hb
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11
Q

Hematocrit

A

Volume of RBCs in blood

- Hematocrit= RBC x MCV (liter/cell)

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12
Q

MCV

A

Mean corpuscular volume

  • Mean of RBC distribution (normal 82-100)
  • Microcytosis= decreased MCV
  • Macrocytosis= increased MCV
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13
Q

Differential diagnosis of neutrophilia: Leukemoid reaction vs CML

A

Leukemoid reaction versus CML (chronic myelogenous leukemia)

  • Stages of myeloid cells present
  • Alkaline phosphatase activity
  • Morphologic findings (toxic changes)
  • Basophilia)
  • Philadelphia chromosome (BCR/ABL)
  • Leukemoid reaction= LAP (leukocyte alkaline phosphatase) elevated
  • CML= LAP depressed
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14
Q

Neutropenia

A

Absolute neutrophil count < 1800/uL

  • Increased susceptibility to infection as neutrophil count drops below 1000/ml
  • Agranulocytosis - virtual absence of neutrophils (depletion of blood and marrow storage pools)
  • May need to use antibiotic prophylaxis
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15
Q

MCH

A

Mean corpuscular hemoglobin

  • Hemoglobin concentration per cell
  • Normal range: 27-34 pg
  • Hemoglobin divided by RBC
  • Limited clinical use
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16
Q

MCHC

A

Mean corpuscular hemoglobin concentration

  • Average hematoglobin concentration per total red blood cell volume, Normal range 32-36%
  • Hemoglobin divided by hematocrit
  • Limited clinical use
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17
Q

RDW

A

Red cell distribution width

  • Coefficient of variation of red cell histogram distribution curve
  • Measure degree of variation of red blood cell size (or anisocytosis)
  • Increase of RDW is associated with anemia from various deficiencies: Iron, B12, folate
  • Normal or low RDW is associated with thalassemia or anemia of chronic disease
  • Not specific, must be interpreted in conjunction of other CBC and red cell indices
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18
Q

Reticulocytes

A

Immature red blood cells containing residual ribosomes

Indicator of red cell production

Measured by automated method or manual count

Clinically used to evaluate anemia

  • Low reticulocyte count: iron deficiency, folate/B12 deficiency, bone marrow failure
  • High reticulocyte count: acute blood loss, hemolysis
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19
Q

ESR

A

Erythrocyte sedimentation rate

  • Measures distance of red blood cells fall in a vertical tube over a given period of time
  • Negative charges on red blood cells prevent stacking
  • Inflammatory proteins (such as fibrinogen, a-, b-, g-globins) increase red cell sedimentation.
  • A more rapid fall of red cells in the test tube, resulting higher stack of red cells – elevated ESR
  • Elevated ESR indicates inflammatory process: useful in monitor disease process, esp. temporal arteritis, polymyalgia rheumatica
  • Not recommended for screening test or diagnostic purpose
  • False positive and false negative common
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20
Q

Physical exam in Anemia

A
  • Known bleeding
  • Hypoxia
  • Hemolysis: jaundice/scleral icterus, pallor, tachycardia, tachypnea
  • Splenomegaly, hepatomegaly
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21
Q

Causes of Microcytic anemia

A

IRON DEFICIENCY: hypochromic anemia
Hemoglobinopathies: THALASSEMIA, sickle cell
Membrane diseases: spherocytosis

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22
Q

Workup of microcytic anemia

A 
Look for symptoms (bleeding, fatigue)
Labs:
- CBCD and smear
- Iron studies: Fe, TIBC, ferritin
- Hemoglobin electrophoresis: Genetic studies for α thalassemia
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23
Q

Causes of Macrocytic anemia

A

Nutritional deficiencies

  • B12
  • FOLATE
  • Both important for DNA synthesis: issues cause increased cell size
Hemolysis (usually)
Myelodysplastic syndrome
Medication related (block DNA synthesis)
- Hydroxyurea  
- AZT and other anti-virals
- Phenytoin 
Toxic exposures
- Alcohol
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24
Q

Workup for macrocytic anemia

A
  • Ask about alcohol consumption and medications, including nonprescription medications, supplements, etc.
  • B12 and folate: Homocysteine and MMA
  • LDH, reticulocyte count, haptoglobin
  • Consider bone marrow biopsy
  • Consider specialized tests for workup of hemolytic anemia
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25
Q

Iron deficiency anemia

A

Most common cause of anemia in US and worldwide

  • Leads to microcytosis due to decreased Hb synthesis
  • Cells hypochromic
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26
Q

Iron metabolism needs

A

Daily iron loss (only 10% taken is absorbed)

  • The baseline daily loss for men/post-menopausal women is 1 mg/day
  • This increases to an average of 1.5 mg/day for menstruating women
  • Lactation increases this by up to another 1 mg/day

Iron absorption:

  • Requires acidic environment in stomach, intact duodenum
  • PPI use, Gastric bypass–> iron deficiency
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27
Q

Causes of iron deficiency

A

Losses:

  • GI (varices, gastritis, AVMs, polyps)
  • GU (menorrhagia, childbirth)
  • Donation/phlebotomy

Increased demand:

  • Pregnancy and lactation
  • Rapid growth (infants, teens)
  • Premature infants

Inadequate intake/absorption

  • Achlohydria (PPIs)
  • Celiac disease
  • IBD
  • Partial gastrectomy- loss of intrinsic factor/acidic environment
  • Bariatric procedures

Malabsorption

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28
Q

Symptoms of Iron deficiency

A

General symptoms of anemia:

  • Fatigue, shortness of breath, dyspnea on exertion, dizziness on standing, impaired exercise tolerance
  • Pica

Signs:
- tachycardia, tachypnea, orthostasis, pallor

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29
Q

Labs in iron deficiency anemia

A

Serum ferritin= decreased

  • Acute phase reactant: protein that increases at time of inflammation
  • Storage form of iron (low= no iron storage in body)

Plus:
- Low serum iron, high total iron binding capacity, LOW percent saturation

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30
Q

Labs in thalassemia (microcytic anemia)

A 
High ferritin (vs iron deficiency)
- Diagnosis with hemoglobin electrophoresis
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31
Q

Treatment of iron deficiency

A 
Oral formulations:
- Ferrous Sulfate 
- Ferrous Gluconate
- Ferrous Fumarate
Side effects= constipation, nausea

Takes a LONG TIME to replete iron:
Ex: ferrous sulfate: 325 mg (65 mg elemental Fe)- 3 pills/day–> 20 mg/day
- Takes 3-6 months to replete anemia
- First see reticulocytosis
- After a week= 1 g increase in hemoglobin

IV formulations:
- Complications of allergic reactions (less common with newer preparations)

Defecit= body weight x (target Hb - Actual Hb) x 2.4 + body iron depot

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32
Q

Megaloblastic anemia

A

Problems with DNA synthesis; dissociation between DNA and cytoplasmic maturation

  • See morphological abnormalities in RBCs, bone marrow examination
  • B12, folate deficiency–> pancytopenia (hypersegmented neutrophils, macrocytic anemia)

MOA; salvagable source of purines and thymidine correct cell cycle defect/apoptosis in folate-deficient erythropoeisis

Clinical causes:

  • Diet, age
  • GI disease, surgery
  • Pernicious anemia
  • PPIs, anticonvulsants, sulfa drugs, DNA synthesis inhibitors (long term use of methotrexate, hydroxyurea, anti-virals)
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33
Q

Biochemistry of B12 (cobalamine)

A
  • Water soluble vitamin
  • Synthesized only by microorganisms
  • Found in varying amounts in most animal products
  • Storage pool is normally adequate for 3-4 years if not longer (vs folate= 3-4 months)
  • Storage is primarily in the liver and enterohepatic recirculation is very important

Absorption:
1. Passive through mucosal surfaces (inefficient)- can give LARGE oral doses, only 1% absorbed

  1. Intrinsic factor: B12 MUST be bound to IF to be absorbed in ileum:
    - B12 released from protein complexes in stomach–> bound to salivary R-binder
    - Enzymes secreted by pancreas (trypsin) cleaves B12 from R-binder–> tranferred to Intrinsic factor
    - IF-B12 complex binds to luminal membrane of enterocytes in ileum
  • Issues with IF synthesis, antibodies against IF, releasing factor, or issues with gastric/intestinal lining–> B12 deficiency
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34
Q

Pernicious anemia

A

Antibodies against Intrinsic Factor (autoimmune condition)

  • Leads to B12 anemia
  • Megaloblastic/macrocytic anemia
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35
Q

MMA, H-cys in B12 deficiency

A

BOTH involved in production of THF–> purine synthesis

B12 needed for Homocysteine–> methionine conversion (DNA methylation)

Methylmalonyl CoA converted to succinyl co-A by B12
(MMA–> Succinyl coA)
* B12 deficiency–> increase in MMA

B12 converts homocysteine to methionine
*Homocysteine ALSO increases in B12 deficiency

  • Folate deficiency–> increases in homocysteine, NOT MMA
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36
Q

Biochemistry of folic acid

A
  • Dietary folates are absorbed rapidly from the upper small intestine with approximately 50% of ingested folate absorbed.
  • The absorption of polyglutamate forms is less efficient the monoglutamate forms.
  • Polyglutamates are hydrolyzed in the lumen and mucosa to monglutamate derivatives.
  • Normal: dietary folates are converted to 5-methyl-tetrahydrofolate (MTHF) within the mucosa prior to entering the portal circulation.
  • High doses of folic acid (>400 ug) can be absorbed unchanged and converted to natural folates in the liver.
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37
Q

Cobalamin-Folate deficiency

A

Circulating form of Folic Acid is MTHF.
The synthesis of nucleotides requires Tetrahydrofolate (THF).
- Requires B12
- High doses of folic acid can temporarily improve the anemia in persons with B12 deficiency.

