BloodBlood

Plasma and Cellular Elements of BloodPlasma and Cellular Elements of Blood HematopoiesisHematopoiesis RBC PhysiologyRBC Physiology CoagulationCoagulation

Blood = connective tissue

extracellularmatrix:Plasma

specialized cells:(Formed elements)RBCs WBCsPlatelets

color ??volume ??

PlasmaPlasma WaterWater Plasma proteinsPlasma proteins

• Albumin (60%)Albumin (60%) Osmotic GradientOsmotic Gradient

• Globulins (Ab)Globulins (Ab)• FibrinogenFibrinogen

MoleculesMolecules• ElectrolytesElectrolytes• NutrientsNutrients• Trace ElementsTrace Elements• Dissolved gasesDissolved gases

Serum = Plasma – Clotting factors

Hem(at)opoiesis =Hem(at)opoiesis = Blood Cell Formation Blood Cell Formation

Few uncommitted, pluripotent Few uncommitted, pluripotent stem cells in red bone marrow in red bone marrow throughout life time throughout life time (Fig 16-2)(Fig 16-2)

Controlled by cytokines, e.g.Controlled by cytokines, e.g.• Erythropoietin Erythropoietin (hormone or cytokine?)(hormone or cytokine?)• CSFs (Colony-stimulating factor)and CSFs (Colony-stimulating factor)and

ILs (interleukins): ILs (interleukins): e.g. M-CSF, IL-3 (= e.g. M-CSF, IL-3 (= multi CSF)multi CSF)

Neulasta (pegfilgrastim) is a CSFNeulasta (pegfilgrastim) is a CSF• Thrombopoietin (TPO)Thrombopoietin (TPO)

Some Terminology:Some Terminology:

• Anemia vs. Leukemia vs. leukocytosis vs. Anemia vs. Leukemia vs. leukocytosis vs. leukopenialeukopenia

Any of various acute or chronic neoplastic diseases of the bone marrow in which unrestrained proliferation of white blood cells occurs, usually accompanied by anemia, impaired blood clotting, and enlargement of the lymph nodes, liver, and spleen.

Leukemias (“white blood”) group of cancerous conditions of WBCs. Named according to the abnormal WBC type primarily involved (e.g. lymphocytic leukemia, myelocytic leukemia). Leukemia is acute (quickly advancing - mostly in children) if it derives from blast-type cells like lymphoblasts, and chronic (slowly advancing - mostly in adults) if it involves proliferation of later cell stages like myelocytes.

Leukemia, lymphoma and myeloma are cancers that originate in the bone marrow (in the case of leukemia and myeloma) or in lymphatic tissues (in the case of lymphoma).

Leukemia, lymphoma and myeloma are considered to be related cancers because they involve the uncontrolled growth of cells with similar functions and origins. The diseases result from an acquired (not inherited) genetic injury to the DNA of a single cell, which becomes abnormal (malignant) and multiplies continuously. The accumulation of malignant cells interferes with the body's production of healthy blood cells and makes the body unable to protect itself against infections.

Leukemia - Leukemia is a malignant disease (cancer) that originates in a cell in the marrow Non-Hodgkin Lymphoma - Lymphoma is a general term for a group of cancers that originate in the lymphatic system

Hodgkin Lymphoma - Hodgkin lymphoma (also known as Hodgkin's disease) is a specialized form of lymphoma and represents about 8 percent of all lymphomas diagnosed each year

Myeloma - Myeloma is a cancer of plasma cells, a type of white blood cell found in many tissues of the body, but mainly in the marrow

Myelodysplastic Syndromes - Myelodysplastic syndromes are a group of diseases that originate in an early blood-forming cell in the marrow

Leukopenia at http://www.merck.com/pubs/mmanual/section11/chapter135/135a.htm

EPO Regulates RBC ProductionEPO Regulates RBC Production ““Hormone” synthesized by Hormone” synthesized by kidneys in in

response to hypoxemiaresponse to hypoxemia

EPO gene cloned in 1985 EPO gene cloned in 1985 Recombinant EPORecombinant EPO now now available available (Epogen(Epogen, Procrit, Procrit))

Use in therapy, abuse in sportUse in therapy, abuse in sport

• Bone marrow damage from Bone marrow damage from chemotherapychemotherapy

• Chronic renal failureChronic renal failure

Your book calls it a cytokine because Your book calls it a cytokine because it is made on demand, not stored. it is made on demand, not stored. (p540).(p540).

