Week 8

Question 1

explain the Rh blood types and how typing is done

Answer 1

Rh factor (named for the rhesus monkey) includes an antigen termed D or Rho(D). If this Rh antigen is present on red blood cells, the person is Rh positive and if it is not present they are Rh negative. The genes associated with positive and negative are D and d where D is dominant so a Dd person is Rh positive. There are NO naturally occurring antibodies for the Rh antigen but people who are Rh negative will make anti-Rh antibodies if they are exposed to positive Rh blood cells (like transfusion or pregnancy).

Typing is done with reagent anti-D antisera added to blood sample. If agglutination occurs = Rh positive. positive is way more common (85% of Caucasian people)

Question 2

**What is the term for the condition occurring in a baby with an incompatible blood type to their mother? explain what causes this problem and the resulting issues

Answer 2

Erythroblastosis fetalis or Hemolytic disease of the newborn. Normally fetal and maternal blood are kept separate across the placenta, so an Rh-NEGATIVE mother is not exposed to an Rh-POSITIVE fetus. Sometimes at birth the placenta tears away and exposure may occur, causing the mother to produce anti-Rh antibodies. This is a problem for future babies that are Rh-positive because the mother’s immune system (specifically immunoglobulin G (IGG) antibodies which are small enough to cross placenta) will destroy the fetus RBCs. The result is a child with high bilirubin, a toxic breakdown product of hemoglobin, leading to jaundice AFTER birth and kernicterus (permanent brain damage).

remember that this only occurs if mom is Rh-negative and baby is Rh-positive. It is permanent and effects ALL of the NEXT children to be conceived, not the first one or the mom. it can rarely occur with ABO incompatibility

Question 3

**What are treatments and prevention for erythroblastosis fetalis (hemolytic disease of the newborn)

Answer 3

Mild cases of jaundice treated by phototherapy with blue light
Serious cases can be treated by an Exchange Blood Transfusion where all of the baby’s blood is replaced with a donor blood, usually O negative. the different blood type lasts about 3-4 months (lifespan of erythrocytes) and by then all the maternal anti-Rh antibodies are gone

Prevention is caused by injecting the mother with RhoGAM, an antibody against Rh, in small doses right after birth or at 28 weeks. This is a passive immunization where the injected antibodies inactivate Rh antigens to mask them from mother’s immune system OR they inhibit the mother’s immune system (via negative feedback) to prevent the mother from making her own anti-Rh antibodies. Thus, she is not sensitized to the Rh antigen.

Question 4

what are the three mechanisms that promote hemostasis and what protein activates the process

Answer 4

hemostasis = cessation of bleeding after blood vessel injury.
Collagen is exposed after breakage of the endothelial lining of a vessel. This protein causes clotting when detecting foreign materials in three steps:
1. vasoconstriction
2. formation of a platelet plug
3. production of a web of fibrin proteins that penetrates and surrounds the platelet plug

Question 5

how does vasoconstriction occur? in what blood vessels does it occur?

Answer 5

It is most effective in small veins, larger arteries usually require outside help to control bleeding (apply pressure). All blood vessels - except capillaries - undergo vasoconstriction as the platelets are activated and attach in a blood clot, releasing serotonin which stimulates constriction of smooth muscles (vessels). This doesn’t last long, but when the vessel relaxes the damage should be plugged by platelets

Question 6

what are platelets and what is the term for a low platelet count and the symptoms?

Answer 6

Platelets or Thrombocytes are cytoplasmic fragments of large megakaryocyte cells. They maintain health and integrity of the endothelium and are destroyed by the spleen or liver (spleen removal can increase platelet count!)

Thrombocytopenia is low platelets in the blood. Causes petechia (pin-prick skin bleeds), purpura (bruising), and epistaxis (nosebleeds).

Question 7

why is erythroblastosis fetalis called that?

Answer 7

Erythroblastosis because due to the hemolysis the bone marrow is pressured to produce lots of erythrocytes to compensate. it will start releasing immature erythroblast cells into the blood stream, so hence erythroblastosis

Question 8

what are possible causes of low platelet count?

Answer 8

Thrombocytopenia can be caused by low production or increased breakdown due to leukemia, drugs, or autoimmune attack. Drug induced thrombocytopenia purpura is due to haptens (molecules too small to stimulate antibody response) that bind platelets and cause antibodies to recognize platelets and attack, Penicillin is a drug which can cause this. Idiopathic Thrombocytopenia Purpura is reduction of platelets for an unknown reason, leading to bruising.