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38
Q

Clinical manifestations of B12 deficiency

A

Hematological:

  • Anemia (fatique, dyspnea, SOB, syncope, chest pain)
  • Leukopenia (recurrent infections)
  • Thrombocytopenia (bleeding)

Epithelial:

  • Generally microscopic changes with macrocytosis, increased multinucleate/dying cells
  • Abnormal pap smears
  • Angular chelitis, glossitis

Neural tube defects, cleft palate

Vascular disease: hyperhomocysteinemia–> arterial/venous thrombotic disease

Neurological:

  • Subacute combined degeneration: degenerate dorsal/lateral white matter in spinal cord–> weakness, ataxia, parasthesias, spasticity, incontinence, paraplegia
  • Dementia (progressive, irreversible)
  • Psychiatric disturbances
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39
Q

Clinical manifestations of Folate deficiency

A

Similar findings as B12 EXCEPT for neuro/psych changes

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40
Q

Lab features of low B12/folate

A
  1. Low B12/folate serum levels
    - lower end of normal B12 can still be symptomatic
    - Serum folate can be elevated artificially- look at RBC content in RBCs
  2. Decreased blood counts + macrocytosis
  3. Anisocytosis + macro-ovalocytes on smear
  4. Hallmark= hyper-segmented neutrophils (> 5% with 5 lobes, > 1% with 6 lobes)
  5. Similar values to hemolytic anemia (due to ineffective erythropoiesis):
    - Elevated LDH (intravascular hemolysis)
    - Low haptoglobin (intravascular hemolysis)
    - Mild unconjugated bilirubin (intravascular hemolysis)
    - Homocysteine (both) and MMA (B12 only) elevations
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41
Q

Testing for pernicious anemia

A
  1. Anti-Intrinsic factor antibodies (50% sensitivity, 100% specificity)
    - Anti-parietal cell antibodies (less sensitive/specific)
    - Elevated serum gastrin/pepsinogen (poor specificity)
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42
Q

Malabsorption syndromes causing B12 deficiency

A

Highly likely:

  • Pernicious anemia
  • Partial/total gastrectomy
  • Tropical sprue
  • Intestinal stagnant loop
  • lack of terminal ileum
  • Diphyllobothrium latum
  • Congenital IF/TC abnormality

Less likely:

  • Simple atrophic gastritis
  • Zollinger-Ellison
  • PPI use
  • Celiac
  • HIV/GVHD, radiation
  • Meds
  • Alcohol
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43
Q

Causes of folic acid deficiency

A
  • Inadequate intake (NOT a concern with vegans)
  • Alcohol
  • Autoimmune (Crohn’s, Celiac)
  • Infections (tropical Sprue, Whipple’s)
  • Bowel resection
  • Infiltrative disorders (scleroderma, amyloid)

Situations with increased folic acid needs:

  • Pregnancy
  • Chronic hemolytic anemia, inflammation
  • Malignancy with high growth
  • Prematurity
  • Excess marrow turnover

Increased loss of folic acid:

  • Dialysis
  • CHF
  • Severe liver disease
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44
Q

Meds causing folic acid deficiency

A
  • Phenytoin, primidone
  • Methotrexate, pemetrexed
  • Trimethaprim
  • Pyrimethamine
  • Methotrexate, trimethoprim inhibit dihydrofolate reductase (DNA synthesis): DHF–> THF
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45
Q

Treatment for B12 deficiency

A

1) Parenteral:
- 1000 ug IM daily for 1 week
- Weekly for 1 month
- Monthly after 1 month
2) orally: 1000-2000 ug /day (maintenance after repletion complete)
3) Monitor K+ during repletion in severe anemia

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46
Q

Treatment for folic acid deficiency

A

Supplements (1-5 mg/day) orally until replete

- Neurological symptoms can worsen if B12 deficiency not treated first

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47
Q

Normocytic anemia

A 
Due to underproduction of RBCs in:
- Iron and B12/folate deficiency
- Hemolysis with underproduction
- Transfused sickle/thalassemia pt
Can also be due to systemic illness:
- Hepatitis
- Sepsis
- Renal failure
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48
Q

Workup of normocytic anemia

A
  • Basic labs to rule out nutritional and hemolytic anemia
  • TSH, Cr, liver function tests, ESR
  • SPEP- look for myeloma
  • Hemoglobin electrophoresis
  • Review of medications and/or exposures
  • Consider viral workup, including HIV and hepatitis
  • Bone marrow biopsy
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49
Q

Anemia of chronic inflammation/kidney disease

A
  • Renal insufficiency or inflammation can lead to normocytic normochromic anemia
  • May be macro- or microcytic
  • Exogenous erythropoietin can be given with caution
  • Thrombotic risk
  • Consider whether treatment is needed/helpful
  • Anemia is poor prognostic sign (esp in older patients) but not clear that treatment is helpful in the absence of symptoms
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50
Q

Medications inducing hemolysis

A 
G6PD deficiency (malarials, sulfa drugs, nitrates, others)
IVIG, winrho- antibody against normal blood cells
lidocaine
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51
Q

Medications blocking RBC synthesis

A

Chemotherapy (methotrexate, cyclosporine, hydroxyurea)

Multiple others (when in doubt, look it up)

Over the counter medications and herbal or “natural” medications can cause anemia

  • Contamination with lead, mercury, other heavy metals
  • Direct effect of listed ingredient
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52
Q

Infectious causes of anemia

A
  1. Parasitic infection: babesiosis, malaria–> hemolytic
  2. Parvovirus (hypoplastic anemia in young patient following flu-like symptoms; may see pure red cell aplasia)
  3. HIV and hepatitis: other causes of bone marrow failure due to another infection, infiltration with malignancy
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53
Q

Hereditary spherocytosis

A

Hereditary Primary membrane disorder: mutations in band 3, actin, ankyrin, Beta- and alpha-spectrin, protein 4.1 (interactions between cytoskeleton and lipid bilayer)

  1. Spectrin Deficiency
    - Mild-Moderate= Autosomal dominant
    - Severe= Autosomal recessive
  2. Beta-Spectrin - 4.1 Interaction
    - Autosomal dominant

Pathophysiology:

  1. Cytoskeletal Abnormality
  2. Membrane Instability
  3. Membrane Loss
    - decreased SA/V ratio (Spherocytosis)
    - increased Osmotic fragility
    - decreased RBC Deformability
  4. Splenic Trapping
  5. Hemolysis

Symptoms:

  • Chronic Anemia: Pallor, Jaundice, Dark Colored Urine, Splenomegaly, Cholelithisis (Gall Stones)
  • Chronic leg ulcers
  • Crises: Aplastic (after parvo infection), Hyperhemolytic, folic acid deficienc
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54
Q

Hereditary Elliptocytosis

A 
Hereditary primary membrane disorder
1. Mild HE (90%)- may have asymptomatic spleen englargement
2. Hereditary Pyropoikilocytosis (HPP)
–  Rare, severe anemia
–  RBC fragmentation
–  Heat sensitivity
–  Autosomal recessive
3. Spherocytic HE (10%)
4. Stomatocytic HE
  • Can see defective spectrin dimer (RBC membrane dimer), deficit spectrin interaction with membrane proteins, defect in protein 4.1/ glycophorin C
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55
Q

Paroxysmal Nocturnal Hemoglobinuria

A

Acquired primary hemolytic anemia

  • Acquired iIntrinsic Membrane Abnormality
  • Deficiency of glycophosphatidylinositol (GPI)= protection from complement-mediated lysis
  • Include Complement Regulators: CD55 & CD 59
  • Sensitivity to Complement with Intravascular Lysis
  • Somatic Mutation in PIG= gene on the X-Chromosome encoding GPI

Associated with: Aplastic Anemia, Venous Thrombosis (Budd-Chiari, spleen, intestines, brain), Bone marrow failure (Pancytopenia, single lineage cytopenia), Fe deficiency

Diagnosis: Flow Cytometry

Treatment: Symptomatic and/or with Eculizumab
- Folic acid, iron therapy, anticoagulation (for thrombotic events)

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56
Q

G6PD deficiency

A 
Cytoplasmic enzymopathy (extrinsic hemolytic disorder)
- Sex-linked (mostly males, some homozygous females)
  • Most common enzyme defect
    Type A= Africans (African descent)
  • Usually present when exposed to oxidant stress, medications (primaquine, dapsone, nitrofurantoin), acidosis, infection

Type B= Western
- Presents during oxidative stress, fava beans

Clinical features:

  • Acute intravascular hemolysis
  • Hemoglobinemia (pink-brown plasma), hemoglobinuria, jaundice (1-3 days after drug exposure)
  • Severe cases= abdominal or back pain
  • Heinz bodies in red cells, bite cells, blister cells, spherocytes
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57
Q

Screening for G6PD deficiency

A

Enzyme should carry out following reactions:

  1. G6PD + NADP –> Phosphogluconate + NADPH
  2. NADPH + blue dye–> NADP+ + colorless complex
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58
Q

PK deficiency

A

Most common glycolytic pathway enzyme deficiency, seen in all ethnic groups.
- Autosomal Recessive

Used in following reaction:
Phosphoenol pyruvate –> Pyruvate (forms ATP)
- Deficiency–> increased permeability of erythrocytes to cations
- Chronic Hemolysis
- Splenomegaly
- Macroovalocytosis
- see 2-3 fold increase in 2-3, DPG (Shifts oxygen saturation curve to right- RBCs unload O2 into tissues more readily–> increased performance)

Diagnosis: made by specific enzyme assay (no clinical/morphological features)

Treatment: transfusion, splenectomy

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59
Q

Autoimmune hemolytic anemia (AIHA)

Warm and Cold types

A

Clinical picture:

  • Anemia of variable severity (heterogenous mix of RBCs)
  • Splenomegaly

Classification:
1. Warm AIHA (70%)= IgG - Mediated
- Seen more commonly in middle-aged women
– Splenomegaly due toSplenic clearance
– Complement Amplifies effect (may or may not be present)
- Spherocytosis, polychromasia
- May be due to medications, lymphoproliferative disorders, autoimmune disorders, idio[athic
- Responds to prednisone, splenectomy, immune suppresion

  1. Cold AIHA= IgM - Mediated
    – Hepatic clearance
    – Complement (C3b) dependence (hemolysis only occurs once complement bound- IgM dissociates centrally but complement remains and destroys RBC in liver)
    - Treatment: keeping warm (does not respond to steroids)

Diagnosis:
AIHA, drugs:
- Positive direct Coomb’s test: antiglobulin test, anti-human globulin test (presence of antibody +/- complement on RBC)
- Evidence of autoantibodies or complement components (C3d or C4) attached to patient’s RBCs

Alloimmunization (+/- AIHA)
- Indirect Antiglobulin test= presence of Ab in test serum

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60
Q

Treatment of AIHA

A
  1. Rx underlying etiology
  2. Prednisone:
    - decreases auto Ab production
    - decreases binding to RBC
    - decreases clearance of sensitized RBC
  3. Splenectomy- may continue to have hemolysisi after splenectomy
  4. Immunosuppressive therapy- if refractory to first 3 treatments
  5. Intravenous Ig
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61
Q

Alpha-thalassemic trait

A

Two genetypes:

  • Heterozygous alpha-Thal-1 (2 on one chromosome, null on other)
  • Homozygous alpha-Thal-2 (one on each chromosome)
  • Usually asymptomatic; decreased hemoglobin
  • Rarely needs treatment
  • If gene deletion on same chromosome (heterozygous), risk of hydrops in children
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62
Q

Hemoglobin H trait

A
  • Absence of 3 alpha-hemoglobin genes results in very little α-globin allowing formation of β-globin tetramers
  • Hemoglobin H is useless as carrier of oxygen
  • Tendency to precipitate

Clinically: Hemoglobin H disease: moderate anemia, hemolysis, sensitivity to oxidative stress
Tx: transfusion, splenectomy, iron chelation

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63
Q

Beta-thalassemia genetics

A

Multiple mutations can cause:

  • Premature stop codon
  • Abnormal protein
  • Protein can be absent (thal0) or altered (thal+)
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64
Q

Beta-thalassemia trait/minor

A

Single gene mutation

Mild, asymptomatic anemia

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65
Q

Beta-Thalassemia intermedia

A
  • Homozygous thalassemia+
  • β thal/hgb E
  • Other mixed presentations
  • May have hb in 5-10 range, some skeletal abnormalities, hepatosplenomegaly
  • Treated symptomatically with transfusion
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66
Q

Thalassemia major (Cooley’s anemia)

A

Absence or severe underproduction of both β -globin genes
- Fatal early in life unless treated with transfusion

Symptoms:

  • Skeletal abnormalities and hepatosplenomegaly
  • Iron overload leads to death in adolescence unless treated. Accumulates in various tissues: Cardiac, Liver, Pituitary, etc.

