Hematology

Question 1

What are the components of the blood?

Answer 1

50% - cells (erythrocytes, leukocytes, thromobocytes)
50%- plasma (90% water, 10% solutes- plasma proteins like albumin, globulin, & clotting factors- fibrinogen/electrolytes/gases)

Question 2

What are the 2 forms of leukocytes?

Answer 2

Granulocytes: neutrophils (main part of pus), basophils and eosinophils
Agranulocytes: monocytes, lymphocytes

Question 3

Tell me about erythropoetin.

Answer 3

• increased ADR’s- PE’s
• matures and stimulates production of RBC’s
• cytokine is produced from kidney and released organically in hypoxic events to produce more Hb (feedback mechanism)
• used in CRF- dialysis and oncology patients (no longer as favourable due to increased viscosity of blood and increased relapse of cancer)
• pay attention to target Hb levels before ordering/administering

Question 4

Tell me about bone marrow and stem cells.

Answer 4

Stem cells –> lymphoid which produce B and T cells
Stem cells –> myeloid which produce megakaryocyte which further produces plts, myeloid also produce monocytes, erythrocytes, eosinophil, basophil, neutrophils

Question 5

What are basophils?

Answer 5

Type of WBC used to attack parasites (ex.malaria) and allergy antigens.

Question 6

What is the structure of hemoglobin?

Answer 6

4 heme, 4 polypeptide portions, 4 iron atoms

Question 7

What causes smooth muscle contraction at the beginning of the clotting process?

Answer 7

Plts modulate plasma proteins that stimulate the release of histamine and serotonin.

Question 8

What are the stages of hemostasis?

Answer 8

1. Injury to the cell which exposes the collagen receptors of the endothelium
2. PRIMARY STAGE- vasoconstriction, platelet aggregation to the site (result of fibrinogen), plt adhesion via the VonWillebrand factor (glue for plts)
3. SECONDARY STAGE- clotting cascade
   - activation of coagulation factors and initiation of thrombin (TF released from injured cells and monocytes, TF & factor 7 activate factor 9,10 to generate thrombin)
   - amplification phase (thrombin activates factor 5,8,11 and more plts)
   - propagation phase (an increase factor 10 is produced which combines with factor 5/calcium/phospholipid form prothrombinase complex which converts F2 (prothrombin to thrombin)
4. Fibrin clot formation and stabilization- thrombin converts fibrinogen to fibrin –> fibrin mesh
5. Prevention of further coagulation and clot breakdown- inhibits further thrombin (activated protein C&5 to slow down factors 5 &8, antithrombin)
   - fibrinolysis (TPA converts plasminogen to plasmin which breaks down the clot –> shows up as d-dimer)

Question 9

Tell me about Virchow’s Triad.

Answer 9

Thrombosis- combined efforts of flow stasis, endothelial damage, hypercoaguable state

Flow stasis: increased with decreased mobility, multiple myeloma & smoking- increased viscosity.
Endothelial damage: cancer, chronic diseases
Hypercoaguable state: increased plt count (cancer)

Question 10

What are the different treatments for the different types of anemia?

Answer 10

Iron-deficiency anemia- PO ferrous gluconate/sulphat/fumerate- constipation, GI upset (less with fumerate), IV venofer/iron dextran (risk of anaphylaxis- administer in hospital/clinic)

B12 deficiency anemia- cobalamin (PO or IM), B12 replacement 1000 mg PO daily

Folate deficiency anemia- folate (PO), important in pregnant women (neural tube defects)

Question 11

Tell me about ASA.

Answer 11

• antiplatelet drug
• inhibits plt aggregation
• prevents artery thrombi (cardiac, stroke)
• a.fib purposes (if cannot take other anticoags)
• do not use in peds without consult
• dose: 80/81 mg PO daily

Question 12

Tell me about warfarin.

Answer 12

• vitamin K antagonist
• inhibits enzyme needed to activate vitamin k
• prevents thrombi in veins and atria of heart (a.fib)
• INR monitoring required (dose adjusted accordingly)
• INR of 2-3 is for prevention
• interacts with many medications

Question 13

Tell me about heparin.

Answer 13

• antithrombin activator (inhibits Xa and thrombin)
• IV, subcut - onset is minutes
• cannot be absorbed through the gut
• PTT or anti-Xa assay monitoring
• Half life 60-90 min (IV), subcut is longer
• hold for at least 4 hrs prior to planned procedures
• urgent reversal: protamine 1 mg/100 units of heparin given in the last 2-2.5 hrs
• cannot cross membranes due to its makeup of long polysaccharide chains- ok to use in pregnancy and when breastfeeding

Question 14

Tell me about LMWH.

