denver school of nursing bio 206 / 308 – ch 19 & 20 hemo path

Denver School of Nursing

Bio 206 / 308 – ch 19 & 20 Hemo PATH

Chapter 19 & 20

Image Source: http://www.beliefnet.com

Source: Huether, McCance Understanding Pathophysiology 4th Ed. 2008

Composition of blood 90% water and 10% solutes 6 quarts (5.5 L = “about 6 liters”) Plasma

▪ 55% to 60% of the blood volume▪ Organic and inorganic elements

Chief Function Delivery of substances needed for cellular

metabolism Removal of wastes Defense against microorganisms and injury Maintenance of acid-base balance

Composition of blood Plasma proteins

▪ Albumins▪ Function as carriers and control the plasma oncotic pressure

▪ Globulins▪ Carrier proteins and immunoglobulins (antibodies)

▪ Clotting factors▪ Mainly fibrinogen

Composition of blood Cellular components

▪ Erythrocytes▪ Most abundant cell in the body

▪ Responsible for tissue oxygenation

▪ Biconcavity and reversible deformity

▪ 120-day life cycle

Cellular components Leukocytes (white blood cells)

▪ Defend the body against infection and remove debris

▪ Granulocytes▪ Membrane-bound granules in their cytoplasm▪ The granules contain enzymes capable of destroying

microorganisms▪ Inflammatory and immune functions▪ Capable of ameboid movement (diapedesis)

After all of your immuno studies what blood cells would you consider to be granulocytes??

Granulocytes Neutrophils

▪ Polymorphonuclear neutrophil (PMN)▪ Phagocytes in early inflammation

Eosinophils▪ Eosinophils ingest antigen-antibody complexes▪ Induced by IgE hypersensitivity▪ Increase in parasitic infections

Granulocytes- basophils Mast cells

▪ Central cell in inflammation▪ Found in vascularized connective tissue

Basophils▪ Structurally and functionally similar to mast cells

Agranulocytes Monocytes and macrophages make up the

mononuclear phagocyte system (MPS) Monocytes Macrophages Lymphocytes-T & B Natural killer (NK) cells

Platelets Disk-shaped cytoplasmic fragments Essential for blood coagulation and control

of bleeding Thrombopoietin

▪ Main regulator of platelets

Spleen Largest secondary lymphoid organ Splenic pulp

▪ Masses of lymphoid tissue containing macrophages and lymphoid tissue

Venous sinuses▪ Phagocytosis of old, damaged, and dead

blood cells▪ Blood storage

Lymph nodes Part of the immune and hematologic

systems▪ Facilitates maturation of lymphocytes▪ Transports lymphatic fluid back to the circulation▪ Cleanses the lymphatic fluid of microorganisms

and foreign particles

The MPS consists of a line of cells that originate in the bone marrow, are transported into the bloodstream, differentiate into monocytes, and settle in the tissues as mature macrophages

Cells of the MPS ingest and destroy microorganisms and foreign material

The MPS is mostly the liver and spleen

Hematopoiesis is the process of blood cell production

Two stages Mitosis

▪ Mitosis stops before the cell enters the peripheral blood

Maturation and differentiation

Stem cell system Pluripotent stem cells Colony-stimulating factors

Bone marrow Also called myeloid tissue Red and yellow bone marrow Adult active bone marrow

▪ Pelvic bones, vertebrae, cranium and mandible, sternum and ribs, humerus, and femur

Erythrocytes are derived from erythroblasts (normoblasts)

Maturation is stimulated by erythropoietin

Sequence Uncommitted pluripotent stem cell,

committed proerythroblast, normoblast, basophilic normoblast, polychromatophilic normoblast, orthochromic normoblast, reticulocyte (nucleus is lost), erythrocyte

In each step the quantity of hemoglobin increases and the nucleus decreases in size

Numbers of circulating red cells in healthy individuals remain constant

The peritubular cells of the kidney produce erythropoietin

Hypoxia stimulates the production and release of erythropoietin

Erythropoietin causes an increase in red cell production and release from bone marrow

