4&5. Hemostasis and RBC disorders Pathoma

Question 1

what is primary hemostasis

Answer 1

injury to a blood vessel that results in a PLATELET PLUG(stabilized by secondary hemostasis)

Question 2

What is secondary hemostasis

Answer 2

Stabilization of the platelet plug via coagulation cascade

Question 3

Steps of thrombogenisis

Answer 3

1)Endothelial damage= vasoconstriction 2)Exposure: vWF is exposed to collagen and binds 3)Adhesion: Platelets bind to vWF via Gp1b (conformational change) platelets release ADP and Thromboxane 4a)ADP helps platelets adhere to endothelium via increased Gp2b/3a receptors4b)platelet aggregation via FIBRINOGEN between Gp2b/3a receptors

Question 4

Where does vWF come from?

Answer 4

Weibel-palade bodies of the endothelial cellsand Alpha-granules of platelets

Question 5

Clinical signs of Primary hemostasis fuck up

Answer 5

Mucosal and skin bleeding(nose -EPISTAXIS-, gi, menstrual))bruising, petechia, purpura

Question 6

Idiopathic Thrombocytopenia Purpura (ITP)what clinical values will you seeTx?

Answer 6

Autoimmune production of IgG antibodies against platelet antigens low platelet count, increased megakaryocytictx-corticosteroids, ivig (the spleen produces the antibodies and also destroys them. so ivig will distract the spleen to give the bodys platelets a chance to recover), splenectomy

Question 7

Microangiopathic hemolytic anemia

Answer 7

Small blood vessels get a platelet thrombus that shears any passing RBCsShcistocytes (helmet cells)

Question 8

Thrombotic thrombocytopenia purpura (TTP)tx=

Answer 8

platelet aggregation that leads to thrombocytopenia (purport from lack of platelets)Deficiency of ADAMTS13 (which breaks down vWF) so you have to much vWF which leads to increased platelet aggregationtx-plasmapharesis, steroids

Question 9

Hemolytic-uremic syndrome

Answer 9

Thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failureseen in children after Etec infection caused by Shiga like toxin

Question 10

Bernard-Soulier syndrome?whats the defect in?

Answer 10

a defect in platelet plug formation due to decrease in Gp1bdefect in platelet-to-vWF adhesionincrease bleeding time

Question 11

Glanzmann Thrombasthenia

Answer 11

genetic deficiency in Gp2b/3aplatelet aggregation is impaired ( G2pb/3a is what connects platelet to platelet via fibrinogen

Question 12

vWF diseasetx-

Answer 12

deficient in vWFtx- desmopressin

Question 13

Vit. K deficiencey

Answer 13

Decrease in synthesis of factors 2,7,9,10,C,S7 having the shortest half-life

Question 14

Warfarin

Answer 14

inhibits vit K synthesis via inhabiting epoxide reductase

Question 15

Heparin induced Thrombocytopenia (HIT)

Answer 15

when you develop IgG antibodies against Heparin-bound platelet factor 4 (PF4)the antibodies activate platelets–> thrombosis and thrombocytopenia elsewhere

Question 16

Disseminated inter vascular coagulation (DIC)whats the best screening test?

Answer 16

Secondary to other dzpathologic activation of coagulation cascadewidespread micro thrombi that leads to ischemia and infarctionConsumption of all these platelets leads to bleeding everywhere else (especially IV and mucosal sites)test- Elevated D dimers (when you split fibrin it produces D dimers)

Question 17

What blocks activation of plasminogen

Answer 17

Aminocaproic acid

Question 18

What two characteristics would you see in a thrombosis

Answer 18

Lines of zahnattachment to vessel wall

Question 19

Vitamin B12 or folate deficiency leads to elevated ________

Answer 19

homocysteine levels

Question 20

TetrahydroFOLATE to methionine

Answer 20

THF–> gives off methyl to Vit. B12—> gives methyl to Homocysteine —-> methionine

Question 21

Whats the role of Protein C or S

Answer 21

Inactivate factors V and VIII in coag cascade

Question 22

whats the deal with factor V leiden

Answer 22

Resistant to degradation/inactivation by Protein C

Question 23

Whats are the anemia subtypes (based off of MCV)mean corpuscular volume (size of red blood cell)

Answer 23

Microcytic MCV 100

Question 24

Role of ferroportinRole of TransferrinRole of Ferritin

Answer 24

Transfers iron into the bloodDelivers iron to liver and bone marrow macrophagesIron Storage

Question 25

Why do you get anemia of chronic dz?

Answer 25

With chronic dz, you get prolonged inflammation. and in order to stop whatever is causing the sickness, the body increases hepcidin (which fucks up ferroportin and prevents release of iron from ferritin ) which decreases iron transport ----\> iron deficiency ---\> anemiaferritin goes up/ TIBC goes downSerum iron goes down

Question 26

What does hepcidin do

Answer 26

Prevents release of iron from storage sites to deprive any infection of iron and kill it off

Question 27

Sideroblastic anemia what are some of the causes Tx?

