Hematology (Week 2--Howard) Flashcards

Question

Causes of anemia (low RBCs or low hemoglobin) due to abnormal Fe metabolism

Answer 1

1) Fe deficiency 2) Defective Fe storage 3) Defective Fe utilization in erythroblasts

Answer 2

1) Increased physiological demand (growing adolescent) 2) Inadequate intake (diet or absorption) 3) Chronic blood loss

Answer 3

Females lose 1mg/day like men but additional 0.5-1mg/day because of menstruation Pregnant women require more (2mg/day) for fetal needs, placenta, and expanded maternal blood volume

Answer 4

1) Defect secondary to chronic disease (TB; this is second most common anemia in the US) 2) Due to **entrapment** of Fe in **macrophages** (results in low plasma Fe, high intracellular/plasma ferritin)

Answer 5

**Hepcidin** is liver peptide that binds/internalizes **ferroportin** in macrophages and duodenal enterocytes so now Fe has no way out of the cell Hepcidin induced by cytokines (so in chronic disease, get low Fe levels in blood but high plasma/intracellular ferritin levels) Note: giving iron doesn't help the problem

Answer 6

**Ferroportin** brings Fe from mother to fetus across placenta Fetal **hepcidin** is present to ensure not too much Fe transported to fetus

Answer 7

Called **sideroblastic anemia** b/c Fe accumulation (as ferritin) in erythroblasts then called sideroblasts (excess ferritin can precipitate to form **hemosiderin**) Can be hereditary (X linked) **defect in heme synthesis** or acquired defect (**lead poisoning** leading to inhibition of heme synthesis enzymes) Note: heme made in erythroblasts of bone marrow (and in liver), and here heme not made correctly

Answer 8

Too much iron in body (absorbed from GI tract) Decreased **hepcidin** activity (because of **defect in HFE**) causes increased Fe absorption from duodenum across ferroportin --\> high plasma Fe levels and Fe accumulation in tissues Clinical effects: bronze skin, liver/heart/pancreas damage, manifests in adults HFE (HLA-linked Fe-loading gene): stimulates hepcidin synthesis Common in Northern Europeans but incomplete penetrance (also depends on diet, etc)

Answer 9

Too much iron in body (absorbed from GI tract) Due to **mutation in hepcidin** or another gene involved in Fe metabolism Manifest early in life and are highly penetrant

Answer 10

A process that minimizes hemorrhage when a blood vessel wall is damaged and that minimizes formation of untimely clots (thrombi) in undamaged vessels

Answer 11

1) Vasoconstriction of damaged vessels (only impt in uterus) 2) Formation of temporary seal by platelets

Answer 12

Formation of a blood clot/fibrin clot (coagulation)

Answer 13

1) **Damage** to blood vessel endothelium 2) Platelets **contact** damaged vessel endothelium 3) Platelets change shape to interact with other platelets better and **adhere** to subendothelium better (using von Willebrand factor in endothelium, etc) 4) Platelets also release **ADP** and **thromboxane** **A2** (by exocytosis), which bind to **other platelets** and trigger their activation 5) Note: remember platelets need to use **von Willebrand factor** (vWf; INSIDE endothelial cells) to bind to vessel endothelium 6) Platelets **accumulate** to entirely fill gap by interacting with other platelets: the plasma protein **fibrinogen** acts as a crossbridge between platelets which all have **GP IIb/IIIa receptors**. Now we have formed the **platelet plug/seal** (Next, platelet plug/seal becomes stabilized by formation of **blood/fibrin clot** (**coagulation**)) Note: activated platelets also release certain growth factors that facilitate healing of injured blood vessels

Answer 14

1) Bind damaged endothelium (triggered by tissue factor then thrombin cleaves thrombin receptor on platelets to activate them) 2) Activated by binding ADP or TxA2

Answer 15

**Prostacyclin (PGI2)** released by normal endothelial cells and **surface integrity** inhibit platelet activation/aggregation

Answer 16

Inhibits hemostasis by blocking platelet activation Inhibits **ADP binding** to receptor on platelets

Answer 17

Inhibits hemostasis by blocking platelet activation COX blocker: blocks synthesis of **TxA2** by blocking COX1 in platelets

Answer 18

Figrinogen helps platelets interact by acting as a **crossbridge** **between 2 platelets** Fibrinogen binds **GP IIb/IIIa receptors** (complex of glycoproteins IIb and IIIa) on platelets