Source: googleimages.com

Oxygen-carrying protein of the erythrocyte

A single erythrocyte contains as many as 300 million hemoglobin molecules

Two pairs of polypeptide chains Globulins

Four colorful iron-protoporphyrin complexes

Adult hemoglobin Two alpha chains and two beta chains

Source: Huether: Understanding Pathophysiology, 4th Edition, 2008

Nutritional requirements Building blocks

▪ Proteins▪ Amino acids

▪ Vitamins▪ Vitamins B12, B6, B2, E, and C; folic acid; pantothenic acid;

and niacin

▪ Minerals▪ Iron and copper

▪ Folate

Iron cycle Total body iron is bound to heme or

stored bound to ferritin or hemosiderin mononuclear phagocytes and hepatic parenchymal cells

Less than 1 mg per day is lost in the urine, sweat, epithelial cells, or from the gut

Transferrin Apotransferrin-w/o Oxygen

Source: Huether: Understanding Pathophysiology, 4th Edition, 2008

Aged red cells are sequestered and destroyed by macrophages of the MPS, primarily in the spleen

The liver takes over if the spleen is absent

Globin chains are broken down into amino acids

Role of B12 & Folate in RBC life span

Porphyrin is reduced to bilirubin, transported to the liver, and secreted in the bile

What is the most common cause of hypocalcemia?

What is the largest protein molecule in blood?

Source: Robbins Pathologic Basis of Disease 8th Edition 2010

Source: Huether, McCance Understanding Pathophysiology 4th Ed. 2008 (Fig 19-13)

Source: Huether, McCance Understanding Pathophysiology 4th Ed. 2008 (Fig 19-14)

Leukocytes arise from stem cells in the bone marrow

Granulocytes mature in the bone marrow

Agranulocytes and monocytes are released into the bloodstream before they fully mature

Growth factors and colony-simulating factors encourage production and maturation of leukocytes

Endomitosis The megakaryocyte undergoes the

nuclear phase of cell division but fails to undergo cytokinesis

The megakaryocyte expands due to the doubling of the DNA and breaks up into fragments

Platelet levels are maintained by thrombopoietin and IL-11

Platelets circulate for 10 days before losing their functional capacity

Hemostasis means arrest of bleeding

Requirements Platelets Clotting factors Blood flow and shear forces Endothelial cells Fibrinolysis

Virchow's Triad - Causes of Thrombosis1) Changes in the blood vessel wall

2) Changes in blood flow

3) Changes in blood composition

1. Vasospasm a)Plug b)Activate coagulation cascade

2. Initiate repair

Platelet plug formation Activation – Calcium essential for

platelet activation Adhesion

▪ von Willebrand factor (vWF)

Activation (Again)

Aggregation

Secretion granules release…

Platelet secretion:

Alpha granules have P-selectins on their membranes and contain fibrinogen, fibronectin, factors V and VIII, platelet factor 4, platelet-derived growth factor, and TGFβ.

Delta granules, contain adenine nucleotides ADP and ATP, ionized calcium, histamine, seratonin, and epinephrine.

What are the 4 most important players of Hemostasis (A&P Review)??

What are the 4 most important players of Hemostasis (A&P Review)?? Thrombinogen Thrombin Fibrinogen Fibrin

Intrinsic pathway▪ Activated when factor XII contacts subendothelial

substances exposed by vascular injury

Extrinsic pathway▪ Activated when tissue factor (TF) (tissue

thromboplastin) is released by damaged endothelial cells

Clot retraction Fibrin strands shorten; become denser

and stronger to approximate the edges of the injured vessel and site of injury

Facilitated by large numbers of platelets within the clot and actin-like contractile proteins in the platelets

Factor F X

F IXaF IX

F XIaF XI

Surface ContactCollagenFXII activator

F XIIaF XII

Intrinsic Pathway

Ca2+

Ca2+

Ca2+Factor F X

F VIIF VIIa

F III (Tissue Thromboplastin)

Tissue/Cell Defect

Extrinsic Pathway

Ca2+

Ca2+

FibrinogenFibrinmonomers

Fibrinpolymers

ThrombinProthrombin I

Factor F Xa

Ca2+

Platelet Factor 3

CrosslinkedFibrin Meshwork

F XIIIa F XIII

F VF Va

F VIIIaF VIII

Lysis of blood clots

Fibrinolytic system▪ Plasminogen and plasmin▪ Fibrin degradation products

▪ D-dimers

Fibrin degradation products

Fibrinogen Fibrin-clot

PlasminPlasminogen

T-PAF XIIaHMWK

KallikreinUrokinase

Streptokinase

Clotting Cascade

Tests of bone marrow function Bone marrow aspiration Bone marrow biopsy Measurement of bone marrow iron stores Differential cell count