Treatment:

  • Bone marrow transplant has been used but is severely limited due to toxicity
  • Hydroxyurea to increase fetal globin production has not been consistently successful
  • Splenectomy can be helpful to increase lifetime of transfused RBCs
  • Iron chelation therapy (improves outcomes- similar to intermedia)
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67
Q

Differential diagnosis of beta-thalassemias

A
  • Iron deficiency anemia
  • Iron studies will show normal iron or overload in thalassemia
  • Other thalassemias
  • Sickle cell variants and other hemoglobin variants: Lack of inflammatory markers in thalassemia
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68
Q

Treatment of Thalassemias

A

Blood transfusions:
Multiple transfusions for anemia for major hemogloinopathies can lead to iron over load
- Iron deposits in heart, liver tissue–> dyfunction

Need to chelate to remove excess iron:

  • Desferol
  • Deferasirox
  • Deferiprone
  • Compliance can be difficult; iron needs to be renally excreted- can’t use in renal failure
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69
Q

Variants of sickle cell disease

A

Position 6 glutamic acid to lysine results in hemoglobin C

Thalassemia (β-thal0)/sickle gives picture similar to sickle cell anemia
- Cells are smaller (lower MCV)

SC disease (sickle hgb/C-hgb) usually milder

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70
Q

Clinical consequences of sickle cell disease

A
  • Spontaneous cell lysis and RBC turnover
  • Increased thrombosis/infarction: Stroke, Pulmonary infarction
  • Chronic inflammation

Multiple secondary complications due to infarcts

  • Splenic infarcts leading to asplenic state and increased risk of bacterial infection
  • Joint damage
  • Non-healing skin ulcers
  • Retinopathy
  • Nephropathy (high comorbidity for HTN)
  • Severe pain
  • Opiate addiction and behavioral issues
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71
Q

Prognosis of sickle cell disease

A

Significant mortality in infants and children

Death rate appears to be falling, especially in young pediatric population ( < 10 years of age)

Median age at death in 2005

  • 37 for men
  • 43 for women
  • Oldest documented sickle cell anemia pt is reported to be 87*
  • Oldest patient at TJU 78
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72
Q

Variable phenotype of sickle cell anemia

A

Hereditary persistence of hemoglobin F
- Fetal hemoglobin does not sickle

Single alpha-hemoglobin gene mutation
- Lower hemoglobin concentration

?? Other mutations/polymorphisms
- TGF-β/smad pathway

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73
Q

Treatment of sickle cell disease

A

Pain medications (opiates usually required)

Hydroxyurea

  • Increases hemoglobin F concentration: Hemoglobin F replaces β-globin (A or S) and does not sickle
  • ? Enlarges cells: Lower hemoglobin concentration therefore less sickling
  • lower mortality, fewer crises, lower cost

Folic acid

Bone marrow transplantation

  • 10+% mortality for full allo-transplant and considered very risky in adults
  • “mini-allo”

Anti-inflammatory/anti-coagulation

  • Ineffective thus far
  • P2Y12 inhibitors??
  • Combinations??
  • Use caution when treating thalassemia patients- macrocytic anemia of thalassemia can get confused with iron deficiency anemia (but these patients already have iron overload)
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74
Q

Acute chest syndrome

A

Seen in sickle cell patients: increased risk during hospitalization

May be preceded by other problems

  • Pneumonia
  • Infarction
  • Embolus

Smoking increases risk
30-50% are idiopathic
Treatment is exchange transfusion

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75
Q

Hereditary persistance of Hemoglobin F

A

No known complications (only found when screening for other hemoglobinopathies)

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76
Q

Hemoglobin E

A

B-thal/hgb E can give thalassemia intermedia picture

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77
Q

Homozygous C disease

A

Position 6 glutamic acid to lysine results in hemoglobin C (sickle cell variant)
Mild anemia, splenomegaly; no treatment required

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78
Q

Hemoglobin D

A

Hemoglobinopathy that can present with a syndrome similar to sickle cell disease

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79
Q

Pathophysiology of hemolytic disorders

A

Premature destruction of RBCs (prior to 120 days)
- Normally RBCs removed by bone marrow, liver, spleen, lymph nodes

Intrinsic disorders:

  • Hereditary spherocytosis, elliptocytosis
  • Acquired Paroxysmal nocturnal hemoglobinurai (PNH)

Extrinsic disorders:

  • Cytoplasmic abnormalities: G6PD deficiency, sickle cell, thalassemia
  • Auto-immune hemolytic anemia, infection, acanthocytosis, fragmentation syndromes, physical agents
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80
Q

Clinical signs and symptoms of hemolytic anemia

A
  • General symptoms of anemia
  • Jaundice
  • Dark urine

Chronic hemolysis:

  • Cholelithiasis
  • Leg ulcers (Sickle cell, spherocytosis)
  • Aplasticcrises
  • Hyperhemolytic crises
  • Skeletal abnormalities
  • Splenomegaly w/ or w/o hepatomegaly (spherocytosis, PK deficiency, thalassemias, AIHA)
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81
Q

Lab signs of hemolysis

A
  1. Reticulocytosis (Polychromasia)
  2. Unconjugated hyperbilirubinemia
  3. Increased fecal and urine urobilinogen
  4. Decreased serum haptoglobin
  5. Elevated Lactate Dehydrogenase (LDH)
  6. Elevated Amino Transferase (AST)
  7. Hemoglobinemia
    – Hemoglobinuria
    – Hemosiderinuria
  • Acquired hemolysis: normochromic, normocytic (elevated reticulocytes–> macrocytosis)
  • Thalassemias/hemoglobinopathies: microcytic, hypochromic
  • Sickle cell anemia: normal indices (relative microcytosis- high reticulocyte)
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82
Q

Diagnosis and treatment of hereditary spherocytosis

A

Labs

  • Anisocytosis (abnormal sizes) without poikilocytosis (variation in shape)- uniformly spherical
  • Two cell populations: spherocytes and reticulocytes (polychromatophilic)
  • Normal MCV
  • Elevated MCHC
  • Negative Coomb’s test

Diagnosis:

  • Family History
  • Anemia
  • Spherocytosis
  • Reticulocytosis
  • increased Osmotic Fragility: % hemolysis curve shifted to left: cell already spherical, less room to expand in hypotonic solution
  • decreased RBC Deformability

Treatment:
Symptomatic
Splenectomy- cures the disease- red cells normalize
- Administer vaccine prior to splenectomy

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83
Q

Extra-cellular hemolytic disorders

A 
A.  Autoimmune Hemolytic Anemia
B.  Iso-immune Hemolytic Anemia
–  Transfusion reactions
–  Erythroblastosis fetalis
C.  Drug Induced Hemolytic Anemia
D.  Infection
E.  Liver Disease
F.  Microangiopathic
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84
Q

Direct antiglobulin test

A
  1. Cells washed to remove serum proteins/nonspecific proteins in RBCs
  2. Test patient’s RBCs for C3 (footprint of IgM) and IgG
  3. Cells attracting Ig or complement will cause clumping
    - Can identify specific cause of clumping

Causes of immune hemolysis:

  • AIH (autoimmune hemolytic anemia)
  • HDN (hemolytic disease of newborn)
  • Drug-induced hemolytic anemia
  • Transfusion reactions
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85
Q

Indirect antiglobulin test

A

Identifies IgG antibodies present in serum (vs RBCs in direct test)

  1. Incubate Type O red cells with serum from patient
  2. Wash RBCs, test for surface antibody/complement (from serum)

Antibody in serum with no cell-bound antibody= allogeneic immunization

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86
Q

Coagulation tests

A

Start with blue top tube: citrate (anticoagulant)
- Vacuum for 4.5 mL of blood (need precise amount- underfilled changes results)

Clot formation: produce fibrin polymers (clot)

  • Time based testing
  • Can be mechanical or optical
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87
Q

Prothrombin time

A

Assay of extrinsic and common pathway
- Depends on VII, X, V, II, I (fibrinogen)

PT testing components:

  • Rabbit brain
  • Tissue thromboplastin (TF)
  • Subject plasma (VII, X, V, prothrombin, fibrinogen)

Testing for:

  1. Warfarin (coumadin) therapy
  2. Screening for:
    - Vitamin K deficiency
    - Deficiency of Factors VII, X, V, II
    - Liver Disease
    - Rare acquired factor inhibitor
  • Problem= impurities in thromboplastin (poor reproducibility)
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88
Q

INR

A

International Normalized Ratio
= (Patient Prothrombin time (PT)/ mean of normal PT)^ ISI

ISI= international sensitivity index (thrombplastin compared with WHO reference thromboplastin)

  • WHO standard= 1.00
  • Target= 2-3
  • INR used to measure linear decrease in Vit K- dependent clotting (based on administration of Coumadin)
  • Mild reductions in multiple clotting factors different from severe deficiency of single clotting factor
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89
Q

Activated partial thromboplastin time (aPTT or PTT)

A

An assay of the intrinsic and common pathway
- Depends on all factors except for VII and XIII

Test to measure:

  1. Monitoring heparin therapy
  2. Screening Test For
    - Deficiencies in factors VIII, IX, XI, XII
    - Von Willebrand disease
    - Lupus Anticoagulants
    - Acquired factor inhibitor
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90
Q

Evaluation of prolonged PT/PTT

A

The first step is usually mixing studies

Performing both tests will suggest whether it is due to factor deficiency or an inhibitor

  • Factor deficiency= normalize with 1:1 mix with normal plasma
  • Inhibitor deficiency= will not normalize when mixed with normal plasma

Based on two principles

  • Inhibitors are present in excess and if present will inhibit normal and patient plasma
  • 50% of any factor is adequate to provide a normal test result
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91
Q

Thrombin Time (TT)

A

Screening test evaluation conversion of fibrinogen to fibrin
- Thrombin= Factor IIa (converts Fibrinogen)

Measures:

  • Low or absent fibrinogen
  • Dysfunctional fibrinogen
  • High levels of fibrin split products (DIC)
  • Myeloma Proteins that act as antithrombins
  • Heparin or Direct Thrombin Inhibitor
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92
Q

Fibrinogen (Quantitative): Claus method

A

Indications: Evaluation of a prolonged PT or aPTT, DIC, or other bleeding disorders, especially in the setting of LIVER DISEASE