Question 9

what is clot retraction?

Answer 9

The platelets contain a lot of filaments (similar to actin/myosin) which contract and cause compression and strengthening of the platelet plug. So bleeding stops when the platelets plug the hole and this is the primary sealer of breaks in vessel walls.

Question 10

what stops platelets from clotting when there is no vessel damage

Answer 10

The endothelium physically separates the blood from collagen and other platelet activators. Endothelial cells also secrete prostacyclin (PGI2, a type of prostaglandin) and nitric oxide (NO) which act as vasodilators and inhibit platelet aggregation. The membrane of endothelial cells also contains CD39 which breaks down ADP in the blood into AMP and Pi, which inhibits platelet aggregation.

Question 11

What is the platelet response when blood vessel endothelium is broken? Specifically, what do they bind and what molecule helps this binding occur

Answer 11

Ruptured endothelium exposes collagen fibers which the platelets bind to. The force of blood flow might pull the platelets off the collagen if it weren’t for Von Willebrand’s Factor, a protein produced by endothelial cells that binds to both collagen and platelets. Binding of glycoprotein receptors on the platelets membrane to VWF helps anchor the platelets to the site of injury agains the shear force of blood flow.

Question 12

What happens in the Platelet Release Reaction

Answer 12

Platelets stick to collagen and then degranulate as their secretory granules release products. The products released are adenosine diphosphate (ADP), serotonin, and thromboxane A2 (a prostaglandin). The ADP and thromboxane A2 recruit new platelets to stick to the platelets on the collagen. The second layer of platelets then undergoes the platelet release reaction and causes more platelets to aggregate. This positive feedback loop produces a Platelet Plug.

Question 13

**The platelet plug will FAIL unless it is reinforced with what? describe the pathway that produces this reinforcement

Answer 13

Fibrin, converted from fibrinogen (a plasma protein). Fibrin is obtained via two pathways:

1. Intrinsic pathway initiated by exposure of plasma to hydrophilic surfaces in vitro (glass) or to negatively charged structs in vivo (collagen, polyphosphates, neutrophil extracellular traps NETs). This Contact Pathway activates factor XII, which activates XI, which activates IX, which activates X, which converts prothrombin (factor II) to thrombin, which converts fibrinogen to fibrin.
2. Extrinsic pathway initiated by tissue factor/thromboplastin/factor III found inside walls of blood vessels and tissue cells. Tissue factor activates factor VII which activates X (and IX) which converts prothrombin (factor II) to thrombin, which converts fibrinogen to fibrin.

Question 14

which clotting factors are made by the liver? what molecule has to be present for their synthesis?

Answer 14

II (prothrombin), VII, IX, and X are made by the liver and require vitamin K. Hence they are called vitamin K-dependent clotting factors. Fibrinogen is also produced in the liver. Liver disease can thus cause hemorrhaging due to impaired blood clotting.

Question 15

What is the essential cofactor required for clotting? which steps is it required for?

Answer 15

Calcium. IX activating X and X activating II (prothrombin)

This is noteworthy because anticoagulation drugs often target calcium. If there is no calcium available, then no clotting will occur.

Question 16

What clotting response occurs in a transfusion reaction?

Answer 16

The extrinsic pathway of clot formation occurs as Tissue Factor (tissue thromboplastin, factor III) is released. This can lead to a sever clotting abnormality called DIC.

Question 17

Which pathway is most important in vivo?

Answer 17

The extrinsic pathway forms clots in vivo while the intrinsic pathway plays an amplification role. This is probably because the extrinsic is much faster (less reactions to do)

Question 18

What molecule is exposed on the surface of activated platelets and what does it do

Answer 18

Phosphatidylserine. This anchors factor VIII and V complexes to the platelet surface to greatly increase formation of thrombin.

Question 19

What color are blood clots in arteries and why

Answer 19

Gray because usually clots are red due to trapped RBCs in the clot, but in arteries blood flow is more rapid and clots generally lack RBCs

Question 20

What is serum

Answer 20

Fluid is squeezed from a clot as it undergoes clot retraction. This fluid is serum, which is plasma without fibrinogen so it does not clot. In labs, serum is obtained by allowing blood to clot and then centrifuging to remove the clot and RBCs

Question 21

How are blood clots removed in vivo?