Answer 14

• subcut,
• DVT prevention and treatment
• indirect anticoag: inhibits F10a and 2a
• Ex: dalteparin, enoxaparin, fondaparinux
• Hold 12-24 hrs before procedure
• Fractioned heparin molecules into smaller chain links
• Anti-Xa monitoring if required
• No urgent reversal agent
• Half life 3-6 hrs
• excreted via renal system

Question 15

Tell me about dabigitran.

Answer 15

• direct thrombin inhibitor (inhibits F2a)
• PO
• advantages compared to warfarin: rapid onset, no monitoring, few drug food interactions, lower risk of major bleeding, same dose for all pts
• use: stroke-related, non-valvular a.fib, prevention and treatment of DVTs
• half life is 15 hrs
• Renal clearance
• do not use if CrCl <30 ml/min
• side effects: dyspepsia, gastritis
• 150 mg PO BID
• stop prior to surgery
• do not give with P-glycoprotein inhibitors- ketoconozole, quinidine (could increase risk of bleeding)
• antedote: idarucizumab (5 gm IV, rapid effect)

Question 16

Tell me about direct Factor 10a inhibitors.

Answer 16

• Ex. rivoroxaban, apixaban, edoxaban
• do not require antithrombin to inhibit target
• PO
• a.fib, DVT’s prevention/treatment
• no INR monitoring
• fixed dosing
• rapid onset, decreased risk of bleeding, fewer drug interactions
• ** unsafe in pregnancy
• can accumulate with p-glycoprotein inhibitors and CYP3A4 inducers and induce bleeding
• effectiveness may decrease if taking St.John’s wart, phenytoin, carbamazepine, rifampin
• renal clearance
• stop 1-2 days before procedure depending on risk of blood loss and renal clearance
• antedote: andexa

Question 17

Tell me about clopidogrel.

Answer 17

• aka plavix
• suppresses plt aggregation by blocking P2Y12 ADP receptors on plt surface
• irreversible receptor blockade
• ticagrelor –> reversible receptor binding
• secondary prevention of atherothrombotic events in ACS and stroke (combined with ASA)
• PO
• can cause serious bleeding
• prevents stenosis of coronary stents
• AE: dyspepsia, diarrhea, rash
• giving PPI for GI upset may cause decreased absorption so only give if at risk for GI bleeding

Question 18

Tell me about iron-deficiency anemia

Answer 18

• aka IDA - most common type of anemia
• Signs and symptoms: SOB, fatigue, increased cardiac workload, increased HR, dizziness, pallor, pale mucous membranes, taste disturbance, ringing in ears, restless leg syndrome, headache, dizziness, glottis, cracks at corner of mouth, spoon shaped nails
• Fe needed to make functional hemoglobin
• Hemoglobin takes up most of the space with RBC’s so less Fe equals less Hb (hypochromic)- cells with be smaller= microcytic
• dx: MCV (mean corpuscular volume) –> if <90 fL= microcytic, decreased Hb size, 1st step to dx- serum ferritin (low)- may be unreliable in chronic disease, malignancy, check serum iron level (low), TIBC (high)
• causes: blood loss (ex.heavy menstruation), decreased Fe in the diet
• tx: ferrous sulphate/gluconate/fumerate PO, IV venofer (start low and slow)
• Patients with moderate to severe anemia should have a repeat CBC as early as 2-4 weeks, and an increase in hemoglobin of 10-20g/L should be seen by 4 weeks
• Anemia should correct in 2-4 months, and supplementation should continue 4-6 months after correction until hemoglobin, mean corpuscular volume, and ferritin normalize

Question 19

Tell me about B12 deficiency.

Answer 19

• vitamin B12 is water-soluble vitamin, used primarily as a cofactor for the synthesis of DNA, fatty acids and myelin, and responsible for the production of healthy red blood cells
• source of B12: leafy vegetables, meat
• required for RBC’s to mature and condense
• causes:
  1) pernicious anemia- autoimmune disorder (antibodies bind to intrinsic factor of parietal cells blocking B12 from absorption)
  2) malabsorption- gastric bypass, celiac disease, infections (ex.tapeworm), bowel resection
  3) dietary insufficiency
• Eldery: stomach gets smaller which leads to decreased absorption
• RBC’s will be large w/o B12 –> macrocytic (MCV= >90 fL
• tx: B12 via IM (to bypass decreased gastric absorption), cyanocobalamin, if just not getting enough B12 (ex. vegan diet) PO B12 available
• monitor B12 levels during pregnancy to facilitate healthy fetal development
• CNS clinical manifestations: neuropathy, ataxia, dementia and loss of proprioception
• dx: B12 level, CBC

Question 20

Tell me about folate-deficiency anema.