Blood tests Large variety of tests

Blood cell counts increase above adult levels at birth Trauma of birth and cutting the umbilical

cord The hypoxic intrauterine environment

stimulates erythropoietin production Results in polycythemia

Children tend to have more atypical lymphocytes as a result of frequent viral infections

Classifications Etiology Morphology

▪ Based on MCV, MCH, and MCHC values▪ Size

▪ Identified by terms that end in “-CYTIC▪ Macrocytic, microcytic, normocytic

▪ Hemoglobin content ▪ Identified by terms that end in “-CHROMIC▪ Normochromic and hypochromic

Anisocytosis Red cells are present in various sizes

Poikilocytosis Red cells are present in various shapes

Physiologic manifestation Reduced oxygen-carrying capacity

Variable symptoms based on severity and the ability for the body to compensate

Classic anemia symptoms Fatigue, weakness, dyspnea, and

pallor


Does anyone know what this condition of “spoon nails” is called?


Koilonychia = spooned nails

Also termed megaloblastic anemias

Characterized by defective DNA synthesis Caused by deficiencies in vitamin B12 or

folate▪ Coenzymes for nuclear maturation and the DNA

synthesis pathway

Pernicious anemia Caused by a lack of intrinsic factor

from the gastric parietal cells Required for vitamin B12 absorption

Results in vitamin B12 deficiency

Pernicious anemia Typical anemia symptoms Neurologic manifestations

▪ Nerve demyelination▪ Absence of intrinsic factor

Others▪ Loss of appetite, abdominal pain, beefy red

tongue (atrophic glossitis), icterus, and splenic enlargement

Pernicious anemia Treatment

▪ Parenteral or high oral doses of vitamin B12

Source: Lippincott Pathophysiology, Williams & Wilkins 2003

Folate deficiency anemia Absorption of folate occurs in the upper

small intestine Not dependent on any other factor Similar symptoms to pernicious anemia

except neurologic manifestations generally not seen

Treatment requires daily oral administration of folate

Characterized by red cells that are abnormally small and contain reduced amounts of hemoglobin

Related to: Disorders of iron metabolism Disorders of porphyrin and heme

synthesis Disorders of globin synthesis

Iron deficiency anemia Most common type of anemia worldwide Nutritional iron deficiency Metabolic or functional deficiency Progression of iron deficiency causes:

▪ Brittle, thin, coarsely ridged, and spoon-shaped nails

▪ A red, sore, and painful tongue

Sideroblastic anemia Group of disorders characterized by anemia Altered mitochondrial metabolism causing

ineffective iron uptake and resulting in dysfunctional hemoglobin synthesis

Ringed sideroblasts within the bone marrow are diagnostic▪ Sideroblasts are erythroblasts that contain iron

granules that have not been synthesized into hemoglobin

Sideroblastic anemia Dimorphism Myelodysplastic syndrome Erythropoietic hemochromatosis Mito becomes not so mighty…

Characterized by red cells that are relatively normal in size and hemoglobin content but insufficient in number

Aplastic anemia Pancytopenia Pure red cell aplasia Fanconi anemia

Posthemorrhagic anemia Acute blood loss from the vascular space

Hemolytic anemia Accelerated destruction of red blood cells Autoimmune hemolytic anemias Immunohemolytic anemia Warm antibody immunohemolytic anemia Drug-induced hemolytic anemia Cold agglutinin immunohemolytic anemia Cold hemolysin hemolytic anemia

Sickle cell anemia

Anemia of chronic inflammation Mild to moderate anemia seen in:

▪ AIDS, rheumatoid arthritis, lupus erythematosus, hepatitis, renal failure, and malignancies