Answer 27

Defect in protoporphyrin synthesis --\> defect in Hb. due to X-linked defect in ALA synthase defect in protoporphyrin leads to iron getting trapped in mitochondria of erythroblasts congenitcal (ALA synthase), lead poisoning, alcoholism, or B6 Deficiency (pyridoxine) tx-B6 pyridoxine

Question 28

what attaches Protoporphyrin to Iron (to make heme) where does this happen

Answer 28

Ferrochelatase in mitochondria

Question 29

Ringed sideroblasts

Answer 29

when protoporhyin synthesis is messed up so iron gets loaded into mitochondria. This iron has nothing to bind to so its trapped there. These iron-laden mitochondrias form rings around the nucleus

Question 30

Thalassemia

Answer 30

Decrease in synthesis of Globulin chains (leads to microctyic anemia)

Question 31

alpha Thalassemia 4 allele deletion 3 allele deletion 2 and 1 allele deletion

Answer 31

Normally you have 4 alpha alleles Defect in A-globin _deletion_ 4 allele-no alpha globin, excess gamma globin, (makes gamma4 -**Hb Barts**) *Hydrops fetalis* 3 allele- very little alpha globin, Excess ß-globin (**HbH)** 2/1 not clinicilaly severe

Question 32

whats the significance of cis vs trans deletions in alpha-thalassemia

Answer 32

cis is when 2 alpha alleles are knocked out on the same chromosome. this can lead to to severe thalasemia in offspring (Prevalent in Asains) Trans isnt that bad (African population)

Question 33

ß-Thalassemia (2 beta genes) Minor (ß/ß+) (normal/diminished) Major (ß°/ß°) both B are wiped out

Answer 33

Gene _mutation_ minor-asymptomatic with Increase in HbA2 _major_ Absent Beta chain, **target cells**, massive erythroid hyperplasia- expansion of hematopoiesis into marrow of Skull and facial bones (crew cut and chipmunk like face) extramedulary hematopoiesis- liver and spleen starts to make it (hepatosplenomegaly) Risk of **Parvovirus** **B19-** aplastic crisis 2° hemochromatosis

Question 34

Macrocytic Anemia (Megaloblastic anemia) MCV? what deficiencies cause it? why do the deficiencies lead to it

Answer 34

MCV\>100 Folate or Vit. B12 deficiency (1 less division so theyre **macro**) due to mess up of DNA precursors **Hypersegmented Neutrophils**

Question 35

whats the role of folate and Vit B12 in synthesis of DNA (flow chart)

Answer 35

Tetrahydro**folate** has a methyl and in order for it to make DNA it has to give that methyl to Vit. B 12 Vit B12 then gives that methyl to Homocystiene. Homocystiene + methyl = Methionine

Question 36

_Folate_ Where is folate absorbed? what casuses its deficiency Clinical findings of deficiency Lab findings

Answer 36

- In the **Jejunum** - Poor Diet (alcoholics,elderly), Increased demand (preggos, cancer, hemolytic anemia), Drugs _methotrexate_ - Megaloblastic anemia (macrocytic RBCs, Hypersegmented Neutrophils), Glossitis - Decreased serum folate(duh), * Increased* Homocysteine( piles up because folate doesnt pass Methyl to vit.b12 --\>so vit b12 cant change homocysteine to methionine Methylmalonic acid is **Normal**

Question 37

_Vit. B12_ (Cobalamin) How is it absorbed/where What causes its deficiency (alot) Clinical and lab findings

Answer 37

First needs to be cleaved by *pancreatic enzymes* Then, it binds to Intrinsic Factor (**IF**) to be absorbed in the **Ileum**. Large hepatic stores so it takes a *long time* to develop deficiency. -caused by insufficient uptake (_Vegan_), malabsorption (_Crohn dz_), _Pernicious anemia_ (Autoimmune destruction of parietal cells- cant make **IF**) Diphyllobothrium Latum (fish tapeworm) - Macrocytic anemia with **Hypersegmented neutrophils**, Glossitis - **Subacute Combined Degeneration of Spinal Cord -**B12 converts methylmalonic acid --\> Succinyl Coa. so without B12 you get a shit tone of mma which is toxic to myelin

Question 38

Pernicious Anemia

Answer 38

Autoimmune destruction of Parietal cells. This leads to a deficiency of **Intrinsic Factor (IF)** Which means you cant absorb Vit B12

Question 39

What are the 2 major processes that Vit B12 are invovled in?

Answer 39

- In the _synthesis of DNA_, by accepting methyl from Tetrahydro**folate**, then giving it to Homocysteine - Converts Methylmalonic acid ----\> Succinyl CoA _myelin synthesis_ too much methylmalonic acid is toxic to myelin

Question 40

_Normocytic Anemia_ MCV? what does the reticulocyte count look like?