Answer 20

• needed for RBC’s to mature (RNA and DNA synthesis)
• tx: dietary folate (fruits and veggies), folic acid supplementation (PO 1-5 mg daily- indefinite tx if malabsorption is the cause)
• causes: nutritional deficiency, alcoholism, malabsorption, increased requirements (pregnancy, lactation, hemolysis), drugs,
• result: megaloblastic cells with clumped nuclear chromatin and leads to intramedullary hemolysis

Question 21

Tell me about hereditary spherocytosis.

Answer 21

• genetic condition- mutation involving ankyrin (proteins) and spectrin (cell membrane)
• RBC takes on the shape of a cylinder due to lack of flexibility of cell membrane due to mutations
• cannot carry O2 as effectively and gets caught in capillaries (in spleen, liver, bone marrow)
• signs: splenomegaly, similar symptoms to other anemia

Question 22

Tell me about G6PDH.

Answer 22

• glucose 6 phosphate dehydrogenase (enzyme) deficiency that contributes to the reduction of ROS which damage hemoglobin (less flexible, will get stuck in capillaries)
• Leads to hemolytic anemia and decreases RBC count
• most often seen in boys (X-linked recessive)
• Coombs test- detect damaged hemoglobin (Heinz bodies- ROS on RBCs)
• Children with G6PD deficiency lack this homeostasis protection and in the presence of these stressors cell injury and hemolysis lead to hyperbilirubinemia
• Testing of G6PD deficiency should be done in all infants with severe hyperbilirubinemia
• fava beans play a role in worsening this deficiency

Question 23

Tell me about sickle cell anemia.

Answer 23

• “chronic hemolytic anemia”
• mutation that changes structure of Hb
• whenever it is not bound to O2 it sickles/polymerizes and gets stuck in the vasculature
• when it binds to O2 it goes back to normal structure
• vaso-occlusive crisis - priapism - ongoing erection, splenomegaly
• dx: peripheral blood smear, CBC (>MCV- macrocytic), screening: sickledex, hb electrophoresis
• tx: increase O2, transfusions, fluid, pain management, hydroxyuria (increases fetal Hb)

Question 24

What is hemorrhagic anemia?

Answer 24

• blood loss which leads to decreased RBC’s and decreased oxygen carrying capacity
• ex. peptic ulcers (acute or chronic blood loss), AAA, trauma
• tx: fluids, transfusions, surgery if needed

Question 25

What is aplastic anemia?

Answer 25

• majority idiopathic cause such as drugs, viruses, radiation
• destruction of bone marrow- stem cells damaged that produce myeloid cells and further produce RBC’s, plts and WBC’s (pancytopenia)
• tx: bone marrow transplant, transfusions
• may have increased infections, increased bleeding (bruises, petechiae)

Question 26

What is thalassemia?

Answer 26

• common in mediterranean ancestry
• Hb is altered in composition (not 2 alphas, 2 betas)
• microcytic (MCV <90 fL)
• Tx: transfusions, Fe, O2, bone stem cell transplant
• types: minor, intermedia, major
• dx: CBC (MCV, Hb), hb electrophoresis, blood smear, normal ferritin level

Question 27

What is anemia of chronic disease?

Answer 27

• second most common anemia
• decreased RBC production by bone marrow
• normochromic, normoccytic
• causes: CRF, cancer, liver cirrhosis, hepatitis B/C, autoimmune disorders (RA/SLE), infection (HIV, osteomyelitis, endocarditis), DM, HF
• dx: CBC (normal MCV), low reticulocyte count, normal or high ferritin level, low serum iron/TIBC/soluble transferrin receptor, increased CRP/ESR (inflam markers)
• tx: treat the underlying cause

Question 28

What is the correlation between anemia and lead poisoning?

Answer 28

• most often paediatric concern
• chronic exposure to lead can = microcytic, hypochromic anemia
• lead interferes with the synthesis of heme
• dx: serum lead level

Question 29

Tell me about the pathophysiology associated with IDA.