Abnormally low values

  • Liver disease
  • DIC and other consumptive states
  • Thrombolytic therapy
  • Congenital a- and hypo- fibrinogenemia
  • Abnormal protein (dysfibrinogenemia)

Abnormally high fibrinogen

  • Acute and chronic stable liver disease
  • Acute Phase Reactant
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93
Q

D-Dimer test

A

Indicates:

  1. On-going coagulation
    - Thrombin generated to cross-link fibrin monomers
  2. Fibrinolysis
    - Plasmin generated to cleave cross-linked fibrin

Major utility= evaluation of:

  • Outpatient DVT, PE
  • Disseminated intravascular coagulation

Excreted by kidney
T1/2= 8 hours

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94
Q

Specific coagulation factor assay

A

Determine the extent to which the patient’s plasma corrects the clotting time of plasma deficient only in a particular clotting factor

Example: add patient plasma to factor VIII-deficient plasma and perform an aPTT on the mix; compare result to standard

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95
Q

Antiphospholipid antibody syndrome (APLS/APS)

A

APLS is an acquired autoimmune thrombophilic condition with:

  • vascular thrombosis or recurrent pregnancy loss, thrombocytopenia
  • laboratory evidence of antiphospholipid antibodies or lupus anticoagulant
  • Can be primary or secondary (associated with SLE)

Testing= antiphospholipid antibodies=

  • anti-cardiolipin antibodies (IgG or IgM)
  • antibodies to Beta-2 glycoprotein (IgG or IgM)
  • Prolonged PTT (lupus anticoagulant): do NOT bleed, but they may clot (results only seen in test tube, not in vivo)
  • Perform mixing study: inhibitors in plasma mixed with normal plasma–> defect not corrected (vs factor deficiency alone which corrects)

ELISA assay

  • 5% prevalence in general population
96
Q

Lupus anticoagulant

A

Immunoglobulin that binds to Phospholipid (PL) used APS testing (enhances coagulation)

Criteria for positive APS test:

1) Increase of any phospholipid dependent clotting time (PT, aPTT, DRVVT, etc.)
2) Failure of correction in a 1:1 mix with normal plasma
3) Correction with the addition of excess phospholipid

97
Q

Dilute Russel Viper Venom Time (dRVVT)

A

Screening test for APLS

Russel viper venom= activator of Factor X–> Xa (clotting cascade)
- Clotting should occur within 23-27 seconds

  1. Mix 50:50 patient and standard blood with venom
  2. Coagulation occurs: deficiency of clotting factor (X or antecedant factors)
  3. No coagulation: presence of Anti-Phospholipid antibodies that block Xa+Va+Ca+phospholipid conversion of Prothrombin to thrombin
98
Q

Isolated Prolongation of PT

A
  • Liver disease
  • Mild DIC
  • Mild vitamin K deficiency
  • Factor VII deficiency (very rare)
  • Warfarin

Lab: repeat, does 50:50 mix correct PT?

  • No= work-up for inhibitor
  • Yes= do factor assays (esp if no DIC, liver dysfunction, Vit K deficiency, coumadin)
99
Q

Isolated prolongation of aPTT

A

No Bleeding:

  • Lupus anticoagulant
  • Heparin
  • Prekallikrein deficiency
  • Factor XII deficiency
  • HMW Kininogen deficiency

Bleeding:

  • von Willebrand disease
  • Hemophilia A (Factor VIII deficiency)
  • Hemophilia B (Factor IX deficiency)
  • Hemophilia C (Factor XI deficiency)
  • Heparin, other inhibitor

Lab: repeat, does 50:50 mix correct aPTT

  • No= workup for inhibitor (LA)
  • Yes= based on history, exam: workup with bleeding time for vWD, Ristocetin cofactor, vEF multimers; factor assays for VIII, IX, XI
100
Q

Isolated prolongation for PT and aPTT

A

Generally due to multiple factor deficiencies caused by:

a) Severe liver disease
b) Disseminated intravascular coagulation
c) Coumadin
d) Severe vitamin K deficiency
e) Therapeutic fibrinolysis
f) Dilutional (massive transfusion)
g) Isolated deficiency of fibrinogen, factors II, V, or X

Lab approach:
Does 50:50 mix correct PT?
no - w/u for an inhibitor
yes - if no DIC, liver dis, vitamin K deficiency, Coumadin, or fibrinolytics, do TT & factor assays

101
Q

Routine platelet testing

A

Complete blood count= measure platelets

  • This is usually done using an automated particle counter.
  • Estimates of platelet size can also be done using modern devices.
  • Primary limitation is related to platelet clumping (Pseudothrombocytopenia)
102
Q

Bleeding time

A

A measure of duration of bleeding following a small standardized incision.

Indications:

  • Screening for platelet function defects
  • Assessment of response to therapy such as DDAVP

However, it is notoriously inaccurate in predicting operative bleeding

103
Q

Platelet Function analyzer (PFA-100)

A

Machine to measure time for citrated whole blood to occlude a pinpoint hole in collagen and ADP/epinephrine-impregnated membrane under shear force

  • Mimics clogging wound/vessel
  • Identifies abnormal platelets (causing enhanced bleeding time

Diseases:

  • Thrombocytopenia, anemia
  • Von Willebrand disease, afibrinogenemia
  • Acquired disorders of platelet function: storage pool, uremia, anti-platelet drugs
  • Congenital disorders of platelet function: Bernard-Soulier, Glanzmann thromboasthenia, storage pool disorders
104
Q

Platelet Light Transmission Aggregometry

A

Testing for aggregation of platelets upon addition of agonists

  • Measure level of aggregation by amount of light that passes through blood sample after adding agonist
  • More light= more aggregation

Platelet defects–> less aggregation, lower light transmission

Agonists:

  • ADP
  • Epinephrine
  • Collagen
  • Ristocetin
  • Thrombin

Abnormal aggregation seen in:

  • Thrombocytopenia, anemia
  • Von Willebrand disease, afibrinogenemia
  • Acquired disorders of platelet function: storage pool, uremia, anti-platelet drugs
  • Congenital disorders of platelet function: Bernard-Soulier, Glanzmann thromboasthenia, storage pool disorders
105
Q

TPO

A

Thrombopoietin= major hormone augmenting megakaryocyte and platelet production

TPO receptors expressed:

  • Megakaryocyte progenitor cells
  • Megakaryocytes
  • Platelets

Negative feedback= regulated by megakaryocyte/platelet mass

Production source:

  1. Liver
  2. Kidney, SMC, marrow stroma
106
Q

Platelet organelles

A

Platelets contain:

  • Microtubules
  • Mitochondria
  • Alpha granules
  • Dense granules
107
Q

Contents of Alpha granules in platelets

A

Aggregation factors:

Fibrinogen
VWF
PF4
PDGF
PAI-1
FVIII
VEGF
bFGF
aIIb-Beta-3
P-selectin
108
Q

Contents of Dense granules in platelets

A

Activation factors:

Calcium
ADP/ATP
Serotonin
5-HT
Epinephrine
109
Q

von Willebrand Factor

A

Involved in first phase of platelet thrombus formation:

  • Platelet tethered to vessel wall by VWF binding to GPIb-IX-V (platelet receptor)
  • Platelet comes to quickly slows as platelet receptor hooks onto VWF on endothelial wall

VWF= endothelial cell secreted glycoprotein or 250 kDa

  • Forms dimers–> multimers
  • ADAMTS13 cleaves ultra-large VWF multimers
110
Q

Platelet activation and adhesion

A

Platelet receptors GPIa-IIa and GPVI-Fcg bind to collagen
- Within seconds, platelet activated by adhesion (collagen-GPVI) and thrombin

Activated platelet then:

  • Changes shape
  • Releases fibrinogen, VWF, ADP, thromboxane, calcium from granules
  • Aggregates with other platelets
  • Flips inner leaflet of membrane–> exposes phospholipids–> activation of fibrin clots (greatly enhances Xa and thrombin formation)
  • Positive feedback loop enhancing thromboxane synthesis and granule secretion
111
Q

Platelet aggregation

A

Activated GPIIb-IIIa (alpha-IIb beta-3) on platelet binds to fibrinogen and VWF on endothelial wall/other platelets
- unable to bind without activation (from collagen and thrombin)

Platelets enhance conversion of :

  • factor X–> factor Xa
  • Prothrombin (II) –> Thrombin (IIa)
112
Q

Bleeding platelet disorders: clinical presentation

A

Mucocutaneous: gingival bleeding, epistaxis, menorrhagia.

Petechiae usually occur in lower extremities, in dependent regions of the body, on the buccal mucosa and soft palate, and at pressure points.

More severe disorders can be accompanied by GI bleeding, GU bleeding, and intracranial hemorrhage.

113
Q

Hemorrhagic platelet disorders

A

Quantitative platelet disorders (thrombocytopenia, thrombocytosis)

Qualitative platelet disorders (platelet dysfunction)

114
Q

Thrombocytopenia (platelet count) and bleeding

A

150-400,000= normal (statistically)
> 100,000= normal hemostasis still occurs
50-100,000= Bleeding with trauma, increased bleeding time
20-50,0000= excessive bleeding with minor trauma
< 20,000= spontaneous bleeding may occur (life-threatening)
< 10,000= high-risk spontaneous bleeding; need prophylactic platelet transfusion

115
Q

Causes of thrombocytopenia

A
  1. Sequestration
  2. Decreased production
  3. increased destruction
  4. Pregnancy
  5. Dilutional

Most common causes of thrombocytopenia:
1. Drug-induced= heparin (most common)

  1. Pregnancy= “Gestational” thrombocytopenia: count >70,000/mL; asymptomatic; resolves after delivery
  2. Hypersplenism= Any cause of splenomegaly (congestive portal HTN from liver disease, heart disease, splenic vein thrombosis)
    - Count usually 50,000/mL-90,000/mL; rarely <40,000/mL
  3. Infection (viral/bacterial): Viral (HIV, HVC), Rocky Mountain Spotted Fever, bacterial sepsis
116
Q

Sequestration of platelets

A

Seen in setting of hypersplenism

117
Q

Decreased production of platelets

A 
1. Infection
Bone marrow infiltration
Immune
Ineffective production (megaloblastosis)
Hypoplasia
HIV
Congenital
118
Q

Increased destruction of platelets

A

Immune:

  1. Drug-induced
  2. Infection
    - Acute and chronic Idiopathic thrombocytopenic purpura (ITP)
    - HIV
    - Hepatitis C
    - APS (antiphospholipid syndrome)

Non-immune

  1. Sepsis/infection
    - DIC
    - TTP-HUS
    - Sepsis
    - Type 2B vWD
119
Q

Evaluation of thrombocytopenia

A
  1. Blood smear (platelet number, size, clumping, granularity; RBC schistocytes and spherocytes)
    - CBC with mean platelet volume (MPV)
    - Immature platelet fraction (IPF= platelet reticulocyte count), RBC reticulocyte count
    - PT, aPTT
    - D-dimer
    - BUN/Creatinine