Answer 21

Factor XII promotes a molecule called kallikrein which converts plasminogen to plasmin. Other agents that convert plasminogen to active plasmin are tissue plasminogen activator (TPA), urokinase, and streptokinase. TPA is released into the blood very slowly by damaged endothelium of blood vessels and activates plasmin. The plasminogen was incorporated into the clot when it formed (thanks to factor XII) and as it slowly activates to plasmin (thanks to TPA or other molecules) it digests fibrin into “split products” and dissolves the clot.

Question 22

What is the term for a dangerous blood clot? What conditions may cause excessive clotting disorders?

Answer 22

Thrombus: a blood clot that obstructs a blood vessel.
Could be due to a hypercoagulable state (abnormal tendency to form clots) from birth control pills especially while also smoking, an inherited genetic defect like factor V Leiden, being bedridden which reduces blood flow in lower extremities, or abnormal vessel lining (atherosclerosis, varicose veins, phlebitis, infection).

Question 23

What problems result from thrombi?

Answer 23

Can obstruct blood vessels and cause heart attacks or strokes. When a thrombus moves away from site of formation it is called an Embolus. Thrombi frequently form in leg veins and then travel as emboli to the lungs - this is called a Pulmonary Embolism. Emboli cause damaging obstructions, blocking blood flow and leading to infarction (tissue necrosis from blood flow insufficiency). Thrombi from the left heart can travel to the brain!

Question 24

What is atresia and when/why does it occur

Answer 24

Follicle atresia is degeneration via apoptosis of secondary follicles. This occurs about 10-14 days after first day of menstruation because only one follicle has continued its growth to become a fully mature Graafian follicle. The other secondary follicles become atretic. Paracrine regulators like androgens and FAS ligand promote follicle atresia while gonadotropins LH and FSH as well as estrogen prevent atresia.

Question 25

Describe the process of ovulation and what happens to the released oocyte

Answer 25

Hormonal stimulation causes a mature Graafian follicle (protected from atresia) to become so large that it forms a bulge on the ovary surface. The follicle ruptures and extrudes its oocyte into the peritoneal cavity in the process of Ovulation.
This released oocyte is a Secondary Oocyte surrounded by a Zone pellucida and Corona radiata. It will degenerate in 24 hours to a few days unless fertilized by a sperm. If sperm passes through zona pellucida and corona radiata the oocyte completes the second meiotic division and is a zygote

Question 26

what changes occur in the ovary after ovulation

Answer 26

The empty follicle is influenced by LH to become a corpus luteum (yellow body) which secretes two sex steroid hormones: estradiol and progesterone. (Ovarian follicles only secrete estradiol). The corpus luteum regresses towards the end of a non fertile cycle to become a corpus albicans (white body) which is non functional.

Question 27

review the hypothalamic-pituitary-ovarian axis

Answer 27

Hypothalamus secretes a single gonadotropin releasing hormone (GnRH) which signals the anterior pituitary to secrete FSH and LH. These both signal cyclic changes in the ovaries. The ovaries secrete estradiol cyclically and progesterone only after ovulation (from corpus luteum). These steroids have feedback effects on GnRH, LH, and FSH.

Question 28

What systemic effects does estradiol have? How does this impact post-menopausal women?

Answer 28

Increases nitric oxide = vasodilation = lower vascular resistance in women
Increases HDL cholesterol (the good cholesterol) and reduces risk of atherosclerosis and cardiovascular disease

After menopause there is an estrogen decline and a woman’s risk of cardiovascular disease increases

Question 29

What is the Menstrual cycle vs the Estrous cycle?

Answer 29

Menstrual cycle: in humans, apes, and old world monkeys there is a one-month cycle of ovarian activity. Menstruation is the shedding of the stratum functionale which thickens each month and is accompanied by bleeding. Menstrual mammals can have sexual intercourse any time of the cycle

Estrous cycle: nonprimate mammals are only sexually receptive (in “heat”) at particular times in their cycles. There is no menstrual bleeding, although some bleeding can occur because of high estrogen, not endometrium shedding!