Answer 29

• In humans with sufficient iron absorption, the body will uptake the iron and store it in the enterocytes, spleen, and liver to maintain a tight balance of iron in circulation. - Iron is held in storage by a protein called ferritin. The transporter transferrin carries the iron to the cells for uptake. The iron binds to hemoglobin and is transported through the circulatory system.
• In the event of iron deficiency, hemoglobin is reduced in the RBC. The decrease in hemoglobin decreases oxygen-carrying capacity resulting in hypoxia.
• To maintain hemostasis the hypoxia stimulates the kidneys to release erythropoietin signalling erythropoiesis in the bone marrow.
• The RBC production increases but the cells are microcytic and hypochromic due to the lack of hemoglobin.
• Fatigue and shortness of breath will be noted at this stage due to decreased oxygen transportation capacity

Question 30

Discuss the physiology of anemia in pregnancy.

Answer 30

• Physiologic anemia of pregnancy and iron deficiency anemia are the two most common causes of anemia in pregnant women
• Dilutional anemia results from natural physiologic changes during pregnancy, meaning this is not a pathological condition. Two things happen:

1) There is an overall increase in RBC mass of about 15- 25%.
2) Total gain of plasma volume by term is 1100-1600 mls which is 40-50% that of a non-pregnant woman.

Hemoglobin and hematocrit levels will therefore be lower.
Since the increase in RBC mass is less than the total gain of plasma volume, a mild physiologic anemia of 10-11 g/dl occurs. It also leads to an increased iron requirement.

Erythropoietin (EPO) is the mediator of increased RBC mass and it increases by 50% during pregnancy to help with physiologic anemia. The RBC lifespan is also slightly shorter.

Iron deficiency anemia in pregnancy is centred around iron deficiency in women in general. With the exception of dilutional anemia, the other risk factors and physiology are the same and centre around lifestyle and diet requirements.

• Dosing for IDA in pregnancy is recommended at 100mg – 200mg of iron orally per day- hemoglobin levels will improve in 1-2 months
• In prenatal women IDA is defined as a Hb < 100 g/L in the 1st and third trimester and < 105 g/L in the second trimester. A ferritin level of < 15 ug/L is a diagnosis of IDA and you would treat with iron supplementation. A ferritin of < 30 ug/L, you would consider treatment with oral supplementation as this suggests early iron depletion.

Question 31

Describe the anemias that should be screened for in childhood.

Answer 31

• Screening: should occur at 6 and 18 months for those infants/children from high-risk groups- low socioeconomic status, indigenous communities, immigrant children or those infants/children fed whole cow’s milk before 9 months or with a sub-optimal intake of iron containing foods
• Increased iron is needed to support the rapid growth and development children undergo in early years of life
• As iron supply is decreased low levels of hemoglobin lead to iron deficient anemia (IDA). This process can have a profound, and sometimes irreversible effect on a child’s cognitive or psychomotor development
• G6PD deficiency
• Sickle cell anemia: Infants born heterozygous will be carriers but those born homozygous will display sickle cell anemia.
• Thalassemia: autosomal recessive pattern
• Universal prenatal screening programs aim to identify those at risk for thalassemia and sickle cell disease
• Hemolytic Disease of the Fetus and Newborn (HDFN) occurs during pregnancy instead of childhood: caused by an ABO or Rh incompatibility between mother and child
• the requirements of iron per kilogram of weight are higher in infancy and early childhood compared to any other developmental stage, owing to rapid growth and associated blood volume expansion during this time
• Most healthy children carried to term are born with iron stores that are sufficient at meeting all physiologic requirements, until about six months
• For infants aged seven to 12 months, the introduction of iron-rich complementary foods is required to meet the Recommended Dietary Allowance (RDA) of elemental iron: 11mg/day

Question 32

What is idiopathic thrombocytopenic purpura?

Answer 32

• aka Immune Thrombocytopenia
• complex immunologic process generally involving platelet destruction and impaired platelet production
• Acute ITP is common in pediatric populations, is often self-limited, usually resolves within 6 months and is commonly secondary to an infectious or immune process
• Chronic ITP is more common in adults, the condition usually lasts longer than 6 months, often gets progressively worse and often has an unknown precipitating cause
• In ITP we have IgG autoantibodies which attack the GPIIa/IIa (Glycoproteins) which normally adhere to platelets to activate fibrinogen to promote aggregation of a platelet clot
• Once the platelets are covered with these IgG antibodies, they start to be removed from the circulation by Fc receptor binding by our mononuclear phagocytes through the spleen by the process of phagocytosis
• Remission in 3 to 12 months in most of the children
• Some children might develop other problems in the long term as consequence of the affected organs: cognitive deficit, kidney insufficiency
• If bleeding occurs: tx includes corticosteroids, IVIG, if severe: hospital