Anemia of chronic inflammation

Pathologic mechanisms▪ Decreased erythrocyte life span▪ Ineffective bone marrow response to

erythropoietin▪ Altered iron metabolism

Polycythemia Overproduction of red blood cells

Relative polycythemia Result of dehydration Fluid loss results in relative increases of

red cell counts and Hgb and Hct values

Absolute polycythemia Primary absolute

▪ Abnormality of stem cells in the bone marrow ▪ Polycythemia vera (PV)

Secondary absolute▪ Increase in erythropoietin as a normal response

to chronic hypoxia or an inappropriate response to erythropoietin-secreting tumors

Leukocytosis Leukocytosis is a normal protective

physiologic response to physiologic stressors

Leukopenia Leukopenia is not normal and not beneficial

A low white count predisposes a patient to

infections

Acute, self-limiting infection of B-lymphocytes transmitted by saliva through personal contact

Commonly caused by: Epstein-Barr virus (EBV)—85% B cells have an EBV receptor site Others viral agents resembling IM

▪ Cytomegalovirus (CMV), hepatitis, influenza, HIV

Symptoms: fever, sore throat, swollen cervical lymph nodes, increased lymphocyte count, and atypical (activated) lymphocytes

Serious complications are infrequent (<5%)

Splenic rupture is the most common cause of death

Malignant disorder of the blood and blood-forming organs

Excessive accumulation of leukemic cells

Acute leukemia Presence of undifferentiated or

immature cells, usually blast cells Chronic leukemia

Predominant cell is mature but does not function normally

Acute lymphocytic leukemia (ALL) Acute myelogenous leukemia (AML) Chronic myelogenous leukemia

(CML) Chronic lymphocytic leukemia (CLL)

Signs and symptoms of leukemia Anemia, bleeding purpura, petechiae,

ecchymosis, thrombosis, hemorrhage, DIC, infection, weight loss, bone pain, elevated uric acid, and liver, spleen, and lymph node enlargement

chronic myelogenous leukemia (CML)

chronic myelogenous leukemia (CML)

CML accounts for about 15% of all leukemia cases in the United States, 4,570 new cases diagnosed in 2007.

The Leukemia & Lymphoma Society estimates that over 21,500 people are living with CML. It can occur at any age, but most often occurs in people over age 50. Only 10% of people diagnosed with CML are under the age of 20.

Source: NIH.gov

Enlarged lymph nodes that become palpable and tender

Local lymphadenopathy Drainage of an inflammatory lesion

located near the enlarged node General lymphadenopathy

Occurs in the presence of malignant or nonmalignant disease

Malignant transformation of a lymphocyte and proliferation of lymphocytes, histiocytes, their precursors, and derivatives in lymphoid tissues

Two major categoriesHodgkin lymphomaNon-Hodgkin lymphomas


Hodgkin Lymphoma Characterized by:

▪ 1) Progression from one group of lymph nodes to another

▪ 2) The development of systemic symptoms▪ 3) Presence of Reed-Sternberg (RS) cells

Non-Hodgkin Lymphoma Characterized by two different types:

▪ 1) B-Cell Neoplasms – Includes myelomas orginating from B cells at multiple stages of differentiation.

▪ 2) T & NK cell Neoplasms – originating from T and NK cells.▪ Unlike HL both types lack RS cells and have different systemic

symptoms

Characterized by the presence of Reed-Sternberg cells in the lymph nodes

Reed-Sternberg cells are necessary for diagnosis, but they are not specific to Hodgkin lymphoma

Classical Hodgkin lymphoma

Nodular lymphocyte predominant Hodgkin lymphoma

Physical findings Adenopathy, mediastinal mass,

splenomegaly, and abdominal mass

Symptoms Fever, weight loss, night sweats, pruritus

Laboratory findings Thrombocytosis, leukocytosis, eosinophilia,

elevated ESR, and elevated alkaline phosphatase

Paraneoplastic syndromes

Source: Huether, McCance Understanding Pathophysiology 4th Ed. 2008 + http://lymphoma.about.com

There are two broad types of Burkitt’s lymphoma – the sporadic and the endemic varieties. There is a very high incidence of this disease in equatorial Africa, and disease in this region is called endemic Burkitt’s lymphoma. Disease in other regions of the world is much less common, and is called sporadic Burkitt’s lymphoma. Though they are the same disease, the two forms are different in many ways.