Question 30

Describe all the steps in the follicular phase of menstruation. Describe the hormones responsible for the events

Answer 30

Begins with menstruation on Day 1. Ovarian steroid hormones are at their lowest during menstruation days (1-5), ovaries contain primordial and primary follicles. Secondary follicles grow after menstruation. Towards the end of follicular phase, ONE follicle in one ovary reaches maturity (Graafian follicle). Estradiol is increased by granulosa secretions and is highest about day 12 making the Estrogen Surge: causes increased sex drive (libido), increases GnRH pulses, increases LH secretion, culminating in a LH Surge which triggers ovulation! (note the positive feedback occurring here)

FSH causes the follicular growth and estrogen secretion through all of this. Increased sensitivity to FSH occurs by estradiol which causes production of more FSH receptors in granulosa cells. So effect of FSH increases despite FSH levels staying the same. LH receptors are stimulated to produce at the end of the phase

Question 31

What is the name for abdominal pain occurring with ovulation

Answer 31

Mittelschmerz. occurs in women as the follicle ruptures to release an egg

Question 32

Name 5 commonly used anticoagulants and how they work

Answer 32

1. Aspirin: permanently damages ability of platelets to aggregate
2. Sodium Citrate or Ethylenediaminetetraacetic acid (EDTA): chelate calcium which is an essential clotting cofactor in factor IX and X. sodium citrate is used in blood bags. easily reversible by adding calcium excess or by body’s metabolism of sodium citrate (CAC)
3. Heparin: activates antithrombin III to inactivate thrombin - acts immediately!!
4. Warfarin (Coumadin): blocks Vitamin K Epoxide Reductase which reduces oxidized vitamin K back to its active form. Gamma-glutamyl carboxylase (in liver) needs activated vitamin K to produce clotting factors II, VII, IX, X. Most common oral anticoagulant. Because of the indirect mechanism, warfarin takes several days to be effective as existing vitamin K needs to be used up.
5. Rivaroxaban (Xarelto): directly inhibits factor X

Question 33

What anticoagulants would you use in an emergency situation? What about for a long term treatment/prevention?

Answer 33

Heparin is commonly given intravenously to prevent clotting immediately during emergencies
Warfarin (Coumadin) is the most common oral prescription. It blocks vitamin K epoxide reductase to decrease active vitamin K and decrease liver production of clotting factors II, VII, IX, and X. It takes a few days to kick in because existing vitamin K needs to be used up, so this is a BAD choice for an emergency. As the only oral anticoagulant, it is great for preventing blood clots in people with atrial fibrillation and to treat venous thromboembolism. (Rivaroxaban (Xarelto) is a new oral drug that is becoming available.)

Question 34

What is DIC and what causes it. How to treat?

Answer 34

Disseminated Intravascular Coagulation occurs when a stimulant of coagulation enters the blood and causes wide spread blood clotting which can use up available platelets and clotting proteins, resulting in Consumptive Coagulopathy, so hemorrhaging occurs. Patients clot and bleed simultaneously! Treat with a low heparin dose or give fresh plasma to replace depleted clotting factors. Best treatment is to remove the underlying cause.
Triggered by:
Obstetrical complications (like a retained dead fetus)
Infection (endotoxin is a DIC stimulator)
Cancer
Transfusion reaction
*Schistocytes: fragmented RBCs

Question 35

What are the four chambers of the heart and what separates them

Answer 35

Left and right Atria are located on top and receive venous system blood
left and right Ventricles are located on bottom and pump into arterial system

The Septum separates the left and right atria/ventricle to prevent mixture of blood from the two sides.

a Fibrous Skeleton layer of non-conductive tissue separates atria and ventricles. Myocardial cells in the atria attach to the upper margin of fibrous skeleton to form a myocardium (single functional unit - gap junctions, connexins). Myocardial cells in the ventricles attack to the lower margin and form a DIFFERENT myocardium. Thus, atria and ventricles are structurally and functionally separated. The fibrous skeleton also forms rings called Annuli Fibrosis around the 4 valves to provide support for valve flaps.

Question 36

Describe the pulmonary circulation pathway

Answer 36

Blood that has depleted oxygen content and increased carbon dioxide returns to the right atrium. Then enters the right ventricle, which pumps the blood into the pulmonary trunk and pulmonary arteries. The arteries transport to the lungs where gas exchange occurs between lung capillaries and air sacs (alveoli) of the lungs. Oxygen diffuses into the blood, CO2 diffuses out of the blood. Then the oxygen enriched (bright red) blood returns to the left atrium by the pulmonary veins.

