Lecture 22 - Blood and Wound Healing

What describes the formation of blood?

hematopoeisis

What describes the maintenance of blood?

hemostasis

What conditions have to do with impaired hematopoeisis?

• sick cell disease

• anemias: iron, vitamin B12, folic acid deficiency; chronic disease/inflammation

What conditions have to do with impaired hemostasis?

• platelet disorders

• coagulation disorders (e.g. hemophilia, von Willebrand disease, clotting factor deficiencies)

• stroke

• wound healing

What is the percent composition of plasma?

• water (92%)

• proteins (7%)

• salts, organic molecules, gases (1%)

What is another name for red blood cells?

erythrocytes

What are platelets split off from?

megakaryocytes

What is the broader term for white blood cells?

leukocytes

What describes the ratio of red blood cells to plasma, expressed as a percentage after centrifugation?

hematocrit

Where are blood cells produced?

in the bone marrow

What describes the production of red blood cells?

erythropoiesis

What describes the production of white blood cells?

leukopoiesis

What is the average volume of one red blood cell?

mean corpuscular volume (MCV)

What is a small unattached cell (diminutive of corpus, body)?

corpuscle

What is the amount of hemoglobin per RBC?

mean corpuscular hemoglobin (MCH)

What is the amount of hemoglobin per volume of one red blood cell?

mean corpuscular hemoglobin concentration (MCHC)

What blood counts are higher in men compared to women?

• hematocrit

• hemoglobin

• red cell count

What are red blood cells (RBC) crucial for, specifically red blood cell hemoglobin (Hb)?

oxygen carrying capacity

About how many hemoglobin molecules does each human red blood cell contain?

270 million

Each iron atom within Hb bind how many oxygen molecules?

one

What is each hemoglobin molecule composed of?

4 globin chains: 2 alpha and 2 beta (each around a heme group)

What does each heme group consist of?

• porphyrin ring

• iron atom at center

What type of scan shows the biconcave disk shape of RBCs?

Scanning Electron Micrographs (SEMs)

What creates the unique shape of RBCs?

cytoskeleton

Where do mature blood cells squeeze through to reach the circulation?

endothelium

What is the stroma composed of?

• fibroblast-like reticular cells

• collagenous fibers

• extracellular matrix

What is erythropoiesis regulated by?

feedback loop

What is erythropoiesis’ feedback loop?

decrease in tissue oxygen concentration → signals the kidneys to increase the production and release of erythropoietin (EPO) into the plasma → increased production and maturation of RBCs

What is the RBC mass under normal circumstances?

kept at an almost constant level by EPO matching new erythrocyte production to the natural rate of loos of RBCs

What is the hemoglobin and red blood cell life cycle?

1. Iron (Fe) ingested from the diet

2. Fe absorbed by active transport

3. Transferring protein transports Fe in plasma

4. Bone marrow uses Fe to make hemoglobin (Hb) as part of RBC synthesis

5. RBCs live about 120 days in the blood

6. spleen destroys old RBCs and converts Hb to bilirubin

7. bilirubin and metabolites are excreted in urine and feces

8. liver metabolites bilirubin and excretes it in bile

9. liver stores excess Fe as ferritin

What is the most common familial hemolytic anemia?

sickle cell anemia

What causes the sickle cell anemia (the prototypic hemoglobinopathy)?

a mutation in beta-globin that creates sickle hemoglobin (HbS)

What is the presence of HbS protective against?

falciparum malaria

Where is the HbS allele prevalent in?

areas where malaria is/was endemic (parts of Africa, India, southern Europe, and the Middle East

In the US, about what percentage of people of African descent are heterozygous HbS carriers?

8%

About what ratio of heterozygous HbS carrier have sickle cell anemia?

1 in 600

Initially, is sickling of red cells reversible on reoxygenation?

yes

What does membrane distortion produced by each sickling episode lead to?

damage of the membrane skeleton → irreversibly sickled cells that are prone to hemolysis

What are two major pathologic consequences of sickle cell anemia disease?

1. red cell membrane damage → chronic moderately severe hemolytic anemia

2. vascular obstructions → ischemic tissue damage and pain crises

About what percentage of the world’s population does anemia affect?

25%

What is the group of diseases characterized by a decrease in either Hb or circulating red blood cells (RBCs) resulting in reduced oxygen-carrying capacity of the blood?

anemia

What can anemia result from?

• inadequate RBC production

• increased RBC destruction

• blood loss

What is a hemorrhage directly associated with?

blood loss

What are production related anemias?

• folate/vitamin B12 deficiency (limits RBC production)

• iron deficiency (limits hemoglobin production)

What are destruction (inflammation/hemolytic) related anemias?

• inflammation

• autoimmune (marked for premature destruction)

• drug induced immune (marked for premature destruction)

• drug induced hemolytic (marked for premature destruction)

What does hemostasis involve?

• platelets

• clotting factors

• endothelium

Where does hemostasis occur at?

site of vascular injury

What does hemostasis lead to?

formation of a blood clot (serves to prevent or limit the extent of bleeding)

How does primary hemostasis keep blood inside damaged blood vessel?

• vasoconstriction

• platelet plug

• coagulation

How does secondary hemostasis involved the coagulation cascade for the deposition of fibrin and clot stabilization?

• maturity of the platelet plug

• production of fibrin

What are the four mechanisms that facilitate hemostasis?

1. vascular constriction

2. primary platelet plug formation (primary hemostasis)

3. clot propagation through fibrin formation (secondary hemostasis

4. clot breakdown through fibrinolysis (breakdown of clots)

What is the mechanism of platelet plug formation?

