Test 3 Flashcards by Amelia Ni

What are the effects of the following on vasculature? Where do they come from?
TXA2
ADP
Thromboplastin (TF3)
Plasmin
PGI2
Nitric Oxide
Endothelin-1
Thrombomodulin
tPA

TXA2: released by platelets, facilitates platelet aggregation
ADP: released by platelets, facilitates platelet aggregation by binding to P2y receptors
Thromboplastin (TF): released by activated platelets and injured endothelial cells,
Plasmin: released by activated platelets?

PGI2: released by uninjured endothelial cells as vasodilator, working against platelet aggregation
Nitric Oxide: released by uninjured endothelial cells as vasodilator, working against platelet aggregation

Endothelin-1: released from injured endothelial cells, causes vasoconstriction
Thrombomodulin: expressed on injured endothelial cells, activates Protein C by helping Thrombin

tPA: released from endothelial cells, converts plasminogen to plasmin

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Where are the following drugs site of action?
Aspirin
ClopidoGREL, TicaGRELor
Abciximab, Eptifibatide, Tirofiban
Vorapaxar

Aspirin: blocks COX1
ClopidoGREL, TicGRELor: blocks ADP receptor
Abciximab, Eptifibatide, Tirofiban: blocks IIb-IIIa receptor
Vorapaxar: blocks thrombin receptor

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What must happen to Vit K before it can be integrated into the coagulation cycle? Then what does it do?

Vit K must be reduced by Vit K reductase

then it helps Vit K dependent clotting factors undergo carboxylation to get activated

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What CFs are Vit K dependent? anything else?

CF II, VII, IX, X

Protein C and S

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What does Thrombin activate?

Thrombin (II) activates:
5, 8 ((normally circulating in blood bound to vWF, thrombin cleaves it), 11, 13
Fibrinogen → Fibrin
Protein C → activated PC
platelets by binding to PAR-1

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What are the 5 elements in the prothrombinase complex

Prothrombinase Complex
1 Ca
2 Activated phospholipid membrane
3 Factor Xa
4 Factor Va
5 Prothrombin

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Walk through steps of fibrinolysis

Fibronilysis:
Endothelial cells replease tPA
tPA converts Plasminogen to Plasmin (after plasminogen’s bound to fibrin)
Plasmin cleaves Fibrin

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What are the drugs that act on the following sites?
blocks COX1
blocks ADP receptor
blocks IIb-IIIa receptor
blocks thrombin receptor

Aspirin: blocks COX1
ClopidoGREL: blocks ADP receptor
Abciximab, Eptifibatide, Tirofiban: blocks IIb-IIIa receptor
Vorapaxar: blocks thrombin receptor

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What are 7 ways blood clotting is controlled?

1: factor activation restricted to activated platelets or damaged endothelium
2: Antithrombin III circulates and inhibits Thombin and Factors 9-12
3: Endothelial thrombomodulin binds and inactivates Thrombin
4: Protein C+S inactivated Factors 5 and 8
5: Endothelial secretion of Tissue Factor Pathway Inhibitor (TFPI) inactivates Factor 10/5 and 9/8 complexes
6: Endothelial secretion of NO and PGI2 inhibit platelet aggregation
7: Endothelial secretion of tPA

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What’s genetic etiology (and mutation), pathophysiology, and clinical presentation for Antithrombin deficiency?
How does it present if Complete AT Deficiency?

genetics: AD for serine protease mutation in Antithrombin that reduces AT activity
Pathophys: Serine protease normally inhibits Factors 9, 10, 11, 12, and 2 (Thrombin)
clinical: DVT, mesenteric vein thrombosis, and recurrent thrombotic episodes by 40yo
Complete AT Deficiency = fatal

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What’s genetic etiology (and mutation), pathophysiology, and clinical presentation for Factor V Leiden?
Which populations see a prevalence?

Genetics: AD, G→A Arg506Gln point mutation in Factor 5’s aProteinC cleavage site
Pathophys: Factor V can’t be cleaved
Clinical: risk DVT and pregnancy loss, decreased susceptibility to spesis and bleeding and PEs
Caucasian/Greek prevalence

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What’s genetic etiology (and mutation), pathophysiology, and clinical presentation for Prothrombin gene mutation?

Genetics: AD, mRNA accumulation of G20210A mutation leads to increased translation and prothrombin (Factor 2) levels)
Pathophys: Increased levels of Prothrombin aka Factor 2
Clinical: risk venous thrombosis

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Differentiate MOA of Heparin, LMWH, and Fondaparinux

Heparin: binds w/ATIII to inactivate Thrombin and Factors 9-12
LMWH: binds w/ATIII to inactivate Factor 10
Fondaparinux: indirect Factor 10 inhibitor

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How do you reverse Heparin, LMWH, Fondaparinux?
Direct Factor 10 inhibitors Rivaroxaban/Apixaban, Warfarin, Direct Thrombin inhibitors Dabigatran/Argatroban/Bivalirudin?

