Heme Flashcards
Variations in normal hemoglobin
Fetal hgb and polycythemia
Hemolytic disease of the new born
Aging (men decrease in testosterone) is not physiologic
Altitude greater than 1000 meters above sea level
Smoking increases carboxyhemoglobin increase in hgb to compensate
Removal and byproducts of RBCs
Life span about 120 days
Removed by macrophages (spleen)
Cells decrease ATP-cell membrane becomes more frail and digested by preolytic and lipolytic enzymes in phagolysosomes
Heme and globulin dissociate-iron is recycle as ferritin and globulin becomes amino acid
Metabolism of bilirubin
Porphyria reduces to unconjugated bilirubin
Conjugated (water and soluble) excreted by liver, intestine or bile
Bacteria in intestinal linen=conjugated bilirubin to urobilinogen
Excreted in feces
Some is reabsorbed and excreted by the kidneys
Gallstone if chronically elevated bili excretion
Oxygen dissociation curve
Right
High pCO2, low affinity for 02, high hydrogen, low pH, high 2-3 DPG, high temp
Left
Low pCO2, low hydrogen, low 2,3 DPG, low temp
HbA
Alpha 2 beta 2 92% of adult hgb
HbA1c
Alpha 2 (beta Nh glucose) 5% of adult hgb, high in DM
HbA2
Alpha 2 beta 2-2% of adult hgb high in beta thalassemia
HbF
Alpha 2 Y 2 major fetal hgb from 3rd to 9th month of gestation, promotes o2 transfer across platelets, high in beta thalassemia
Hb grower 1,2 and Hb Portland
Present in early embryo, function unknown
Trigger of RBC production
Low o2 due to anemia/hypoxia
Decreased blood volume
Poor blood flow
Pulmonary disease
Increased levels of androgens
Key components of a hemoglobin molecule
Krebs cycle form succinylco-A
Each molecule has 2 polypeptide chain globulins alpha and beta
4 components of the iron plus protoporphyrin (heme)
Heme synthesized in the mitochondria can carry one molecule of 02 each
Protoporphyrin bound with ferrous iron (binding oxidizes to Fe2+ to oxyhemoglobin) releases 02 deoxyhemoglobin without the reaction Fe 3+ Hb (methoemoglobin) cannot bind to 02
4 components of sets of alpha and beta each can carry one 02 molecule (max 4 molecule per RBC)
Hematopoiesis
7 days
Controlled by erythropoietin in the kidneys tissue 02 levels stimulate bone marrow
Flat bones of pelvis, vertebrae, cranium and mandible
Transcription of erythropoietin is mediated by hypoxia induced factor 1
Epo binds to receptors and stimulates erythroid cell division and proliferation and inhibits apoptosis
In infants process starts in the yolk sac then switches to liver at two months after birth goes to marrow
If extra RBC are needed process occurs in liver and spleen
Pluripotent
Pluripotential hematopoietic stems cells in the bone marrow differentiate
Committed stem cells turn into colony forming units then blastocysts and immature RBC erythroblasts, reticulocytes and then erythrocytes
Anemia
Reduction in total erythrocytes, hgb, hct
Women hgb less than 12
Men hgb less than 13
MCV
Mean corpuscular volume aka size
MCHC
Mean corpuscular hemoglobin concentration aka amount of hgb in RBC compared to size and color
RDW
Red cell distribution width
Microcytic anemia
MCV less than 80
If serum iron and ferritin low-iron deficiency anemia
If serum urine normal or elevated, serum ferritin normal or elevated, or TIBC normal, hgb electrophoresis normal is alpha abnormal in beta- thalassemias
Serum iron normal or deceased, serum ferritin normal or elevated, TIBC normal or decreased, hgb electrophoresis is normal-chronic disease
Normocytic Anemia
MCV 80-100
Causes acute blood loss, chronic disease, hemolysis, infection, inflammation, malignancy, renal insufficiency, sickle cell
Marcocytic anemia
MCV greater than 100
If serum B12 low, hemocysteine elevated, serum folate low
Then test methylmaloic acid
If elevated- vitamin B12 deficiency
If normal- folate deficiency
If serum B 12 and folate are normal causes include alcoholism, bone marrow disease, hypothyroidism, liver disease, medication like chemotherapy and antivirals
Iron studies
Iron 70% in hgb/30% stored
Ferritin-acute phase reactant/amount stored of iron
Transferrin-ability of body to transport
Iron brining capacity (TIBC) protein available to bind iron (high in iron deficiency anemia, low in inflammatory or malignancy)
Types of anemia
Anemia of chronic illness, hemolytic, aplastic, sickle cell, pernicious, folate deficiency
Anemia of chronic illness
Rule out diagnosis
2nd most common
Due to chronic infection, inflammation, chronic disease
Pro inflammatory cytokines, inhibit erythropoietin production. Destroys immature erythroblasts
Stimulates release of hepicidin- control irons absorption in blood and GI tract, blocks release of iron reticuloendothelial system, decreases oral iron absorption leading to deficiency
Hemolytic anemia
Destruction of RBCs due to genetics, ABO incompatibility, autoimmune (lupus, RA), drugs (NSAID, cephalosporins) newborns- hyperbilirubinemia,
High bili, high pH, high uric acid, high hemoglubinuria, decreased haptoglobin
Aplastic anemia
Usually stem cell disorder
Congenital, chemo, viral, autoimmune
Bone marrow bx
All cells lines down
Iron deficiency anemia
Chronic blood loss, diet, malabsorption, pregnancy, increase in children during growth periods
Sickle cell
Autosomal recessive-hemolytic
Disease or trait
1:500 AA
hgb low 02 capacity
Exacerbations/crisis-infection, dehydration, hypoxia, vasoocclusion, pain
Increased risk for MI, CVA, pulm injury.