Trivia Dept.: Neulasta® Trivia Dept.: Neulasta® (pegfilgrastim) stimulates production (pegfilgrastim) stimulates production of WBCof WBC

Running Problem: Blood Doping

The Erythrocyte (RBC)The Erythrocyte (RBC) Biconcave Disk, 7 Biconcave Disk, 7 μμ

diameter, Carry Odiameter, Carry O22

120 day lifespan120 day lifespan No mitochondria, no No mitochondria, no

nucleusnucleus• ATP from glycolysisATP from glycolysis

Bag of HbBag of Hb HCT = hematocrit = PCVHCT = hematocrit = PCV MCV-Mean Cell VolumeMCV-Mean Cell Volume

• ↓↓ in Fe-deficiency anemiain Fe-deficiency anemia

Hemoglobin (Hb)Hemoglobin (Hb)

[Hb] often reported in CBC[Hb] often reported in CBC• Four globulin proteins Four globulin proteins (Fig 18-8)(Fig 18-8)

Two Two αα-- Two Two ββ-- Each has the heme groupEach has the heme group Heme is a porphyrin that binds FeHeme is a porphyrin that binds Fe

Fe is considered a trace mineralFe is considered a trace mineral• Meat, beans, spinachMeat, beans, spinach• Stored in liver, “recycled”Stored in liver, “recycled”• Fe deficiencyFe deficiency

Hemoglobin (Hb) Synthesis and Hemoglobin (Hb) Synthesis and BreakdownBreakdown

Requires iron (Fe) + Vit. BRequires iron (Fe) + Vit. B12 12 (cobalamin)(cobalamin)

Reversible binding between Fe & OReversible binding between Fe & O22

Hb Breakdown:Hb Breakdown:

• Hb Hb → → Bilirubin Bilirubin → → bile. bile.

HyperbilirubinemiaHyperbilirubinemia

• Too fast causes icterus (jaundice)Too fast causes icterus (jaundice)

• HbA vs. HbFHbA vs. HbF

Fetal Hb has two Fetal Hb has two chains instead of two chains instead of two chains chains

HbF is designed to steal oxygen from maternal blood in placenta. Replaced shortly after birth.

CO is a product of incomplete combustion (complete combustion producesCO2 and H2O.) This obviously includes exposures to fires by victims and fire fighters but also includes smokers (cigars produce more CO than cigarettes - up to 20% CO Hb possible). Exhaust fumes are a common source of CO exposure. A recent report detailed high levels of CO exposure in enclosed pickup truck beds from a backdraft of exhaust fumes into the back of the truck.

Carbon monoxide also binds coordinately to heme iron atoms in a manner similar to that of oxygen, but the binding of carbon monoxide to heme is much stronger than that of oxygen. The preferential binding of carbon monoxide to heme iron is largely responsible for the asphyxiation that results from carbon monoxide poisoning.

RBC DisordersRBC Disorders Too high PCV:Too high PCV:

• Polycythemia vera Polycythemia vera (PCV ~ 60-70%)(PCV ~ 60-70%)

• DehydrationDehydration

AnemiasAnemias (O(O22 carrying capacity of blood too low) carrying capacity of blood too low)

• Hemorrhagic anemiaHemorrhagic anemia Fe deficiency anemiaFe deficiency anemia

• Hemolytic anemiaHemolytic anemia, due to genetic diseases (e.g. Hereditary , due to genetic diseases (e.g. Hereditary spherocytosis) or infectionsspherocytosis) or infections

• Pernicious anemiaPernicious anemia Vit. BVit. B1212 Deficiency Deficiency

• Aplastic anemiaAplastic anemia

• Renal anemiaRenal anemia ↓ ↓ EPOEPO

• Sickle Cell AnemiaSickle Cell Anemia

Polycythemia vera most commonly due to bone marrow cancer. Hematocrit can become as high as 80%. Secondary poycytemia when less oxygen is available (high altitudes) or EPO production increased. Polycythemia vera is a clonal stem cell disorder characterized by excessive erythrocyte production. Its etiology is not fully established, but hypersensitivity to interleukin-3 may play a role in the sustained erythrocytosis observed in this disease. Polycythemia vera usually occurs within the age range of 20-80, with 60 being the mean age of onset. The disease is slightly more common in males than in females. Clinical features include headaches, weakness, weight loss, and pruritus (itching without visible eruption on the skin). Major Criteria

total RBC vol men > 36 mg/kg; women >32 mg/kg arterial 02 saturation > 92% Splenomegaly Fe deficiency anemia USUALLY A SECONDARY RESULT OF

HEMORRHAGIC ANEMIAS. But also due to inadequate intake of iron containing foods or impaired absorption. Results in microcytes (pale small RBCs)

Pernicious anemia (p.621) leads to large pale cells due to developing RBCs not dividing.

Aplastic anemia due to some toxic chemicals and drugs and ionizing radiation. E.g.: arsenic, chloramphenicol. Fallout from nuclear bomb, excessive exposure to X-rays. Cancer and cancer chemotherapy. Marrow destruction of course affects all formed elements, anemia is just one symptom.