Heparin: Protamine
LMWH: Protamine, but RecombFactor 7a is more effective
Fondaparinux: RecombFactor7
Rivaroxaban/Apixaban: can’t
Warfarin: Vit K
Dabigatron/Argatroban/Bivalirudin: Idarucizumab

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Rivaroxaban/Apixaban, and Dabigatran/Argatroban/Bivalirudin MOA?

Rivaroxaban, Apixaban = Direct Factor 10 block

Dabigatran, Argatroban, Bivalirudin = Direct Thrombin (Factor 2) and Factor 10 block

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What are the 2 Factor 10a inhibitors drugs?

What’s the 3 Direct Thrombin inhibitor drugs?

Factor 10a inhibitor: Rivaroxaban, Apixaban

Direct Thrombin inhibitors: Dabigatran, Argatroban, Bivalirudin

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What’s the most common inherited hypercoaguable disease?
most common aquired hypercoaguable?
most common inherited hemophilia disease?
most common drug-induced thrombocytopenia in adults?

Inherited Hypercoaguable: Factor V Leiden
Acquired Hypercoaguable: Antiphospholipid Ab syndrome
Inherited Hemophilia: vWD
Drug induced thrombocytopenia: HIT (heparin induced thrombocytopenia)

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Differentiate ITP and HIT

Immune Thrombocytopenic Purpura: Abs target GP IIb/IIIa (usually, rarely Ib/9), bind to Fc receptors on macrophages
HIT: body makes Ab to Heparin+Factor4, Abs bind to platelets, splenic macrophages remove platelets

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Differentiate vWD and Glanzmann’s thrombasthenia

vWD: vWF defect, doesn’t allow platelets to clot appropriately
Glanzmann’s thrombasthenia: GPIIb/IIIa defect

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How can you treat ITP?

ITP tx:
steroids 
IV IgG to compete w/macrophage activity against  
IGs
splenectomy
immunosuppression

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50% of CLL pts have thrombo_________, d/t ________

50% of CLL pts w/CLL have thrombocytopenia, d/t lack of normal differentiation of megakaryocytes and bone marrow repalcement

What’s the genetic etiology, pathophys, and clinical presentation for von Willebrand Disease?

Genetic etiology: AD
pathophys: vWF mutations affect primary hemostasis (platelet adhesion to endothelium defect) and secondary hemostasis (Factor8 not stabilized and gets degraded)
Clinical: mucocutaneous bleeding, high variability of penetrance to create quantitative and qualitative mutations

What gene is mutated, pathophys, and clinical presentation for Bernard Soulier syndrome?

Genetic etiology: GP1b alpha
pathophys: mutations in GP1b don’t allow vWF to bind
Clinical: assoc w/intermarriage, easy bruising, excessive bleeding, petechiae, epistaxis, heavy menstrual flow

What’s the normal synthesis, processing, release, and storage of von Willebrand Factor?

synthesis: continually secreted from endothelial cells in small amounts
Processing: CK region on C terminal allows for dimerization, D region on N terminal allows for multimerization
release: when endothelium stimulated by Histamine, Thrombin, Fibrin, and beta-adrenergic agonists
storage: vWF normally in serum stabilizing Factor8, and in Weibel-Palade bodies in endothelial cells

Why use Desmopressin to treat vWD, and why's there subsequent fluid intake concerns?

Desmopressin causes vWF release from endothelial cells | Desmopressin stimulates renal V2 receptors, increasing H2o resorption and can have hyponatremia CNS ADEs

What's the genetic etiology (and mutation), pathophys, and clinical presentation for Hemophilia A? why's it more common in men?

Genetic etiology: X-liked recessive, X inversion makes 2 Factor 8 copies Pathophys: Factor8 deficiency Clinical: excessive bleeding, esp in joints, soft tissue, mucocutaenous, intracranial, muscle... severity correlates w/level of deficit

What's the genetic etiology (and mutation), pathophys, and clinical presentation for Hemophilia C? why's it more common in Ashkenazi Jews?

Genetic etiology: AR, 2 point mutations Pathophys: Factor 11 deficiency Clinical: oral cavity and urinary tract bleeding after injury, but spontaneous bleeding is uncommon

How does Aminocaproic acid help clotting factor deficiencies? How does Tranexamic acid?

Aminocarpoic acid and Tranexamic acid inhibit fibrinolysis by blocking Plasminogen activation

What's genetic etiology, pathophysiology, and clinical presentation for Protein C/S deficiency? What happens w/a complete deficiency?

Genetics: AD Pathophys: deficiency in Protein C Clinical: NOT assoc w/mesenteric vein thrombosis, at risk for warfarin-induce skin necrosis, venous thrombosis by 40yo Complete deficiency lethal w/o tx, w/tx will have purpura fulminas, DIC, thrombosis, and blindness can occur d/t intrauterine retinal thrombosis

How does Protamine reverse Heparin/LMWH?

Protamine binds Heparin or LMWH better than they bind to their substrates, inactivating them

What's the genetic etiology (and mutation), pathophys, and clinical presentation for Hemophilia B? why's it more common in men?

Genetic Etiology: X-linked recessive, missense substitution Pathophys: Deficiency in Factor 9 Clinical: severity correlates w/severity of mutation, but in general B is less bad than A

What are the natural controls of fibrinolysis?