Pernicious anemia
Low B12
Less effective DNA synthesis and short RBC life
Unable to absorb B12 (lack intrinsic factor), dietary, autoimmune
Parasthesias, balance, oral pain, increase in homocysteine
Folate deficiency anemia
Impaired RNA/DNA synthesis
Dietary deficiency, poor absorption, drugs (ASA) maternal deficiency can results in neural tube defects
Decreased RBC production, decreased reticulo count, normocytic and normochromatic
Aplastic or anemia of inflammation
Decrease RBC, decreased reticulo count, macrocytic, normochromatic, low B 12 level
Pernicious anemia
Decrease RBC, decreased reticulo count, microcytic and hypochromatic
Iron deficiency anemia
Anemia low hgb low hct normochromatic normocytic
Acute blood loss
Thalassemia
Autosomal recessive disorder alpha and beta types, mutation on HBB gene
Effect synthesis of hgb A-change in ratio changes the structure of hgb making RBC less stable and more likely to break down
Alpha is less severe than beta
Risk of iron overload- hemosiderosis
Increases RBC increases reticulo abnormal shapes, inherited
Sickle cell, spherocytosis, thalassemia
Increases RBC increases reticulo, schistocytea, acquired
Autoimmune hemolytic anemia
Agranular leukocytes
-cyte cells
Lymphocytes 20-25%, monocytes 5-10%
Lifespan: Weeks to months for lymph, monk 10-20 hours in blood, months in tissue
Role: lymph-ID and neutralize foreign organisms, develop T and B cells, mono-phagocytosis
High lymph count indicates infection and inflammation, low with steroids
High Mono count indicates myelodyplasia, Protozoa, rickettsia
Granular leukocytes
-Phil cells
Neutrophils 60-70%, eosinophils 2-4%, basophils 1%, Seg or polys
Life span: in blood 4-8 hours, tissue 4-5 days
Role: neutrophils are 1st responders, eosinophils-allergy/parasites, mast cells
Leukemia
Leukocytes in BM -/+
Overproduction-crowds marrow can’t produce other cells, other organs are infiltrated with leukocytes (spleen, liver, lymph, CNS)
Types: two types: myelodysplastic (acute myeloid leukemia) and lymphoid
(Acute lymphoblastic leukemia, chronic lymphocytic leukemia)
Acute myloid leukemia
Myelodysplatic type
Epigenetic alterations
Myeloproliferative neoplasms, chronic myeloid, polycythemia Vera, essential thrombocytopenia
Acute lymphoblastic leukemia
Lymphoid type
Philadelphia chromosome
Chronic lymphocytic leukemia
Lymphoid type
Philadelphia chromosome
B cells fail to mature needed for humoral immunity increases risk for encapsulated infections
Lymphoma
Proliferation of lymphocytes into lymph system
Three types: Hodkins, non hodkins, burkitts
Hodkins lymphoma
B cell (reed stern berg) common risk factor is EBV
Presents as mediastinal node
Non Hodkins lymphoma
Heterogenous B cell, T cell and NK cell
Common risk factor is hereditary, chemical, EBV, HHV-8, HIV, hep C, transplant suppression
Presents as nodes in neck, groin, axilla
Burkitts lymphoma
B cells
Common risk factor is EBV, peds
Presents as jaw, facial, bone and abd node enlargement
Myeloma
Clonal plasma cell cancer producing a monoclonal immunoglobulin
Proliferation of plasma cells in bone marrow does not allow for production of other cells lines
Type multiple myeloma
Multiple myeloma
Plasma cell-slow proliferation in bone marrow, increase in IgG, bence jones protein in urine,
Lytic bone disease- myeloma cells, hepatic growth/parathyroid hormone, cytokines/osteoclast activation/increase bone reabsorption cause bone lesions and increase in serum Ca
Fractures and Renal failure
Vascular injury
Results in vasospams, smooth muscle constricts, local humoral response activates substances vessel endothelium, platelets arrive, secrete thromboxane
Increase platelets expression/aggregation low dose ASA inhibits
Hemostatic platelet plug formation
Occludes small vascular disruptions without activating coag cascade
Three steps adhesion, activation and aggregation
Platelets adhere to exposed collagen become sticky and adhere to collagen and von wildebrand factor
Activation: platelets change shape and form pseudopods and activates archidonic pathway
Aggregation: stabilization or platelet plug requires coag factors-thromboxane
Clot formation
Coag cascade triggers (15-20 seconds) 1-2 minutes of bleeding is not stopped by plug
May be triggered by immune or inflammatory response
Platelets aggregation and fibrin thread form true clot in 3-6 minutes
20-60 minute clot retracts to further occlude
Extrinsic clotting pathway
Also called tissue factor pathway