Depending on H&P:
Hepatitis C serology, PF4-heparin Abs, antiphospholipid Abs, abdominal CT or U/S, bone marrow exam

120
Q

Treatment of thrombocytopenia

A
  1. Treat underlying disease (antibiotics, steroids for ITP)
  2. Platelet Transfusions:
    - For bleeding: Transfuse to get platelet count to >40,000/mL until bleeding stops
  • Prophylactic (i.e., no bleeding): Controversial; for Procedures:
  • Minor surgery - 50,000/mL
  • Major surgery - 80,000/mL
  • Studies in leukemic patients define a “trigger” of 10,000/mL

NOTE: hospitalized thrombocytopenic patients are alloimmunized- do not respond well to platelet transfusions

121
Q

Causes of Drug-induced thrombocytopenia

A 
Immune-mediated platelet destruction:
Heparin
- Antibiotics (vancomycin, etc.)
- Sulfonamides
- Sedatives
- Anticonvulsants
- GP IIb-IIIa inhibitors
- Quinine and Quinidine

Suppressed platelet production:

  • Chemotherapeutic agents
  • Ethanol
  • Thiazides

Diagnosis of drug-induced thrombocytopenia:

  • NOT associated with abnormalities in other blood cells or splenomegaly
  • often not definitive (in-patients on many meds)
  • Platelet recovery ~7 days after exposure removed

Management:

  • Withdraw offending drug
  • Corticosteroid use in some cases
122
Q

Heparin-induced thrombocytopenia (HIT)

A

Clotting disorder (NOT bleeding disorder) seen in 1-3% Patients exposed to herparin

  • Usually within 4-14 days after heparin exposure in naiive patients (12 hours with recent exposure)
  • Platelet tranfusions can increase thrombosis
  • Stopping heparin will not prevent thrombosis
  • Warfarin contraindicated as acute monotherapy
  • Differential diagnosis in many hospitalized patients

Characteristics:

  • Thrombocytopenia (platelet 20-100,000)
  • Life and limb-threatening thrombosis

Nature of Heparin exposure causing HIT:

  • Type of Heparin: UFH > LMWH
  • Dose and duration: high dose > low dose
  • Dose and duration of current exposure: long-term > short-term
  • Route of administration: IV > SC, flushes, catheters, heparin-coated devices
  • Clinical setting: especially cardiac, orthopedic, or intensive care

Pathogenesis:

  1. HIT antibody= directed against heparin and PF4 complex
    - Common following cardiopulmonary bypass
  2. Platelet factor 4 (PF4)= platelet alpha granules released on platelet activation, secretion
  3. Heparin
  4. Platelet Fc receptor (binds platelet to complex)

Sequelae:

  1. Thrombosis (~50%)= platelet activation-induced thrombogenic microparticles (phospholipid)
  2. Amputation (~21%)
  3. Death (~30%)
123
Q

Diagnosis of HIT

A

Clinical diagnosis:

  1. Thrombocytopenia (nadir 15,000-150,000/mL or >50% baseline)
  2. Timing (day 5-10 from heparin, or 50%) or skin necrosis at SQ heparin sites
  3. Dx supported by lack of other causes of thrombocytopenia

Labs (adjunct testing):

  1. PF4 ELISA: antibodies against PF4-heparin (HIT Abs)
    - High sensitivity, low specificity
  2. Serotonin release assay (SRA): functional HIT antibodies dependent on heparin, activate platelets
    - High specificity, labor intensive
    - looking for release of granules due to antibodies (antibodies may not be present
124
Q

Treatment of HIT

A

All exposure to heparin must be discontinued.

Therapy with alternative anticoagulants (such as direct thrombin inhibitors= DTI) is strongly recommended because of the prothrombotic tendency.

  • Argatroban
  • Lepirudin

Perform confirmatory tests

125
Q

ITP= Idiopathic (immune) thrombocytopenic purpura

A

Autoantibody formed against platelet antigens
- usually one of the major platelet glycoproteins: GP IIb-IIIa, GP Ib-IX complex

Pathophysiology:

  1. Autoimmune peripheral platelet destruction, mostly in the spleen by macrophages bearing Fc receptors for IgG
  2. Inadequate marrow megakaryocyte response

Unknown etiology

  • Not associated with abnormalities in other blood cells, coagulation abnormalities, splenomegaly
  • Adequate bone marrow megakaryocytes
  • Diagnosis of exclusion
  • associated with viral illness in children, idiopathic in adults
126
Q

Treatment of ITP

A

First line

  • Corticosteroids
  • IV Ig
  • IV anti-D (RhoGAM)= antibodies suppressing immune response to Rh factor
  • Rituximab (anti-CD20 mAb)
  • TPO-mimetics
  • H. pylori eradication
  • Splenectomy

Second line

  • Vincristine
  • Cyclophosphamide
  • Azathioprine
127
Q

TTP= Thrombotic thrombocytopenic purpura

A

Due to ultra-large VWF multimers

Systemic microvascular thrombosis characterized by:

  • thrombocytopenia
  • microangiopathic hemolytic anemia
  • tissue ischemia and infarction

Acute, severely debilitating illness

Usually fatal without treatment

Inhibition or absence of VWF-cleaving metalloprotease, ADAMTS-13 (usually an autoantibody)

Treatment: Fresh plasma infusion (take care of ultra-large vWF)

128
Q

Ultra-large von Willebrand factor

A

“Ultra sticky” vWF= spontaneously binds platelets

Treatment:

  1. Acquired (antibody against ADAMTS13):
    - Plasma exchange
  2. Congenital (absent ADAMTS13 production- lack of cleavage):
    - Plasma infusion

+ Vigorous supportive care

129
Q

Quantitative platelet defects: Thrombocytosis

A

Elevated platelet count (millions per uL)
Seen in:
- Chronic inflammatory states (cancer, infection)= reactive thrombocytosis (benign, no therapy required)
- Myeloproliferative disorders: see bleeding or thrombosis

130
Q

Qualitative platelet defects

A

Platelet hyperreactivity and myocardial infarction–> may suggest platelet dysfunction when there’s prolonged bleeding:

  1. Without thrombocytopenia
  2. Without coagulation abnormalities

Acquired types:

  1. Drugs (aspirin): block platelet function
  2. Uremia: uremic platelets in normal plasma= normal function; uremic plasma= inhibition of normal platelets
    - Myeloproliferative (stem cell) disorder)
    - Cardiopulmonary bypass
    - Acquired von Willebrand disease
    - Acquired storage pool disease
  • Diagnose qualitative platelet defects with measures of platelet funciton: bleeding time, platelet aggregation studies, PFA-100
131
Q

Primary Hemostasis

A

Results in the formation of a platelet plug. Needs platelets, von Willebrand factor and vessel wall. Bleeding time is a measure of primary hemostasis.

132
Q

Secondary Hemostasis

A

Needs clotting factors. Prothrombin time, activated partial thromboplastin time and thrombin time are used to assess this.

133
Q

Monitoring anti-platelet therapy

A

Assays used:

  • Standard lumiaggregometry (light aggregation)
  • PFA-100 (platelet function analyzer)
  • Flow cytometry for VASP (vasodilator-stimulated phosphoprotein)
  • VerifyNow (test of aspirin, IIbIIIa inhibitors, clopidogrel)
  • Need to test due to marked variability in inter-individual response to anti-platelet therapy- if platelet inhibition ISN’T occuring with intervention, increased risk of coronary events, poor outcomes
134
Q

Platelet defect vs Coagulopathy

A

Platelet defects:

  • Characteristic petechiae
  • More common in women than men

Coagulopathy:

  • Characteristic hemarthoses
  • Common to have family history
  • More common in men than women
135
Q

Acquired hemorrhagic disorders

A

Common:

  • Liver disease
  • Post-op
  • Renal failure
  • DIC
  • Vit K deficiency

Less common

  • Coumadin
  • Myeloproliferative disorders
  • Aspirin
  • Autoimmune

Rare

  • Myeloma
  • Vasculitis
  • Amyloid
  • Waldenstrom’s
  • Acquired factor inhibitors
136
Q

Congenital hemorrhagic disorders

A
  • vWD (1-2% general population)
  • Hemophilia A (1 in 5000 males)
  • Hemophilia B (1 in 30,000 males)
  • Other factor deficiencies (uncommon)
137
Q

Liver disease and coagulopathies

A
  • A hemorrhagic tendency based on deficiency of any combination of coagulation factors.
  • Decreased clearance of fibrin degradation products.
  • Decreased g-carboxylation of the vitamin K dependent clotting factors.
  • Thrombocytopenia (secondary to congestive splenomegaly & decreased thrombopoietin)

Coagulation factors made in liver:

  • I (fibrinogen), II (prothrombin), V, VII (shortest half-life–> deficiency apparent first), VIII, IX, X, XI, XII, XIII,
  • Protein C, Protein S
  • Antithrombin
  • TFPI
  • Plasminogen
138
Q

Liver disease: testing and treatment for coagulopathies

A
  • PT is very sensitive to factor VII deficiency and factor VII has the shortest half-life, PT is almost always prolonged in liver disease.
  • Factor VIII is produced in vascular endothelium as well as by hepatocytes. It is rarely decreased until very severe liver disease.
  • Fibrinogen levels are often maintained except in severe liver disease or liver failure.
  • Treatment is primarily supportive with FFP and Platelet transfusions as needed.
139
Q

DIC: Manifestations

A

Disseminated intravascular coagulation
DIC is a syndrome characterized by the escape of the clotting process from its normal inhibitory controls. Serious, sometimes lethal, disorder.

Manifestations:

  • acute or chronic
  • systemic (rarely localized)
  • bleeding, thrombosis or both, with consequent organ dysfunction
140
Q

DIC: Causes

A

Due to an underlying illness:

  1. Excess tissue factor:
    - Obstetric complications (abruptio placenta, amniotic fluid embolism)
    - Promyelocytic leukemia (Tissue Factor in granulocyte precursors)
    - Malignant tumors
    - Miscellaneous (massive trauma, heat stroke, burns, extensive surgery)
  2. Endothelial cell injury and/or factor XII activation
    - Septicemia (particularly gram – (endotoxin release)
    - Shock
141
Q

DIC: Pathophysiology

A
  • Bleeding results (paradoxically) from excessive intravascular coagulation.
  • Continuous thrombin formation: consumption of its substrates (fibrinogen, platelets, factor V, VIII).
  • Fibrinolysis always present to a variable degree. As a result, fibrin(ogen) is degraded as well as factor V and VIII.
  • Fibrin degradation products accumulate; these inhibit stable clot formation and platelet function.
142
Q

DIC: diagnosis

A

The clinical setting is often suggestive of DIC - e.g., obstetrical complication, post-op, sepsis, etc.