Natural controls of fibrinolysis: PAI = Plasminogen activator inhibitors, inactivates tPA Alpha 1 antiplasmin, inactivates plasmin that escapes the area

What's the most common organ affected by amyloidosis, and how do you diagnose, and most common cause of death?

Amyloidosis most commonly affects kidneys Dx: Congo red stain, then birefringence apple green most common cause of death is progressive renal failure

What types of renal involvement is seen in amyloidosis?

Amyloidosis 1) non-selective proteinuria 2) Nephrotic syndrome 3) Chronic renal failure

What are 3 types of Langerhans Histiocytosis, and differentiate? Common feature?

Langerhans Histiocytosis (APCs of skin) 1) Eosinophilic Granuloma-localized, no skin involvement, pathologic fxs 2) Hand-Schluller-Christian-disseminated skin rash, scalp rash, diabetes insipidus, exophthalmos, kids >3yo 3) Letterer-Siwe-fulminant and fatal, malignant, skeletal defects in kids <2yo ALL have Birkbek granules like tennis rackets on EM

how to differentiate Hand-Schuller-Christian from Multiple Myeloma? (focus on HSC)

HSC: radiolucent skull lesions BUT diabetes insipidus and exopthalmos in kids >3yo, 30% have liver and spleen involved MM: black men >65yo w/lytic skull lesions BUT hypercalcemia, renal failure d/t Bence Jones proteins (light chains), pathologic vertebral fxs, and hypercalcemia

What cells does EBV infect? what is subsequently affected?

EBV infects Bcells, but Tcells react against infected Bcells and become large/activated/Atypical

Clinical presentation of Mono?

Common: Fatigue, sore throat, muscle aches, cervical lymph node and facial and eyelid swelling Less common: Rash, tonsilar pseudomembrane, splenomegaly

Pathophys behind Antiphospholipid Antibody Syndrome? How does coagulation cascade get messed up? Who gets this?

Antiphospholipid Antibody Syndrome: Autoantibodies against phospholipids, esp Cardiolipin, Apolipoprotein H, and Lupus anticoagulant Abs against Apo-H bind Protein C and S, blocking them, creating thromi Preggos, assoc w/pregnancy complications like miscarriage, stillbirth, placental infarctions, preterm delivery, severe pre-eclampsia

What are 2 viral infections assoc w/AIDS? What're the 2 fungal infections? What's the Protozoal infection? assoc w/?

HSV and CMV Cryptococcus (most common cause of meningitis) and Histoplasma Toxoplasmosis, assoc w/Periventricular CAlcifications

What blood disorder's common in cancer, and why? What happens clinically? What types of cancer?

Acquired Thrombophilia's assoc w/malignancy bc cancer cells activate clotting system by releasing procoagulants and inflammatory cytokines Will see DVT w/PE Pancreas, lungs, AML, MM and BrCa

What are Orthochromatic Normoblasts? What else are they called?

Orthrochromatic Normoblasts aka nucleated RBCs are immature RBCs w/Hg and Pyknotic (condensed) nucleus

What's the cause of iron deficiency anemia in adult men and postmenopausal women until proven otherwise?

GI loss d/t malignancy or lesion!

What is Mycosis fungoides? what cells are affected and what's it look like? Differentiate from Sezary Syndrome

Mycosis fungoides: T-helper cell tumor that hones to skin, Neoplastic Tcells have cerebriform appearance Sezary Syndrome: T-helper cell tumor w/generalized, exfoliative erythoderma

What makes up the Intrinsic Tenase? | What makes up the Extrinsic Tenase?

``` Extrinsic = 3a, 7a, Ca, PL, 10 Intrinsic = 9a, 8a, Ca, PL, 10 ```

What are the 2 LMWH drugs, and their MOA?

Enoxaparin and Dalteparin bind to ATIII to potentiate the inactivation of Factor 10

What 3 drugs can you use in Hemophilia tx, and why?

Hemophilia tx: Desmopressin increases vWF and F8 release from Weibel-Palade bodies Aminocaproic acid and Tranexamic acid inhibit fibrinolysis by blocking Plasminogen

What are N gonorrhoeae's methods of evading Abx?

N. Gonorrhoeae: Alters proteins of ribosomes, topoisomerase, and PBPs, beta-lactases, efflux pumps

What are Enterococcus's methods of evading Abx?

Enterococcus: Makes D-ala-D-lactate wall, so Vancomycin resistant

``` What are the MOA of the following Abx? Glycopeptides(Vancomycin): Beta-lactam: Tetracyclines: Chloramphenicol: Macrolides: Sulfonamide: Trimethaprim: Fluoroquinoloes: ```

Glycopeptides(Vancomycin): binds directly to D-ala-D-ala wall Beta-lactam: binds to PBP Tetracyclines: block 30s ribosome Chloramphenicol: block 50s ribosome Macrolides: block 50s ribosome Sulfonamide: PABA analog Trimethaprim: block dihydrofolate reductase Fluoroquinoloes: block RNA topoisomerase (like DNA gyrase)