Answer 19

Monoclonal antibody that binds **GPIIb/IIIa** to block those sites so fibrinogen can't bind Is used to decrease risk of thrombus formation

Answer 20

This happens after platelet plug of fibinogen holding platelets together has happened **Intrinsic pathway**: damaged surface --\> kininogen and kallikrein recognize damage and activate XII (Hageman factor) --\> activate XI --\> activate IX --\> VIIIa bound to IXa activates X --\> final common pathway **Extrinsic** **pathway**: trauma --\> activate VII --\> tissue factor bound to VIIa activates X --\> final common pathway **Final** **common** **pathway**: Va with Xa converts prothrombin to thrombin --\> thrombin converts fibrinogen to fibrin --\> XIIIa cross-links fibrin to clot

Answer 21

Soft clot: 3D aggregate of fibrin monomers with no crosslinks Hard clot: covalent bonds between gln and lys resides of adjacent fibrin monomers (crosslinks) created by Factor XIIIa

Answer 22

1) Rapid and efficient 2) No clotting under normal conditions 3) Self-limiting 4) Removal of clots as healing occurs

Answer 23

No fibrin molecules present--only fibrinogen! **Fibrinogen** is a dimer and each monomer has (A-alpha, B-beta, gamma) peptides and does not aggregate because A and B are negatively charged and repel each other **Thrombin** (only activated from prothrombin by clotting cascade) converts fibrinogen to **fibrin**, by removing negatively charged A and B to create (alpha, beta, gamma) peptides. Now **Factor XIIIa** helps fibrin monomers aggregate

Answer 24

Yes, kininogen and kallikrein recognize test tube as damaged blood vessels and initiate intrinsic pathway

Answer 25

Intra-membranous protein in connective tissue of vessel wall that sticks out from fibroblast when there is trauma/damage In vivo, this is what **triggers** clotting cascade! Binds to **VIIa** to activate it (so VIIa can turn X --\> Xa) Exists in blood in inactive state on particles derived from dead WBCs, and activation occurs by unknown mechanism (maybe lipid reorganization)

Answer 26

In vivo, yes crosstalk (factor VIIa can activate factor IX) In vitro, no crosstalk (with no tissue factor you completely eliminate extrinsic factor)

Answer 27

**Extrinsic** pathway (using **VIIa**) **initiates** clotting and becomes active, but then inhibitors come into play to inhibit extrinsic pathway (inhibit VIIa) **Intrinsic** pathway is needed to **prolong** clotting cascade as extrinsic pathway becomes inhibited Clotting initiated by extrinsic pathway, completed/prolonged by intrinsic pathway

Answer 28

Can use different clotting tests to determine where deficiency is

Answer 29

No problem! Can still clot because of tissue factor in vivo and extrinsic pathway

Answer 30

NO! Platelets enhance clotting in vivo by assembling activated clotting factors on their surface, but are not required

Answer 31

Used to speed clotting in people with hemorrhage, etc

Answer 32

**Serine proteases**: remove part of preursor portion (**II, VII, IX, X,** XI, XII, kallikrein) **Nonprotease activators/accelerators**: stabilize other factors (V, VIII, tissue factor, high molecular weight kininogen) **Stabilizer of factor VIII**: von Willebrand factor (in plasma) Transamidase that **crosslinks fibrin**: factor XIII **Nonprotein factors**: stabilize many clotting factors (Ca2+ and membrane phospholipids)

Answer 33

1) Cleaves thrombin receptor on platelets to **activate platelets** (second pathway of platelet activation, which is initiated by tissue factor) 2) Cleaves V and VIII to **form active Va and VIIIa** 3) **Limits clot formation** by eventually cleaving Va and VIIIa (along with thrombomodulin)

Answer 34

1) **Thrombin binds thrombomodulin** (intramembranous protein that sticks out into blood) --\> thrombin-thrombomodulin complex activates **protein C** --\> active protein C binds **protein S** --\> together, **cleave Va and VIIIa** --\> clotting is terminated (hydrolysis products) 2) **Antithrombin** (produced by liver) binds active protease (IIa (thrombin) and Xa especially) and inactivates them --\> antithrombin-inactive protease complex (heparin binds this complex and increases activity 1000x)