There is no laboratory test specific for DIC. However the most common lab abnormalities:

  • Prolonged PT, aPTT and TT
  • Decreased fibrinogen
  • Thrombocytopenia (usually not <30,000/mL)
  • Presence of FDPs (not specific), D-dimers (more specific)
143
Q

DIC: treatment

A
  1. Treat underlying cause
  2. Supportive care (maintain BP, etc.)
  3. Transfusion (FFP, cryoprecipitate, platelets)
  4. Possible role of Activated Protein C
  5. Heparin (when thrombosis dominates picture)
  6. Antifibrinolytic (maybe, but only if fibrinolysis dominates picture; even then, give heparin)
144
Q

Vitamin K-dependent clotting factors

A 
II (Prothrombin)
VII
IX
X
Protein C, S

Factors require gamma-carboylation (occurs in liver) that uses reduced Vitamin K–> Gla domains

  • Gla domains on factors essential for chelation of Ca++–> adherence to phospholipid surfaces
  • Coumadin blocks Vit K metabolism–> no Gla domain formation–> no adherence
145
Q

Vitamin K deficiency

A

Causes:

  1. Inadequate dietary intake, malabsorption, antibiotics and medications that inhibit vitamin K epoxide reductase.
  2. Coumadin blocks reduction of Vitamin K (blocks gamma carboxylation of clotting factors)

Coumadin overdose is common (and potentially dangerous):

  • Elevated INR without bleeding: withhold coumadin
  • Elevated INR with bleeding: withhold coumadin, give Vit K, consider FFP, PCCs
  • In newborns, severe deficiency causes Hemorrhagic Disease of the Newborn.

Lab findings:

  • PT is prolonged (Remember FVII’s short half-life)
  • In severe deficiency the PTT also lengthens
  • Can be diagnosed by Factor pattern but in practice is usually based on correction with Vit K.

Treatment:

  • oral or parenteral vitamin K
  • FFP (frozen fresh plasma) is effective, but is usually not required.
  • PCCs= Prothrombin Complex Concentrates (includes factors II, VII, IX, X) are sometimes used
146
Q

Renal failure and coagulopathies

A

Renal failure–> uremia–> platelet dysfunction depends on degree of plasma urea levels

147
Q

Hemophilia A: Pathophysiology

A

Factor VIII deficiency:
- IXa-VIIIa-platelet-calcium complex serves as the major activator of factor X.

  • 1 in 5000 male births (carried on X chromosome): 20-30% spontaneous mutations. 1/2 carry intron 22 inversion due to homologous recombination
  • Factor VIII circulates as a non-covalent complex with vWF to avoid immune destruction
148
Q

Hemophilia A: Clinical manifestations

A

The diagnosis of severe hemophilia is usually made in the first year of life.
- Moderate or mild disease may go undiagnosed for decades.

Screening: aPTT
Diagnosis: Factor VIII level
* Be cautious in the interpretation of FVIII levels as stress, pregnancy, and oral contraceptives can increase levels.

Severe hemophilia:

  • Factor VIII levels <1% of normal
  • Suffer from spontaneous joint and soft tissue bleeds
  • Bleeding with circumcision

Moderate hemophilia:

  • Factor VIII levels 1%-5% of normal
  • Spontaneous bleeds are much less common
  • Excessive bleeding with minor trauma/surgery

Mild hemophilia:

  • Factor VIII levels above 5%
  • Generally bleed only after trauma or surgery.
149
Q

Hemophilia A: treatment

A

Treatment is usually in the form of intravenous Factor Replacement Therapy.

  • Dosage and frequency of any factor replacement is based on goal levels, volume of distribution, and half-life.
  • General goals are 30%-50% for minor bleeds and 80%-100% for major bleeds.

For mild patients who are known to be responders DDAVP is a reasonable option in many situations.

  • DDAVP is a synthetic analogue to vasopressin
  • Induces a robust release of FVIII in selected patients
  • Do not use in severe disease as these patients are not able to respond to this medication
150
Q

Hemophilia B (Christmas disease): pathophys

A

X-Linked disorder: Incidence is 1:30,000 live male births

  • Factor IX: vitamin K-dependent serine protease; upon activation by factor XIa or FVIIa-TF converts factor X to Xa.
  • It is essentially impossible to distinguish it from Hemophilia A clinically.
  • Factor IX is activated by either FXIa or FVIIa: FIXa is the serine protease that directly activates Factor X
  • Factor IXa-VIIIa-platelet-calcium complex= major activator of factor X
151
Q

Hemophilia B: labs and treatment

A

Screening test is the aPTT
- Distinguish it from Hemophilia A by factor specific assays

Treatment:

  • recombinant (Benefix) concentrates
  • plasma derived (mononine) concentrates
  • Alternatively can be treated with prothrombin complex concentrates (PCC’s).
  • Only use plasma if above not available
152
Q

Hemophilia C (parahemophilia)

A

Autosomal Recessive Factor XI deficiency

  • Phenotype is highly variable
  • Highest proportion in persons of Ashkinazi Jewish descent

Screen: aPTT

Clinical: Bleeding is often in areas of increased fibrinolysis (oral cavity, GU tract)

Treatment: plasma

153
Q

Von Willebrand Disease

A

vWF= manufactured in endothelial cells and megakaryocytes.

  • Stored in Weibel-Palade bodies in the endothelium and a-granules in platelets
  • Serves to tether platelets to sub-endothelial collagen after vascular injury
  • Also serves as the chaperone protein for Factor VIII

Disease: relatively common (1% on screen)

  • Genotype M=F; Phenotype F > M (obstetrics)
  • Presents like platelet function disorders

Types:
Type 1: Partial quantitative defect
- Most common (70%-80%)
Type 2: Qualitative Deficiency
- 2A loss of high molecular weight multimers (increase vWF ADAMST-3 cleavage)
- 2B gain of function mutation with excess platelet binding with increased clearance of vWF
- 2M poor function with normal multimer pattern
- 2N impaired FVIII binding: VIII normally bound to vWF (protects from degradation- made together in endothelium

Type 3: Virtually complete absence of vWF

Conditions associated with elevated vWF:
Pregnancy
Oral contraceptives
Liver disease
Inflammation
Exercise
Stress
Traumatic venipuncture
Post-operative state
154
Q

Treatment of von Willebrand disease

A
  1. DDAVP/Stimate: causes release of Weibel-Palade bodies
  • Usually (but not always) effective in Type 1 patients and some Type 2.
    Ineffective in Type 3 and absolutely contraindicated in Type 2B
  1. Plasma derived vWF-FVIII concentrates
    Cryoprecipitate
  2. Antifibrinolytic therapy (EACA or Transexamic acid)
  3. Hormonal medications (Particularly helpful for control of menorrhagia)
155
Q

Glanzman Thrombasthenia

A

IIb-IIIA complex abnormal (platelet function disorder)

- Platelets can’t bind to one another

156
Q

Bernard-Soulier

A

Ib-V-IX complex abnormal- no receptor for platelet

- Platelets can’t bind to vWF

157
Q

Storage diseases causing platelet dysfunction

A

Grey platelet syndrome: alpha granule transport defect

Dense granule deficiency

158
Q

Virchow’s triad

A

Pathogenesis of DVT and PE

  1. Stasis (hospitalization, long flight, immobilization)
  2. Impaired vascular integrity
  3. Systemic hypercoagulability
159
Q

Clinical presentation of DVT

A

None (asymptomatic)- majority
Extremity pain
Extremity swelling (asymmetric)
Death (5.5% if untreated)

160
Q

Clinical presentation of PE

A 
None (asymptomatic)
Shortness of breath
Chest pain
Tachycardia (unexplained)- most common
Anxiety
Hemoptysis
Cyanosis with large emboli
Sudden death (25%)
161
Q

Diagnosis of DVT

A

Doppler ultrasound

Venogram

162
Q

Diagnosis of PE

A

Chest X-ray (difficult to visualize embolus)
Lung ventilation/perfusion scan
Chest CT scan
Pulmonary angiogram (rare)
Blood D-dimer= high negative predictive value (rule out PE in ER)
- Fibrin stablized by factor XIII–> clot–> body breaks down fibrinogen–> fibrinogen degradation product (D-dimer)
- Test detects breakdown of fibrinogen

163
Q

Hypercoagulable states

A
  • Surgery/Trauma= tissue factor (TF) exposure, stasis
  • Immobilization= stasis
  • Malignancy= TF exposure, stasis
  • Pregnancy/postpartum= stasis, increased coagulation, decreased anticoag, genes
  • Estrogen and OCPs= increased coag, decreased anticoag, genes
  • Antiphospholipid syndrome= Endothelial cell dysfunction
  • Autoimmune disease/SLE
  • Homocysteinemia (deficiency of folate, B12 (high MMA= B12))= Endothelial cell dysfunction
  • DIC
  • Hyperviscosity syndrome
  • Myeloproliferative disorders, PNH
  • Nephrotic syndrome
  • Hyperlipidemias
  • Diabetes
  • Smoking
164
Q

Pregnancy and thrombosis

A

Pregnancy= 6-fold increased of VTW

  • PE= most common cause of maternal death (then pre-eclampsia/eclampsia/HELLP)
  • Risk greatest up to 6 weeks post-partum

Mechanisms:

  • Stasis
  • Venous compression (gravid uterus)
  • Altered hemostatic factors
165
Q

Oral Contraceptive Pills and Venous thromboembolism

A

Poorly understood, but oral hormone replacement/contraceptives increase clotting factors
- Estrogen= pro-coagulant

166
Q

Acquired Hyper-Homocysterinemia

A

B6/B12 deficiency

- Causes vessel, endothelial cell damage

167
Q

Thrombotic microangiopathy

A

Non-immune hemolytic anemia

Form platelet plugs–> mesh-like buildup in tissues (microvascular thrombosis)

  • Red cells try to travel through mesh, breakdown–> hemolytic anemia
  • Thrombocytopenia

Can cause:

  • Neurologic issues (TTP= neurologic only)
  • Renal issues

Labs:
LDH increase
Low haptoglobin
Thrombocytopenia and non-immune anemia

Differential diagnosis:
- TTP (neuro only)
- Hemolytic uremic syndrome (HUS) (kidney only)
- Disseminated intravascular coagulation (DIC)
- Malignant hypertension
- Vasculitis
- Systemic lupus erythematosus (SLE)
- APLS
- HIV
Renal allograft
168
Q

Hemolytic uremia syndrome (HUS)

A

Clinical picture overlaps with TTP:

  • Systemic TMA
  • Renal failure predominates
  1. Sporadic (typical in adult): no precipitating factor
  2. Epidemic (typical in childhood): hemorrhagic gastroenteritis from E. coli of serotype 0157:H7; bacteria produce Shiga toxin, which damages glomeruli
169
Q

Inherited thrombophilias: clinical manifestations

A

1) ~50% occur without provocation
2) DVT of legs and pelvis most common sites.
3) Increased incidence of superficial thrombophlebitis
4) Most evidence supports no association between arterial thrombosis and APCR or prothrombin 20210
5) There is an association between arterial thrombosis and deficiencies of AT, Protein C, or Protein S