Thrombocytopenia Platelet count <150,000/mm3

▪ <50,000/mm3—hemorrhage from minor trauma▪ <15,000/mm3—spontaneous bleeding▪ <10,000/mm3—severe bleeding

Essential (primary) thrombocythemia Thrombocythemia is characterized by

platelet counts >400,000/mm3

Myeloproliferative disorder of platelet precursor cells ▪ Megakaryocytes in the bone marrow are

produced in excess

Microvasculature thrombosis occurs

Qualitative alterations in platelet function demonstrate an increased bleeding time in the presence of a normal platelet count

Platelet function disorders result from platelet membrane glycoprotein and von Willebrand factor deficiencies

Manifestations Petechiae, purpura, mucosal bleeding,

gingival bleeding, and spontaneous bruising

Disorders can be congenital or acquired

Vitamin K deficiency Vitamin K is necessary for synthesis and

regulation of prothrombin, the prothrombin factors (II, VII, IX, X), and proteins C and S (anticoagulants)

Liver disease Liver disease causes a broad range of

hemostasis disorders▪ Defects in coagulation, fibrinolysis, and

platelet number and function

Hemophilia A-1/5000-sex linked : Xp28-loss of factor VIII-female : modest reduction…X

inactivation (Lyon Hypothesis)

Hemophilia B-loss of factor IX, Xp27…

disease

Intrinsic Pathway-initiated: negatively charged surface

a. damaged endotheliumb. surface contact with foreign

substancesc. PTT

Extrinsic Pathway-initiated: activation tissue thromboplastin

a. cell injury endothelium/othersb.PT

PTT = Partial Thromboplastin TimeThe PTT test is used to investigate unexplained bleeding or clotting. Specific evaluation of the coagulation factors XII, XI, IX, VIII, X, V, II (prothrombin), and I (fibrinogen) as well as prekallikrein (PK) and high molecular weight kininogen (HK)

PT = Prothrombin time PT evaluates hemostasis, the process that the body uses to form blood clots to help stop bleeding. A PT test evaluates the coagulation factors VII, X, V, II, and I (fibrinogen).

INRINR (International Normalized Ratio) is also used for patients on what TX??

Factor F X

F IXaF IX

F XIaF XI

Surface ContactCollagenFXII activator

F XIIaF XII

Intrinsic Pathway

Ca2+

Ca2+

Ca2+Factor F X

F VIIF VIIa

F III (Tissue Thromboplastin)

Tissue/Cell Defect

Extrinsic Pathway

Ca2+

Ca2+

FibrinogenFibrinmonomers

Fibrinpolymers

ThrombinProthrombin I

Factor F Xa

Ca2+

Platelet Factor 3

CrosslinkedFibrin Meshwork

F XIIIa F XIII

F VF Va

F VIIIaF VIII

Hemophilia A – Genetic deficiency in Clotting factor VIII

Hemophilia B – Genetic deficiency in Clotting factor IX(Christmas Disease)

Transmission of A & B is via recessive X linked inheritance however 1/3 of cases occur due to spontaneous mutations.

IncidenceAll forms of hemophilia are relatively rare. It affects ALL racial groups and is found worldwide.

Estimated 10,000 individuals with Hemophila in the UK Hemophilia A affects 1 in 5,000 to 10,000 males in the UK Hemophila B affects 1 in 30,000 males in the UK

Source: National Center for Biotechnology Information - http://www.ncbi.nlm.nih.gov

Complex, acquired disorder in which “clotting and hemorrhage simultaneously occur”

DIC is the result of increased protease activity in the blood caused by unregulated release of thrombin with subsequent fibrin formation and accelerated fibrinolysis

Endothelial damage is the primary initiator of DIC

By activating the fibrinolytic system (plasmin), the patient’s fibrin degradation product (FDP) and D-dimer levels will increase

Because of the patient’s clinical state, the disorder has a high mortality rate

Treatment is to remove the stimulus

Clinical signs and symptoms demonstrate wide variability Bleeding from venipuncture sites Bleeding from arterial lines Purpura, petechiae, and hematomas Symmetric cyanosis of the fingers and

toes

denver school of nursing bio 206 / 308 – ch 19 & 20 hemo path

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