Hematopoietic Biomedical

What cells are blood cells derived from?

Multipotent hematopoietic stem cells AKA hemocytoblasts

The first division of blood cells is self-replacement. What is the product of the second division?

Differentiation into myeloid or lymphoid lines

How long does it take for the yolk sac and liver to make red blood cells (erythropoiesis)?

Yolk sac: 3-8 weeks

Liver: 6 weeks

When do the spleen and bone marrow produce red blood cells?

Spleen: from week 10 to week 28

Bone marrow: from week 18 to adulthood

At birth, erythropoiesis occurs in what two organs?

Liver and bone marrow

What chains is embryonic hemoglobin made out of? What structure can they be found in?

2z and 2 e chains. Yolk sac

What chains is fetal hemoglobin made out of? Where can they be found?

2a, 2y chains

Liver

Does fetal or maternal Hb have higher affinity for oxygen? Why?

Fetal

Due to less avid binding of 2,3-BPG allowing the fetal hemoglobin to steal extra O2 from maternal Hb across the placenta - shifts O2 dissociation curve to the left

What chains does adult hemoglobin contain? Where is it found?

2a, 2b. Found in the bone marrow

When does adult Hb finish producing?

After 1 year

What does each molecule of Hb contains and how many O2 can they each bind?

4 heme + 2a globulins + 2b globulins. Each can bind 1 O2

What antibodies do type A and type B blood contain?

Anti-b and anti-a antibodies, respectively

What antibodies do type AB and type O blood contain?

no antibodies (universal recipient) and anti-A/anti-B antibodies (universal donor), respectively

Does Rh+ blood have an antigen?

Yes, D antigen

What does Rh incompatibility in pregnancy result in?

Hemolytic disease of the newborn

True or false: Rh- needs exposure to Rh antigen to develop IgG antibodies

True

True or false: erythrocytes facilitate bringing O2 to tissues and CO2 removal

True

Does hypoxia increase or decrease EPO production?

Increases

What is gas exchange facilitated by? Where is this molecule produced?

EPO

in the interstitial cells of peritubular capillaries in the kidneys

Chronic kidney disease is associated with low EPO. What kind of anemia does this result in?

Non-hemolytic normocytic anemia

What is the shape of RBCs?

Biconcave; increases surface to volume ratio

True or false: RBCs have a nucleus and organelles

False

What is the significance of the membrane protein spectrin?

Maintains concave shape

What is the sole energy source of RBCs and what pathways do they gave energy from?

Glucose. Glycolysis and pentose phosphate pathway

What are reticulocytes and what do they retain?

Young RBCs, retain ribosomal RNA

What would a high reticulocyte count + anemia signify? Low reticulocyte and anemia?

high reticulocyte and anemia = hemolysis or blood loss

low reticulocyte and anemia = bone marrow dysfunction

What is the chloride-bicarbonate anti porter? What happens at the tissue and lung level?

Exchanges Cl- for HCO3 to buffer blood pH

Tissues: takes up Co2 → forms HCO3

Lung level: releases Co2

Function of platelets AKA thrombocytes. What are they stimulated by and what is their lifespan?

Clot formation and hemostasis

Stimulated by TPO from the liver and kidneys

Lifespan is 8-10 days

What cells are thrombocytes derived from and where are many of them stored?

Megakaryocytes

1/3 stored in spleen

What is the relative platelet concentration in the blood as seen in splenomegaly and asplenia?

Splenomegaly - excessive spleen storage so thrombocytopenia

Asplenia: no storage and therefore all platelets are in circulation so thrombocytosis

After injury, what do platelets bind to aggregate?

vWF and fibrinogen

Platelets release dense and alpha granules. What are examples of each?

Dense - ADP, Ca+

Alpha - vWF, fibrinogen

What receptors bind vWF and fibrinogen?

vWF: Gp1b

fibrinogen: Gp2b/3a

What triggers mast cell release?

Allergic responses (type 1)

tissue trauma

complement system

IgE cross-linking with antigens

What are the degranulation products of mast cells?

Histamine, heparin, eosinophil chemotactic factors

What are dendritic cells and what do they do?

phagocytic antigen-presenting cells. they bridge innate and adaptive immune system. They are the main inducers of humeral immunity

Which cells are derived from monocytes and present antigens on MHC II molecules?

Dendritic cells

What are the two main classes of lymphocytes?

Granulocytes and mononuclear cells

There are 3 kinds of granulocytes. What are they and what cell type are they derived from?

Derived from myeloblasts

1. Neutrophils (first responders in bacterial infections)

2. Basophils (allergic and inflammatory responses)

3. Eosinophils (parasitic infections)

What are granulocytes stimulated by?

GM-colony stimulating factor

What two cells types are considered to be monocular cells? And what are their origins?

1. Monocytes: derived from myeloblasts. Differentiate into macrophages when entering tissues

2. Lymphoid cells: derived from common lymphoid progenitors. Includes B cells, T cells, NK cells

What is bandemia?

Elevated young neutrophils

What is the most common WBC in blood and tissue?

Neutrophils

How many lobes do neutrophils have?

3-4

What are band neutrophils and when would they be seen elevated on labs?

Immature neutrophils, elevated in infections or chronic myeloid leukeamia

How many lobes do hypersegmented neutrophils have and in what conditions would they be seen elevated on labs?