170
Q

Congenital venous thrombotic disorders

A
  1. APC resistance= Factor V Leiden (-/+ or -/-)
  2. Excess procoagulant (prothrombin 20210 A, factors VIII, XI)
  3. Abnormalities of natural anticoagulants: antithrombin deficiency, protein C, S deficiency
171
Q

Activated Protein C Resistance (APCR)

A

Factor V Leiden Mutation: Arg 506 to Gln

Protein S and activated Protein C inactivate Factor Va (decreased clotting)
- Deficiency–> Factor Va constitutively active
- If protein C can’t cleave factor Va= APCR–> called Factor V Leiden Mutation
HYPERCOAGULABLE state

  • More common in Caucasians (5% general population)
  • 80-fold increase in VTE risk in FVL homzygotes
172
Q

Factor V deficiency

A

Excess bleeding (opposite of Factor V Leiden mutation)

173
Q

Excess Procoagulant

A
  1. Increased Prothrombin 20210 A:
    * Mutation at nucleotide number 20210
    elevated prothrombin (factor II) levels
    * High prevalence northern European ethnicity
    - 1-3% of general population
    - 5-10% with thrombosis
    - up to 20% if familial thrombosis
    * Heterozygotes have ~3-fold increased risk of venous thrombosis
  2. Elevated Factor VIII
  3. Elevated Factor XI
174
Q

Antithrombin deficiency

A

Hypercoagulable state seen in young adults (heterzygous)
- Thrombosis in pregnancy particularly common
Resistance to Heparin, low-molecular weight heparins

Can’t suppress Factors: XIIa, XIa, IXa, Xa, Thrombin–> unrestricted coagulation

175
Q

Thrombin Role

A

Activation of platelets:

  • Aggregation
  • Release reaction
  • TxA2 Synthesis

Activation of monocytes

  • Cytokines
  • Tissue Factor

Activaiton of endothelial cells

  • Cytokines
  • Tissue factor
Activation of coagulation cascade clot formation:
- Fibrinogen--> Fibrin
- XIII--> XIIIa
Amplification of clotting:
- V--> Va
- VIII--> VIIIa
176
Q

Fibrinolysis

A

Plasminogen is converted to plasmin by plasminogen activators:

  • uPA (urokinase plasminogen activator= prevalent in urinary system)
  • tPA (tissue plasminogen activator)

Plasmin degrades cross-linked fibrin and releases D-dimer

177
Q

Fibrinolytic system inhibition

A

Plasminogen activator inhibitor (PAI-1)

Alpha-2 antiplasmin (binds to free plasmin- NOT plasmin chewing up clot)

Thrombin-activatable fibrinolysis inhibitor (TAFI)

178
Q

Antiglobuin test (Coomb’s test)

A

Hemagglutination:

  • IgM antibodies= cause hemagluttination due to size (large enough to overcome repellant between RBCs)
  • IgG antibodies= Cannot cause hemagglutination (too small)

Anti-human globulin (AHG):

  • blood bank laboratory reagent that reacts with IgG antibodies on red blood cells to cause hemagglutination
  • “bridges the gap” between IgG antibodies
  • allows the blood bank to detect red cells coated with IgG antibodies
    1. Direct antiglobulin test (DAT)= determines what is on RBCs
    2. Indirect antiglobulin test= determines what is in serum
179
Q

Intravascular hemolysis

A

Due to IgM antibodies–> hemagglutination in circulation

  • Mechanical destruction of RBCs by complement fixation/lysis
  • Lysis of RBCs–> free RBC stroma–> vasoactive peptide–> clotting cascades/anaphylatoxin release

Signs/symptoms:

  • Back pain
  • Hemoglobinemia (Red plasma)
  • Hemoglobinuria
  • Red Urine
  • Fever
  • Coagulopathy
  • Hypotension
  • Pulmonary compromise
  • Disseminated Intravascular Coagulation (DIC)
  • Vascular collapse
  • Renal failure
  • DEATH
180
Q

Extravascular hemolysis

A

Due to IgG antibodies

  • IgG inefficient in complement-mediated lysis
  • Occurs thru clearance of IgG-coated RBCs by RES (reticuloendothelial system)–> broken down within RES cells

Signs/Symptoms:

  • Paucity of signs and symptoms
  • Low-grade fever
  • Drop in RBC count due to immune destruction of RBCs
181
Q

Signs/Symptoms of Intra or Extravascular hemolysis

A
  • Spherocytes
  • Circulating nucleated RBCs
  • Reticulocytosis
  • Elevated LDH (Lactate Dehydrogenase)
  • Elevated Bilirubin
  • Low Haptoglobin
182
Q

ABO blood group system

A

ABO antigens are complex carbohydrates on red cell glycoproteins/glycolipids

  • Precursor chain glycoconjugate
  • “H” chain made by adding a fucose to the precursor chain glycoconjugate
  • ABO antigens determined by ABO genetic loci that encode glycosyltransferases that may or may not modify the “H” chain
183
Q

ABO Antigens (transferases)

A

“O”- non-functional, does not modify H chain

A- adds galactosamine to H chain

B- adds galactose to H chain

184
Q

ABO antibodies

A

IgM antibodies (some IgG can be made)

Arise naturally in individuals lacking the corresponding antigen

Arise after infancy following stimulation by cross reacting environmental antigens
- Bacteria colonizing the gut

Cause hemagglutination of antigen positive red cells at body temperature

  • Why ABO incompatible red cell transfusion can be a FATAL complication!
  • Solid organ transplant rejection
185
Q

Rh Blood Group system

A

After ABO, Rh is next most important antigen system

Unlike ABO antigens, Rh antigens are membrane lipoproteins found only on human RBCs

Inherited as a “set” from each parent

Two homologous genes:

  • D gene product is the Rh factor
  • CE gene has all the other Rh antigens
186
Q

Rh Antibodies

A

Do not occur naturally, usually IgG

Alloimmunized to Rh antigens by exposure to human RBCs via several routes:

  • Rh negative patients may make IgG anti-D antibodies following:
    1. transfusion with D positive blood
    2. pregnancy with an Rh positive fetus

This occurs in 80% of normal, Rh negative patients when exposed to D positive RBCs

187
Q

Hemolytic disease of the Newborn (HDN)

A

Maternal IgG antibodies are transported across the placenta (but not IgM – it’s too big!)

Presence of maternal IgG specific for antigens on fetal RBCs can result in HDN

HDN caused by IgG anti-D is more severe than other antibodies:

  • Rh negative mother with anti-D is pregnant with Rh positive fetus
  • Anti-D can cause hemolysis of fetal RBCs (Hydrops fetalis) and edema, organ dysfunction (erythroblastosis fetalis)

ABO HDN= caused by antibodies to other Rh antigens, ABO system, etc

  • Milder than anti-D HDN, can occur DURING first pregnancy (vs after)
  • Seen in IgG component of maternal ABO antibodies (group O mom with Group A/B fetus)
  • NO PREVENTION for this type of HDN
188
Q

HDN prevention

A

Used to be a frequent cause of fetal loss: Rh negative women sensitized during a pregnancy with Rh positive fetus

  • Usually due to fetal maternal hemorrhage (FMH) during delivery
  • All subsequent pregnancies with Rh positive fetuses would be at risk

Since the 1960s, HDN has been prevented by injecting Rh negative mothers with anti-D from sensitized donor plasma

RhIG= Rh immune globulin:

  • Decreased incidence of HDN due to anti-D to < 0.1% of Rh-incompatible pregnancies
  • ONLY effective in Rh-negative mother naive to D antigen (alloimmunized mothers have no benefit)
  • Given in 3rd trimester, again at delivery
189
Q

Glycolipid antigens

A

IgM- only react at room temperature (therefore clinically insignificant)

190
Q

Glycoprotein antigens

A

IgG- reactive at body temperature

- Clinically significant

191
Q

Blood compatability Testing

A

“Type and Screen”

  • Type= Blood sample tested for ABO type, D antigen
  • Screen= Antibody screen on serum (for unexpected antibodies)- tested against reagent red cells

Red cell transfusion: avoid incompatability with ABO hemagglutins
- ex: O can ONLY receive O, AB can receive all types

Plasma transfusion: avoid incompatability with ABO antigens
- ex: O can receive any plasma, AB can only receive AB plasma

Platelet transfusion: Rh factor important (some RBCs in product)

192
Q

Crossmatch in transfusion compatibility

A

Patient’s serum mixed with RBCs in unit to be transfused: monitor for agglutination

  • Positive antibody screen: crossmatch demonstrates unit is compatibly
  • Negative antibody screen: crossmatch confirms ABO compatability
193
Q

Blood product testing

A
  • Anti-HIV-1, -2
  • HBsAg
  • Anti-HBc
  • Anti-HCV
  • Anti-HTLV-I, -II
  • Syphilis
  • Trypanosome antibodies

Nucleic Acid Testing:

  • HIV
  • HBV
  • HCV
  • West Nile Virus
  • Additional CMV testing for immunodeficient (transplant) recipients:
  • anti-CMV
  • Reduce/filter leukocytes out

Screen for bacterial contamination (platelets stored at room temperature)

194
Q

Acute Hemolytic Transfusion Reaction (AHTR)

A

ABO incompatible blood transfusion leading to intravascular hemolysis

195
Q

Delayed Hemolytic Transfusion Reaction (DHTR)

A

Patients with antibodies from previous transfusion/pregnancy but at time of pre-transfusion screen had too little antibody to be detected
- Will be able to see antibody shortly after transfusion

Symptoms: anamnestic antibody response, extravascular hemolysis

196
Q

Delayed Serologic Transfusion Reaction (DSTR)

A

Patients develop new antibody after RBC transfusion

  • Antibody formation takes longer than DHTR
  • Antibody detection after transfused cells cleared from circulation (no hemolysis)
  • Rationale behind type and screen < 3 days before transfusion (detect newly formed antibodies)
197
Q

Febrile Non-hemolytic transfusion reaction (FNHTR)

A

1% of transfusions, accompanied by rigors

  • Distinguish from fever in AHTR
  • See patient anti-leukocyte antibodies: react with leukocytes in tranfused product
  • OR, donor cytokines from activated leukocytes during storage
  • Do NOT recur (property of donor blood)
  • Prevented by pre-storage leukoreduction of blood products, pre-transfusion meds, acetominophen
198
Q

Allergic Transfusion Reaction

A

Local erythema, urticaria to full-blown anaphylaxis
- Seen in ~3% of all transfusions

Treatment:

  • Pre-transfusion antihistamines
  • Removal of plasma from blood components
  • Slow rate of transfusion
199
Q

Tranfusion Associated Circulatory Overload (TACO!)