Answer 35

Anti-coagulant, injected IV Prevents clot formation by increasing **antithrombin** activity

Answer 36

II, VII, IX, X Protein C, Protein S

Answer 37

Vitamin K **modifies clotting factors** by turning **Glu-to-Gla** residues (just add carboxy group) so that they can **bind Ca2+ and become active** Vitamin K does this modification in the **liver**, so once blood is sent out from the liver, it has glu-to-gla-transformed (ready to be active) clotting factors

Answer 38

Anti-coagulant, prevents clot formation--rat poison causes them to bleed to death Inhibits action of vitamin K (vitamin K needs to be reduced to work again, and warfarin inhibits this) Warfarin inhibits **vitamin K reductase** Activity of warfarin function of age, race, weight, height, smoking, other meds, diet, and \>30 genes Warfarin acts in the liver!! Warfarin competes with oxidized vitamin K, so if OD on warfarin, can give vitamin K to try to stop hemorrhage but will take a long time

Answer 39

1) Vitamin K **oxidized** when it does glu-to-gla to activate clotting factors 2) Vitamin K reductase **reduces** vitamin K back so it can activate more clotting factors Warfarin inhibits vitamin K reductase Warfarin inactivated by CYPs

Answer 40

**Heparin**: blood will **not** clot if heparin in test tube because heparin combines with antithrombin and inhibits proteases/clotting factors from forming clots **Warfarin**: blood **WILL** clot if warfarin in test tube because clotting factors in blood have **already done glu-to-gla transformation (in liver) and are active**

Answer 41

Synthetic pentasaccharide similar to heparin but more specific for Factor Xa

Answer 42

Ca2+ chelators; bind up Ca2+ so can't activate clotting factors and clotting can't occur If add these to test tube, blood won't clot Never use these in vivo of course!

Answer 43

Dabigatran (Pradax): specific inhibitor of thrombin Rivaroxaban and Apixaban: specific inhibitor of factor Xa Bivalirudin: synthetic peptide analog of hirudin, thrombin inhibitor present in saliva of leech

Answer 44

Mix **normal** **blood** with patient's blood: If heparin OD then normal blood's clotting factors will be cleaved by heparin and combined blood won't clot If warfarin OD, then normal blood's clotting factors have undergone glu-to-gla transformation and will help combined blood clot (basically can restore clotting function with normal clotting factors from normal blood) "Heparin just freaking kills everything in its way"

Answer 45

1) **Plasminogen** from liver converted to **plasmin** by **TPA** (from vascular endothelium) --\> plasmin breaks down fibrin clot and releases **fibrin split products** (**D-dimers**) Recombinant forms of TPA used in stroke patients: Alteplase and Tenecteplase

Answer 46

D domains on fibrin monomers **attach** to each other to form dimers when plasmin breaks down a fibrin clot--called D-dimers Antibody can recognize D-dimers but not fibrin monomers D-dimers elevated in thromboembolism in brain, infection, neoplasia

Answer 47

Lab test (not used anymore) to assess primary hemostasis Incision in wrist and see how long takes to stop bleeding

Answer 48

Clotting time in presence of added **tissue** **factor** (obtained from animal brain tissue) Measures **extrinsic** and **final** common pathway International normalized ratio (INR) = PT of patient's blood:PT of normal blood (INR of normal blood is 1)

Answer 49

Add **kaolin** (clay) which triggers intrinsic pathway and see how long until clotting Measures **intrinsic** and **final** common pathways

Answer 50

Add **diatamaceous earth** to blood to see time to clotting Similar to APTT Used to **monitor heparin levels** when high doses given (in cardiac bypass surgery)

Answer 51

Russell's viper venom (converts factor X to Xa) added to blood in test tube and time to clotting measured

Answer 52

**PT** used for **warfarin** levels (remember PT extrinsic, warfarin given outpatient/oral) **PTT** used for **heparin** levels (remember PTT intrinsic, heparin given inpatient/IV) (PT and PTT should be affected by both but aren't actually in practice) Anti-Xa activity test used for LMWH and Fondaparinux (PTT not sensitive to these drugs)

Answer 53

1) Vasoconstriction problem (only women) 2) Thrombocytopenia (decreased platelets) 3) Platelet dysfunction 4) Deficiency/defect in in clotting factor (hereditary hemophelia vs. acquired vitamin K deficiency) 5) Inhibitors of clotting factors (heparin, antibodies if autoimmune) 6) Excessive fibrinolysis 7) Combo of above