6+ lobes, seen in B12/folate deficiency

Large cells with kidney-shaped nucleus and “frosted glass” cytoplasm. These differentiate into macrophages upon entering tissues

Monocytes

These phagocytose bacteria, debris and senescent RBCs. They have a long tissue lifespan and present antigens via MHC II (adaptive immunity)

Macrophages

How are macrophages activated?

GM-CSF stimulates production → Th cells release interferon-y which activates macrophages → macrophages release TNF-a → granuloma formation

What are the tissue-specific macrophages for the CNS, liver, skin?

CNS: microglia

Liver: kupffer cells

skin: langerhaus cells

Histocytes and bones. What tissues are these specific to in terms of macrophages?

Connective tissue and bone

Marker for macrophages, binds to lipid A of gram-negative bacteria

CD14

What do eosinophils release to counteract mast cell histamine release?

histaminase and arylsulfatase

Which WBCs are considered to be large and have a bilobed nucleus?

Eosinophils

These are associated with innate immunity and require no antigen or antigen-presenting cell

NK cells

What are NK cells responsible for?

Recognizing and inducing apoptosis in infected or abnormal cells lacking MHC markers or with attached antibodies

Compare and contrast B and T cells

B cells: build antibodies. Humoral immune response. Mature in bone marrow, requiring IL-7. Differentiate into plasma cells (produce antibodies) and memory B cells (reactivated during secondary immune responses). Help T cells.

T cells: target infected cells. cellular immune response. Mature in the thymus. Differentiate into helper T cells (key target for HIV infection), cytotoxic T cells (destroy virally infected or abnormal cells) and regulatory T cells (develop tolerance to self-antigens to prevent autoimmunity)

What are the surface markers for B cells?

CD19, CD20, CD21 (receptor for EBV)

What are the surface marker for cytotoxic T cells and helper T cells?

CD8 and CD4, respectively

What are the key components of blood?

Plasma 55%: 92% water, 7% protein (albumin), 1% nutrients/electrolytes

Buffy coat <1%: platelets, leukocytes

Erythrocytes 45%

Maintains oncotic pressure, transports hormones. Is made by the liver

Albumin

What is the interstitial fluid made up of?

Plasma and proteins

Where does blood synthesis occur?

Begins in the mitochondria, then moves to the cytoplasm then ends in the mitochondria

What is the rate limiting step of blood synthesis and what nutrient does it require as a cofactor? What is this step inhibited by?

ALA synthase catalyses glycine + succinyl-CoA → delta-ALA. Requires B6. Inhibited by high levels of glucose and heme

What is sideroblastic anemia?

X-linked deficiency in ALA synthase

Protoporphyrin + Fe → heme. What it this step catalyzed by and where? What inhibits this step?

Ferrochelatase in the mitochondria

Inhibited by lead poisoning. Symptoms of lead poisoning include abdominal pain, headache and fatigue

Where are senescent RBCs phagocytosed?

Spleen, liver and bone marrow

What are the steps of hemoglobin breakdown?

Globin is broken into amino acids and recycled for new protein synthesis. Iron is stored in the liver or spleen as ferritin or hemosiderin. Non-iron portion is converted to biliverdin by heme oxygenase, which is then converted to uncongugated bilirubin

This molecule brings iron to the bone marrow for incorporation into new erythrocytes

Transferrin

Excessive RBC destruction or impaired bilirubin conjugation/excretion → jaundice . What is this condition called?

Hyperbilirubinemia

What is the extrinsic coagulation pathway activated by? Factor 12a activates what? This pathway is critical for initiating what? What lab test measures this pathway (Ca must be added to test tube for pathway activation)

Activated by tissue factor which activates Factor 12 → 12a. 12a activates factor 10.

This is critical for initiating clot formation

PT or INR measures this pathway

Process: Factor 12 → 12a → 11 → 11a →9 →9a → 10 → 10a

What is this pathway? What is it triggered by? What lab value would measure this pathway? What nutrient is required for proper function of this pathway?

Intrinsic/amplification phase

This is triggered by exposure to collagen, basement membrane or activated platelets.

Partial thromboplastin time (PTT) measures this pathway

Requires calcium for proper function

Describe the common pathway

Factor Xa converts prothrombin to thrombin. Thrombin transforms fibrinogen into fibrin, which forms the fibrin mesh

Thrombin activates 13 which stabilizes the fibrin mesh

What are the vitamin-K dependent factors?

Factors 2, 7, 9, 10, protein C and protein S

What does von Willebrand fator do and where is it released from?

Binds to exposed collagen, released from endothelial cells and alpha granules of platelets

What binds vWF via the Gp1b receptor?

Platelets

What receptors does ADP bind to, upregulating the Gp2b/3a receptors?

P2Y12 receptors

What are examples of pro-aggregation factors and anti-aggregation factors?

Pro: Thromboxane A2 → vasoconstriction, increased aggregation

Anti: Prostacyclin and NO → vasodilation, decreased aggregation

Converts inactive clotting factors into active forms via gamma-glutamyl carboxylase. Neonates and long-term antibiotic users are at risk for deficiency

Vitamin K

What is fibrinolysis?

Breaks down fibrin mesh into fibrin degradation products, via plasminogen → plasmin

Inhibits thrombin and factor Xa. Enhanced by heparin

Anti-thrombin

What are protein C and protein S activated by? What do they inactivate?

Activated by thrombin-thrombomoduli complex (TTC). Inactivate factors 5a and 8a

What are the effects of a factor 5 leiden mutation?

Resistance to protein C = hypercoagulability