Unlike all other arteries and veins in the body, pulmonary arteries carry low oxygen blood and pulmonary veins carry oxygen rich blood!

Question 37

describe Systemic circulation

Answer 37

oxygen rich blood in the left atrium enters the left ventricle and is pumped into the aorta (very large artery) where it ascends a short distance, makes a U turn, and descends through the thoracic (chest) and abdominal cavities. Arterial branches from the aorta supply oxygen rich blood to all of the organ systems. Oxygen depleted blood (dark maroon) drains from tissues into systemic veins. These veins ultimately empty into the Superior and Inferior Venae Cavae that return the oxygen poor blood to the right atrium.

Question 38

How would you be able to tell left from right ventricles when dissecting a heart?

Answer 38

The left ventricle has a much thicker muscular wall because it performs a much greater amount of work (by a factor of 5-7) than the right. The rate of blood flow has to be matched despite this difference, so the left is built thicker and stronger to keep up with the output of the right.

Question 39

Name the types of heart valves and explain how they open and close. Name the structures that help support closed valves

Answer 39

Within the fibrous skeleton there are one-way Atrioventricular (AV) Valves. Between the right atrium and ventricle the AV valve has three flaps and is called the Tricuspid Valve. Between the left atrium and ventricle the AV valve has two flaps and is called the Mitral or Bicuspid Valve. AV valves allow flow only from atria to ventricles. Opening/closing occurs due to pressure differences. When ventricles are relaxed, the venous return of blood to atria causes pressure in the atria to be greater, so AV valves open to allow blood to enter ventricles! When ventricles contract, intraventricular pressure rises and closes AV valves. The Papillary Muscles and Chordae Tendineae contract in ventricles help to support the closed valve and prevent ventricle contraction from pushing flaps too much and everting them

Question 40

What are platelet aggregation inhibitors use for? What are some commonly used drugs and how do they work?

Answer 40

Platelet aggregation inhibitors prevent clot formation and coronary thrombosis, a major cause of myocardial infarction. Aspirin irreversibly inhibits the enzyme *cyclooxygenase, which is required for prostaglandin formation. Aspirin thus inhibits the ability of platelets to produce the prostaglandin thromboxane A2, which is needed for platelet aggregation. Since platelets are not complete cells, they cannot regenerate new enzymes; aspirin thus inhibits cyclooxygenase for the life of the platelets. Clopidogrel (Plavix) inhibits the ability of ADP to promote platelet aggregation. Dipyridamole interferes with the ability of platelets to produce ADP. Glycoprotein IIb/IIIa drugs are monoclonal antibodies that block the platelet plasma membrane receptors needed for platelets to bind to collagen and to von Willebrand’s factor, preventing platelets from sticking to the wound site.

Question 41

What diseases are caused by an inherited defect in clotting factors? Which factor do they effect?

Answer 41

Hemophilia A is inherited as an X-linked recessive trait which has been prevalent in the royal families of Europe. In hemophilia A, a defect in one subunit of factor VIII prevents this factor from participating in the intrinsic clotting pathway. Von Willebrand’s disease, involving a defect in another subunit of factor VIII, is inherited as an autosomal recessive trait and is the most common bleeding disorder. The clotting difficulty is due to a deficiency of von Willebrand factor, a large glycoprotein needed for rapidly circulating platelets to adhere to collagen at the site of vascular injury. Hemophilia B (Christmas Disease) is inherited as a defective X-linked gene for factor IX. Recent reports of gene therapy for both forms of hemophilia involve the delivery of DNA sequences packaged within viral vectors (carriers).

Question 42

What are thrombolytic agents? Where do we derive them from and what are they helpful for treating?

Answer 42

Thrombolytic agents are drugs that function as protease enzymes to convert plasminogen to plasmin, thereby promoting the dissolution of blood clots. Recombinant DNA technology has allowed the production of tissue plasminogen (fyi, these are a type of Zymogen) activator (t-PA, or alteplase; there is also r-PA, or reteplase), but products derived from Streptococcus bacteria—urokinase and streptokinase—are also used to produce plasmin. These can promote the dissolution of blood clots in the treatment of such conditions as deep vein thrombosis, stroke, coronary thrombosis, and pulmonary embolism. Thrombolytic agents must be used carefully because of the risk of hemorrhage.