1. exposed collagen binds and activates platelets

2. release of platelet factors

3. factors attract more platelets

4. platelets aggregate into platelet plug

What is platelet adhesion largely mediated by?

interactions with vWF

What does vWF act as?

a bridge between the platelet surface receptor glycoprotein lb (Gplb) and exposed collagen

What do platelets rapidly change shape rollowing?

adhesion (conformational change)

What do smooth disc platelets convert to?

spiky “sea urchins” with greatly increased surface area

Along with platelet changes in shape, what other event occurs to create platelet activation?

secretion of granule contents

What does the conformation change that occurs with platelet activation allow?

binding of fibrinogen, that forms bridges between activated platelets, leading to their aggregation

What does the balance between the anticoagulant and procoagulant activities determine?

• clot formation

• propagation

• dissolution

What can antithrombotic properties of endothelium be divided into?

• activities directed at platelets

• coagulation factors

• fibrinolysis

What may bleeding disorders stem from?

• abnormalities of vessels (including supportive connective tissue)

• platelets

• coagulation factors

(alone or in combination)

• systemic conditions that inflame or damage endothelial cells

• deficiencies of platelets (thrombocytopenia)

What may disorders of primary hemostasis be due to?

1. increased destruction of platelets, which can be immune-mediated or non-immune-mediated

2. decreased production of platelets

3. platelet dysfunction

What describes the immune reaction to the use of heparin, leading to paradoxical hypercoagulation, and reduced platelet count?

Heparin-Induced thrombocytopenia (HIT syndrome)

What are examples of diseases of inherited defects involving coagulation factors?

• Hemophilia A

• von Willebrand disease

What clotting factor do people with hemophilia A lack?

clotting factor VIII

What clotting factor do people with hemophilia B lack?

clotting factor IX

What clotting factor do people with hemophilia C lack?

clotting factor XI

What describes an abnormally high tendency of the blood to clot and is usually caused by alteration in coagulation factors?

hypercoagulability

What is hypercoagulability an important risk factor for?

thombosis

Alterations that lead to hypercoagulability can be divided into what groups of disorders?

1. primary (genetic)

2. secondary (acquired)

What describes a solid mass within a chamber of the heart or within a blood vessel?

thrombus

Where can thrombi develop?

anywhere in the cardiovascular system

What are factors predisposing to thrombus formation (ie. Virchow triad)?

• stasis of blood

• hypercoagulability

• endothelial damage

What is a common predisposing condition in patient who develop venous thrombi?

stasis of blood

Where does endothelial damage play a major role?

in many arterial thrombi

What hereditary conditions are predisposing to thrombosis (i.e. primary hypercoagulable states)?

• Factor V Leiden mutation

• prothrombin gene mutation

What is the incidence of factor V Leiden mutation in the Caucasian population?

2-15%

What hereditary condition predisposing to thrombosis causes an elevated level of prothrombin?

prothrombin gene mutation

What is the incidence of prothrombin gene mutation of the general population?

prothrombin gene mutation

What are acquired states predisposing to thrombosis (i.e. secondary hypercoagulable states)?

• myocardial infarct

• tissue damage (e.g. surgery, trauma, burns)

• cancer

• prosthetic cardiac valves

• disseminated intravascular coagulation (DIC)

• heparin-induced thrombocytopenia

• anti-phospholipid antibody syndrome

What are the fates of thrombi?

• propagation

• organization

• recanalization

• dissolution

• embolization

In Virchow’s Triad, what conditions are in the hypercoagulable state?

• malignancy (diagnosed or occult)

• pregnancy/post-partum

• inflammatory bowel disease

• nephrotic syndrome

In Virchow’s Triad, what drugs are in the hypercoagulable state?

• estrogen contraceptives

• estrogen

• tamoxifen, raloxifene

In Virchow’s Triad, what are the thrombophilia in the hypercoagulable state?

• antiphospholipid antibodies

• prothrombin gene mutation

• protein S or C deficiency

• Factor V Leiden

• antithrombin deficiency

• factor VIII/XI excess

In Virchow’s Triad, what is included in the endothelial injury?

• trauma/surgery

• venopunctures

• chemical irritation

• indwelling catheters

• atherosclerosis

In Virchow’s Triad, what is included in the circulatory stasis?

• immobility/paralysis

• surgery: >30min gen anesthesia

• obesity

• acute medical illness requiring

• hospitalization

What is Transient Ischemic Attack (TIA) caused by?

systemic activation of coagulation

What does Transient Ischemic Attack (TIA) result in?

formation of thrombi throughout the microcirculation

What are the consequences of Transient Ischemic Attack (TIA)?

1. platelets and coagulation factors are consumed

2. fibrinolysis is activated

widespread activation of both the coagulation system and the fibrinolytic system

What is the mechanism of a Transient Ischemic Attach (TIA)?

release of tissue factor and widespread damage to endothelial cells

What is a detached thrombus (intravascular solid, liquid, or gaseous mass) that is carried by the blood from its point of origin to a distant site?

embolus

What does an embolus usually do the a distant site?

tissue dysfunction or infarction

What describes the vast majority of emboli derive from dislodged thrombi?

thromboembolism

Less commonly, what are emboli composed of?

• fat droplets

• bubbles of air or nitrogen

• atherosclerotic debris (cholesterol emboli)

• tumor fragments

• bits of bone marrow

• amniotic fluid

What eventually happens to emboli in embolism?

emboli lodge in vessels too small to permit further passage → partial or complete vascular occlusion → depending on their origin, emboli may arrest anywhere in the vascular tree

What is the primary consequence of system embolization?

ischemic necrosis (infarction) of downstream tissues, except for pulmonary circulation

Where do pulmonary emboli originate from?

deep venous thrombi

What are pulmonary emboli responsible for?

most common form of thromboembolic disease

What are complications of pulmonary thromboemboli?

• sudden death

• pulmonary infarct

• pulmonary hypertension