Answer 54

Many babies **vitamin K deficient** at birth, so always administer vitamin K at birth Vitamin K made by bacteria in GI tract but baby doesn't have bacteria in GI tract at birth Mom can pass on some vitamin K to baby but baby doesn't have fat to store vitamin K in Baby's liver not fully functional at birth so needs extra vitamin K to do glu-to-gla transformation

Answer 55

Hereditary blood clotting disease (can bleed easily, bruise, bleed into joints) X-linked recessive deficiency in factor **VIII** (intrinsic pathway, measure PT!) Have \<5% normal factor VIII activity (A = 8)

Answer 56

Hereditary blood clotting disease (can bleed easily) X linked recessive deficiency of factor **IX** (intrinsic pathway, measure PT!) (B = 9)

Answer 57

Hereditary blood clotting disease (can bleed easily) Deficiency of von Willibrand factor Fairly common

Answer 58

Love to clot Hypercoagulation disorders Untimely intravascular clot formation due to imbalance between anticoagulant and prothrombotic activities of plasma Can be hereditary or acquired

Answer 59

1) Factor V mutation (**Factor V Leiden**): mutation makes factor V **resistant to protein C** so can't break down clot, keep on clotting 2) Prothrombin G20210A mutation: **overproduction of prothrombin** 3) **Deficiency** in level or activity of **protein C, protein S, antithrombin** Note: mutations above only manifest when other factors occur also (oral steroid contraceptives cause increases/decreases in clotting factors) or when have another thrombophilia mutation too

Answer 60

Caused by: 1) **Vascular infection** or **inflammation** (induced expression of tissue factor; have ongoing coagulation/inflammation that decreases levels of antithrombin, protein C, protein S) 2) **Severe trauma** 3) **Cancer** (induced expression of tissue factor) 4) **Pregnancy** (hormone changes) 5) **Antiphospholipid** **syndrome**: autoimmune antibodies against phospholipids on cell membranes cause increased clots (can also cause fetal loss in pregnancy) Treatment: anticoagulants or platelets or plasma, control underlying condition (ex: treat infection)

Answer 61

Widespread, occurs throughout most of vasculature; get both **thrombi** and **bleeding** Systemic activation of coagulation --\> intravascular deposition of fibrin --\> thrombosis of small/midsize vessels can cause organ failure --\> increased clotting means depletion of platelets and coagulation factors --\> bleeding Medical emergency

Answer 62

Rare, severe liver disease due to increased iron/hemosiderin, and iron/hemosiderin deposition (hemosiderosis) on liver and other tissues Clinical features: fetal death or illness/impaired growth at birth, evidence of liver failure (low albumin, low glucose, coagulopathy, low fibrinogen, thrombocytopenia, anemia), siderosis Diagnose by looking for siderosis in biopsied liver or salivary gland Pathogenesis: maternal IgG against fetal liver tissue damage baby's liver --\> **damaged liver can't produce enough hepcidin** --\> **too much iron transport across placenta** --\> **iron deposits on liver and other tissue** (Note: this mother will probably have the same thing happen in future pregnancies) Tx: anti-oxidents, liver transplantation; during pregnancy weekly IV administration to mother of IgG from other donors to compete with mother's anti-fetal liver IgG so donor IgGs cross placenta more than mother's bad IgG

Answer 63

**Heparin**: IV; **in-patient** **Warfarin**: oral; **outpatient** (even though easy to over- or under-dose warfarin!)

Answer 64

Help prevent formation of initial platelet plug 1) Aspirin (NSAIDs) 2) Plavix (Clopidogrel) 3) Abciximab

Answer 65

Help prevent full formation of blood clot (after platelet plug has formed) 1) **Ca2+ chelators** (oxalate, EDTA) 2) **Heparin** (unfractionated heparin, LMWH (enoxaparin = Lovenox), Fondaparinux (more specific for factor Xa) 3) **Warfarin** (= Coumadin) 4) Synthetic specific protease inhibitors that don't require patient monitoring (**Dabigatran** (Pradax) and **Bivalirudin** inhibit thrombin; **Rivaroxaban** and **Apixaban** inhibit Xa)

Answer 66

Alteplase Tenecteplase