Release by damaged endothelial cells if the blood vessels and activated factor VII (VIIa)
Primary role
Measures by PT
Leads to common pathway, converge at factor X and thrombin
Intrinsic clotting pathway
Also called contact activation pathway
Vessel wall damage causes negatively charged endothelial substents to come into contact with hageman factor (XII)
Role is to support extrinsic
Measures by PTT
Leads to common pathway converge at factor X and thrombin
Common clotting pathway
Role in both prothrombin activation
Measures by factor VII, V, X, PT, fibrinogen
Leads to fibrin clot (stops bleeding, prevents spread of inflammation and infection Lee invaders near site of injury initiates formation of 2 fibrinopeptides A&B) chemotatic for neutrophils and increases vacuole permeability, provide a network for healing
Clotting system can be activated by
Extrinsic and intrinsic pathways. Both routes lead to activated of factor X and thrombin. Thrombin is on an Wayne that activates fibrinogen do form for in and small FPs. Fibrin comes together to form a clot FPs are highly active chemotatic factors and cause increase in vascular permeability
Common sequence of extrinsic and intrinsic pathway
Vascular damage- prothrombin
Prothrombin-thrombin
Thrombin (enzyme) fibrinogen- fibrin-clot
Factor V Leiden
CLOTTING
Autosomal dominant
Factor Va resists activated protein C lacks breakdown causes excess thrombin
Antiphospholipid syndrome
CLOTTING
acquired, autoimmune antibodies to plasma proteins and clotting factors
Complications in pregnancy
Thrombotic thrombocytopenic purpura (TTP)
CLOTTING
Generic/autoimmune
High amounts of VWF lacks enzymes to breakdown and platelets aggregate
Thrombocytopenia
Micro vascular thrombi
Immune thrombocytopenic purpura
BLEEDING
acquired
Viral, time limited
Platelets phagocytized by macrophages causing too few platelets
Presented to CD4 cells IgG antibodies bind to platelets no problem with bone marrow
Hemophilia A
BLEEDING
Inherited/genetic
X linked recessive common deficiency in factor VIII
aPTT high.PT normal platelets normal (intrinsic pathway)
Hemophilia B
BLEEDING
Inherited/genetic
X linked recessive deficiency in factor XI
aPTT high.PT normal platelets normal (intrinsic pathway)
Von wildebrand factor
Helps platelets adhere to one another
Too high- TTP
Too low- von wildebrand disease
Von wildebrand disease
BLEEDING
Disorder of clotting factor that results in bleeding
Inherited autosomal dominate
Low levels of VWF and factor VIII
Low levels lead to decreased platelets and adhesion which leads to bleeding
DIC
CLOTTING AND BLEEDING
widespread clotting may lead to blockage or blood flow to organs and lead to multi organ failure
Excess in clotting may consume platelets and clotting factors results in bleeding in setting of widespread clotting
Release of procoagulants (tissue factors) wide spread endothelial injury-micro vascular clots-trauma, sepsis, CA
Labs Low platelets low clotting factors, high PT, aPTT, d dimer
Microvascular clots cause distal tissue injury ischemic tissues
Virchows triad
For hyper coagulable disorders
Hyper coagulable state
Vessel damage
Venous stasis
Factors related to risk of acquires thrombosis
Arterial or venous
Immobile, MI, CA, obesity, estrogen therapy, pregnancy, sickle cell
Embolism
Prevention
Intervention-ASA, heparin, mobilize and decrease stasis
Protein essential for clot dissolution
Thrombin and plasminogen activators
Thrombin absorbed by fibrin fibers
Antithrombin III (AT3) blocks thrombin on fibrinogen inactivating thrombin
Heparin with AT 3 increases removal of thrombin 100 fold removed XIIa, XIa, Xa
Plasminogen activators- plasmin, clot formation plasminogen trapped, endothelium release tissue plasminogen activator (tpa) converts plasminogen to remove clot after vessel healed, proteolytic enzymes: digest fibrin fibers, fibrinogen, prothrombin, and factors V. VIII, XII
Aging and coagulation
Blood clots move easily levels of fibrinogen factor V, VII, IX, VWF, increase platelet activation
Less active and chromic inflammation
Hemostasis
Prevention of blood loss through vascular spasm, formation of platelet plug and formation of fibrous clot
Categorizing leukemias
Acute- blast cells are present or chronic-well differentiated cells
Lymphocytic-too many lymphoblastic
Or myelogenous- too many myeloblast
Inherited coagulopathies
Von wildebrand disease
Factor V lidien, protein c deficiency, protein s deficiency
Acquired coagulopathies
Uremia
Antiphospholioid syndrome, cancer, pregnancy