Answer 40

- MCV 80-100 - Increased reticulocyte count/percentage (falsely elevated) due to destruction of RBCs You must correct it tho.

Question 41

In normocytic anemia, what are the perameters for when you correct the reticulocyte count? Whats the equation

Answer 41

\>3% indicates good response by bone marrow; suggests _peripheral destruction_ underprodcution Reticulocyte count x (Hematocrit/45) in the example it would be a bone marrow problem

Question 42

Extravascular hemolysis Which Anemia does it cause What are clinical findings

Answer 42

- Normocytic anemia - Extravascular destuction occurs from macrophages in spleen - Anemia with Splenomegaly, **Jaundice** due to unconjugated bilirubin (increased risk for gallstones), marrow hyperplasia with corrected reticulocount \>3% remember that when hemoglobin is broken down, the protoporhyrin of heme gets turned into Unconjugated billirubin

Question 43

Intravascular Hemolysis What type of anemia does it cause lab findings

Answer 43

- Normocytic Anemia - Destruction of Hemoglobin in the blood vessel. Haptoglobin (binds to free Hb and brings it back to spleen) Hemoglobinemia, Hemoglobinuria, Hemosiderinuria

Question 44

Haptoglobin

Answer 44

Binds free hemoglobin (**Hb)** and brings it back to spleen. levels of haptoglobin are decreased in intravascular hemolysis bc they get used up

Question 45

Hereditary Spherocytosis clinical findings how is it diagnosed tx?

Answer 45

Extravascular hemolysis due to defect in RBC membrane (ankyrin, band 3, spectrin are protein fuckups) Small round RBC with no central pallor (premature removal by spleen) Increased MCHC (mean corpuscular hemoglobin concentration) only dz with this - Splenomegaly, Aplastic crisis (ParvoVirus B19 infection) - osmotic fragility test - Splenectomy

Question 46

_Sickle Cell Anemia_ whats the mutation? what causes the sickling What protects against the sickling (tx) clinical findings

Answer 46

Auto Recesive mutation in the ß gene (glutamic acid with valine) - Stressors such as Low O2, high altitude, acidosis, dehydration - HbF(fetal), give **hydroxyurea** to increase HbF '-Aplastic crisis (parvovirus B19), Painful crisis: dactylitis (sausage fingers), acute chest syndrome, avascular necrosis **Autosplenectomy** *(howell jolly bodies)*- due to infarct of the spleen. increases risk of infection S. pneumonia **Salmonella osteomylitis**

Question 47

Hemoglobin C whats the mutation

Answer 47

Auto Recessive mutation in ß Chain _Glutamic acid_ is replaced by _Lysine_

Question 48

Paroxysmal nocturnal hemoglobinuria (PNH) why does it happen? lab findings what does it lead to Tx

Answer 48

aquired dsyfunciton of GPI via *hematopoietic stem cell* (anchors decay-accelerating factor **-****DAF CD55-** that protects RBC from complement activation) at night we breath slower leading to respiratory acidosis --\> activation of compliment (**intravascular hemolysis)** which will fuck up these RBCs since theyre predisposed already - hemoglobinemia, hemoglobinuria - leads hemolytic anemia (duh), pancytopenia, **thrombosis** 10% of pts develops **AML** **-**tx **eculizumab** (compliment inactivator)

Question 49

_G6PD deficiency_ whats its function what causes oxidative stres what cells does this produce? Clinical signs

Answer 49

X-linked Recessive d.o --\>reduced half life of G6PD (increases RBCs succeptible to oxidative stress) G6PD helps create NADPH. NADPH helps produce glutathione which protects against oxidative stress -Infections, **Fava Beans** **Heinz bodies & Bite cells** Back Pain from all the released Hb(nephrotoxic)

Question 50

_Immune hemolytic Anemia_ What are the different types what are they associated with

Answer 50

_Warm IgG_: EXTRAVASCULAR chronic anemia due to IgG binding to RBC and removing membrane (results in spherocytes). Associated with *SLE* and CLL (**Methyldopa**) / (Warm weather is GREAT) _Cold IgM:_ Acute anemia triggered by cold. Associated with *CLL,* ***M***ycoplasma pneumonia, Infectious **M**yonucleosis. (Cold weather is MMMiserable)

Question 51

What is the Coombs test? Direct. vs indirect

Answer 51

_direct_- do i have cells already bound by IgG? you give them anti- IgG. so if the answer is yes, the RBCs wil agglutinate and percepitate _Indirect_- Does the pt have antibodies in their serum? normal RBCs added to patients serum. if serum has the antibodies, the RBCs agglutinate when Coombs is added

Question 52

Whats the CD for hematopoeitic stem cells? Give the lineage of everything that it can produce

Answer 52

CD34