Sickle cell anemia HbS instead of normal HbA. One in 100 black newborns in US. Malaria connection: RBCs loose potassium which is essential for survival of parasite (plasmodium)

Platelets = ThrombocytesPlatelets = Thrombocytes Megakaryocyte (MK) is Megakaryocyte (MK) is

polypoid. polypoid. MechanismMechanism??

MK produces ~ 4,000 plateletsMK produces ~ 4,000 platelets

• Lifespan 10 days.Lifespan 10 days.

Platelets contain gra-Platelets contain gra-nules filled with clotting nules filled with clotting proteins & cytokinesproteins & cytokines

Activated when blood vessel Activated when blood vessel wall damagedwall damaged

HemostasisHemostasis

= = Opposite of hemorrhage Opposite of hemorrhage stops bleeding stops bleeding

Too little hemostasis Too little hemostasis too much bleeding too much bleeding

Too much hemostasis Too much hemostasis thrombi / emboli thrombi / emboli

Three major steps:Three major steps:

1.1. VasoconstrictionVasoconstriction

2.2. Platelet plugPlatelet plug Temporarily blocks the hole Temporarily blocks the hole

1.1. Platelet-derived cytokines further the processPlatelet-derived cytokines further the process

3.3. Coagulation cascadeCoagulation cascade (= clot formation seals hole (= clot formation seals hole until tissues repaired)until tissues repaired)1.1. Two pathways: Extrinsic and IntrinsicTwo pathways: Extrinsic and Intrinsic

4.4. After vessel repair, plasmin dissolves the clotAfter vessel repair, plasmin dissolves the clot

Steps of HemostasisSteps of Hemostasis

Vessel damage exposes collagen fibersVessel damage exposes collagen fibers

Platelets adhere to collagen Platelets adhere to collagen & release factors & release factors

local vasoconstrictionlocal vasoconstriction & & platelet aggregationplatelet aggregation

decreased blood flowdecreased blood flow platelet plug formation platelet plug formation

+ feedback loop

Steps of Hemostasis cont.Steps of Hemostasis cont.

1.1. Two coagulation pathways converge Two coagulation pathways converge onto common pathwayonto common pathway

1.1. Intrinsic Pathway.Intrinsic Pathway. Collagen exposure. All Collagen exposure. All factors needed are present in blood. Slower. factors needed are present in blood. Slower.

2.2. Extrinsic Pathway.Extrinsic Pathway. Uses Tissue Factors Uses Tissue Factors released by injured cells and a shortcut.released by injured cells and a shortcut.

2.2. Usually both pathways are triggered Usually both pathways are triggered by same tissue damaging events.by same tissue damaging events.

3.3. The different factors can be subject The different factors can be subject to a variety of problemsto a variety of problems

1.1. HemophiliaHemophilia2.2. Hypercoagulable statesHypercoagulable states

Vit K needed for synthesis of several clotting factors

Structure of Blood ClotStructure of Blood Clot

SEM x 4625

Plasmin, trapped in clot, will dissolve clot by fibrinolysis

Clot formation limited to area of injury: Intact endothelial cells release anticoagulants (heparin, antithrombin III, protein C).

Clot Busters & Clot Busters & AnticoagulantsAnticoagulants

Dissolve obsolete or Dissolve obsolete or unwanted clotsunwanted clots

Enhance fibrinolysisEnhance fibrinolysis

Examples:Examples: Urokinase, Urokinase, Streptokinase & t-PAStreptokinase & t-PA

Prevent coagulation by Prevent coagulation by blocking 1 or more steps blocking 1 or more steps in fibrin forming cascade in fibrin forming cascade

Inhibit platelet adhesion Inhibit platelet adhesion plug preventionplug prevention

Examples: Examples:

Coumadin (warfarin) blocks Vit KCoumadin (warfarin) blocks Vit K

EDTA chelates CaEDTA chelates Ca2+2+

Aspirin prevents platelet plugAspirin prevents platelet plug

Coumarin and warfarin block Vit K action (Vitamin K is cofactor in synthesis of several coagulation factors.

Ca chelators (EDTA and citrate) only in vitro

Heparin inhibits activity of thrombin (produced by basophils)

Aspirin prevents platelet plug fomation

Hemophilia It is sometimes called Christmas disease after

Stephen Christmas, the first patient described with this disease. In addition, the first report of its identification was published in the Christmas edition of the British Medical Journal.

In more recent history, royal watchers know that Queen Victoria of Britain's son Leopold had hemophilia, and that two of her daughters, Alice and Beatrice, were carriers of the gene. Through them, hemophilia was passed to the royal families in Spain and Russia, leading to one of the most famous young men with the disease, Tsar Nicholas II's only son Alekei.