A

Blood products transfused at excessive rate/volume

Symptoms= Hypertension, plethora

200
Q

Acute Hypotensive Reaction

A

Patients on ACE-I- faulty bradykinin metabolism

- Distinguish from anaphylaxis

201
Q

Transfusion Related Acute Lung Injury (TRALI)

A

Donor-derived anti-leukocyte antibodies react with patient leukocytes

  • Severe febrile reactions
  • Transfusion-related acute lung injury= white cell aggregates trapped in lung capillary bed

Avoided by using male donors for plasma

202
Q

Transfusion Associated Graft-versus-Host disease (TA-GVHD)

A

Seen in severely immunocompromised patients

  • Transfused lymphocytes engraft, target patient
  • Prevent by irradiating cellular blood products (2500 cGy)
  • Seen more frequently in HLA-haploidentical relatives (must be irradiated, even with immunocompetent recipients)
203
Q

Erythrocyte lifespan

A

120 days (10^12 made per day)

204
Q

Granulocytes lifespan

A

0.5 days (10^11 made per day)

205
Q

Platelet lifespan

A

9 days (10^11 made per day)

206
Q

Site of erythrocyte synthesis in development

A

Embryonic: Yolk sac

Fetus: Liver, spleen, extravascular, appendicular bones

Birth/after birth: bone marrow
- Over life, changes from long bones to axial skeleton (sternum, ribs, vertebrae, pelvis)

207
Q

Requirements for erythropoeisis

A

1) Stem cells
2) Stroma (microenvironment within bone marrow)
3) Growth factors

208
Q

Stem cells

A
  • Multi-potent (produce all different cell lines and possible endothelial cells)
  • Self-renewing (can maintain its own cell pool)
  • Capable of repopulating (bone marrow transplant)
  • Capable of differentiation into mature precursors
  • Are present in very low numbers and are morphologically indistinct
  • Capable of mobility and redistribution through the circulation
209
Q

Hematopoietic Hierarchy

A

Multipotent hematopoietic stem cell–>
1 ) Common myeloid progenitor:
- Megakaryocyte–> thrombocytes
- Reticulocyte (RNA)–> RBC (Erythrocyte)
- Mast cell
- Myeloblast–> basophil, neutrophil, eosinophil, monocyte(–> macrophage)

2) Common lymphoid progenitor
- Small lymphocyte–> T lymphocyte, B lymphocyte(–> plasma cell)
- Natural killer cell (large granular lymphocyte)

210
Q

EPO

A

Erythropoietin: stimulates maturation of RBCs from stem cells (bone marrow)
- Made in kidney, liver

  • Cortical interstitial cells in kidney produce EPO
  • Senses hypoxia–> increased HIF–> increased EPO
211
Q

GM-CSF

A

Granulocyte-megakaryocyte colony stimulating factor

  • White blood cell (myeloid cell) growth factor
  • Made in T-lymphocytes, mesenchymal cells
G-CSF= monocytes, mesenchymal cells, neutrophils
M-CSF= mesenchymal cells, monocytes
212
Q

Hematopoietic growth factors

A

EXCEPT for EPO:

  • GF production is redundant
  • Stromal cells can stimulate multiple types of growth factors
  • They have overlapping functions
  • In combination, they are more potent
213
Q

Principle of bone marrow transplant

A

Give bone marrow (stem) cells back (via transfusion)

- Will migrate to recipient bone marrow–> stem cells–> hematopoeisis

214
Q

Decreased clonal cell production

A

Stem cell suppression:
Multipotent stem cell bone marrow aplasia:

  • Aplastic anemia: RBCs, platelets, WBCs gone
  • Red cell aplasia: MDS, PNH (only lose RBCs)
  • Sideroblastic anemia
  • RBC Production defect: lose 1 gm/dL of hemoglobin per week
  • Hemolysis/hemorrhage: lose HUGE amount of RBCs faster
215
Q

Decreased nonclonal cell production

A

Stem cell suppression:

Committed precursor suppression:

  • Aplastic anemia: loss of all myeloid cell types
  • Red cell aplasia
  • White cell aplasia (agranulocytosis)
  • Amegakaryocytic thrombocytopenia
  • Anemia due to renal disease
216
Q

Increased clonal cell production

A

Clonal expansions: proliferation and expansion of single stem cell line with suppression of normal population

  • Polycythemia Vera (high hematocrit)
  • Essential thrombocytosis (increased platelets)
  • Primary Myelofibrosis
  • MDS (thrombocytosis)
  • CML= chronic myelogenous leukemia (increased WBCs/neutrophils)
  • CMMoL
217
Q

Increased nonclonal cell production

A

Secondary erythrocytosis
Secondary thrombocytosis
Leukemoid reaction

218
Q

Increased destruction of clonal cells

A

PNH (paroxysmal nocturnal hematuria)

219
Q

Increased destruction of non-clonal cells

A

Hemolytic anemia
ITP (idiopathic thrombocytic purpura)
Agranulocytosis

220
Q

Red cell Maturation

A
  1. Decrease in cell size
  2. Decreasing nuclear-cytoplasmic ratio
  3. Nuclear maturation (chromatin clumping/extrusion)
  4. Cytoplasmic maturation (hemoglobin)

Hemocytoblast–> committed proeythroblast–> Erythroblast–> Reticulocyte–> Erythrocyte

  • Progenitor compartment within bone marrow:
  • BFU-E (burst-forming units)= cells with high repopulating abilities
  • CFU-E (colony-forming units)= cells with lower repopulating abilities
221
Q

Erythrocyte morphology

A

Non-nucleated biconcave disc

  • Slightly smaller than normal lymphocyte nucleus
  • Central pallor (1/3 cell diameter)
  • Released into blood as reticulocyte (extrudes RNA)
  • 120 lifespan (1% replaced per day= 1% reticulocytes)

Reticulocytes (precursors):

  • Slightly larger, diffusely basophilic cytoplasm (no central clearing)
  • Supra-vital staining of RNA-ribosomal complexes
  • Increased numbers: increased production (markedly increased in hemolysis)
222
Q

HIF

A

Hypoxia inducing factor: stimulated by low O2

  • Acts as transcription factor for EPO
  • In normal O2 levels–> O2 binds HIF–> prevents EPO transcription
  • Cortical interstitial cells in kidney produce EPO
  • Senses hypoxia–> increased HIF–> increased EPO
223
Q

Polycythemia vera

A

Mutation in Bone marrow JAK-STAT signalling pathway

- Excessive erythrocytosis

224
Q

Secondary erythrocytosis

A
  1. Hypoxia (smoking, high altitude, shunt)–> appropriately high plasma EPO
  2. Abnormal HIF signalling–> inappropriately high plasma EPO. Seen in:
    - Tumors
    - von Hippel-Lindau syndrome
    - Inherited HIF defects
225
Q

Clinical uses of EPO

A
  • Anemia of renal failure
  • Anemia of prematurity
  • Myelodysplasia (refractory anemia; sideroblastic anemia)
  • Anemia of chronic disease (inflammatory or malignant)
  • With surgical procedures (autologous transfusion)
226
Q

Major components of hemostasis (+ function)

A
  1. Blood vessel:
    - Constriction
    - subendothelial collagen
    - Tissue factor
  2. Endothelial cells:
    - Secrete: platelet inhibitors, vasodilators, plasminogen, activators (digests clots)
    - Surface for anticoagulants
  3. Platelets:
    - Plug formation
    - Phospholipid for coagulation
  4. Plasma proteins:
    - Coagulation factors
    - Inhibitors of coagulation
227
Q

Coagulation proteins/factors

A

1) Serine proteases:
- Factor IIa, VIIa, IXa, Xa, XIa, XIIa
2) Cofactors:
- Factor Va, VIIIa, TF
3) Fibrinogen
4) Factor XIII

228
Q

Coagulation: Extrinsic pathway of Xa generation

A

Generates initial thrombin for coagulation cascade

1) Injury: Tissue factor (TF) on endothelial cells exposed to blood
2) TF complexes with factor VII
3) TF-VIIa complex activates factor X–> Xa
4) Xa + Va + Calcium–> Thrombin activation (converts II to IIa)

229
Q

Coagulation: intrinsic pathway of factor Xa generation

A

Amplification of thrombin generation (initiated by extrinsic pathway)

1) Platelet polyphosphates–> factor XII–> XIIa
2) XIIa: prekallikrein–> kallikrein–> enhanced XIIa generation
3) XIIa + HMWK (high molecular weight kininogen): XI–> XIa conversion
4) XIa + Ca: IX–> IXa
5) IXa + VIIIa: X–> Xa
6) Xa + Va + Calcium–> Thrombin activation (converts II to IIa)

  • Clotting begins once thrombin formation begun
230
Q

Anticoagulant system

A

1) Antithrombin:
- Direct inhibitor of coagulation proteases (serpin family)
- Inactivates thrombin, factors IXa, Xa, XIa, XIIa
- Inactivates VIIa after binding to TF
* Heparin enhances formation of AT-thrombin complexes

2) Protein C:
- Vitamin K dependent serpin
- Protein C circulates as zymogen
- Thrombin binds thrombomodulin
- Thrombomodulin/Thrombin complex binds and activates protein C–> activated protein C (APC)
- Inactivates Va, VIIIa
* Protein S= cofactor for APC (60% inactive form in circulation, 40% active)

3) Tissue factor pathway inhibitor (TFPI):
- Complexes with phospholipid/factor Xa complex
- Inhibits TF-VIIa complex
- Shuts off extrinsic pathway

231
Q

Fibrinolysis

A

Fibrin clot dissolved–> restored vascular patency

1) Plasminogen synthesized in liver
2) tPA in endothelial cells released upon injury
3) tPA activates Plasminogen–> plasmin
4) Fibrinolysis regulated by alpha2-antiplasmin, plasminogen activator inhibitor type 1 (PAI-1)

*Urokinase (u-PA)= urogenital tract form of tPA

232
Q

Protein C & S deficiencies

A

Seen in young adults: heterozygous molecular defects

Symptoms:

  • Venous thrombosis
  • Prone to warfarin-induced skin necrosis
  • Homozygotes prone to neonatal purpura fulminans
  • 0.5-0.8% prevalence in general population
233
Q

Homocysteinemia

A

Measure homocysteine levels (do NOT perform DNA testing)
- Increased risk of venous thromboembolism

  • 5% prevalence general population
234
Q

Laboratory screens for hypercoagulable states

A
  • APCR screen (if +, Factor V Leiden DNA test)
  • Lupus Anticoagulant screen
  • Anticardiolipin & anti-b2 GPI Antibodies
  • Homocysteine levels
  • Prothrombin 20210 A variant
  • Factor VIII activity
  • Protein C activity
  • Protein S antigen
  • Antithrombin activity
235
Q

Venous stasis and thromboembolism: pathophysiology

A

Venous stasis–> valve hypoxia (Hg desaturation)

  • Hypoxia–> damage to endothelium on next to valve can become hypoxic
  • Damage to endothelium–> clot formation
  • Clot–> thromboembolism

Heme/Onc (6 decks)

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