Test 3 Flashcards
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
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
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
What CFs are Vit K dependent? anything else?
CF II, VII, IX, X
Protein C and S
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
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
Walk through steps of fibrinolysis
Fibronilysis:
Endothelial cells replease tPA
tPA converts Plasminogen to Plasmin (after plasminogen’s bound to fibrin)
Plasmin cleaves Fibrin
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
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
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
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
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
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
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
Rivaroxaban/Apixaban, and Dabigatran/Argatroban/Bivalirudin MOA?
Rivaroxaban, Apixaban = Direct Factor 10 block
Dabigatran, Argatroban, Bivalirudin = Direct Thrombin (Factor 2) and Factor 10 block
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
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)
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
Differentiate vWD and Glanzmann’s thrombasthenia
vWD: vWF defect, doesn’t allow platelets to clot appropriately
Glanzmann’s thrombasthenia: GPIIb/IIIa defect
How can you treat ITP?
ITP tx: steroids IV IgG to compete w/macrophage activity against IGs splenectomy immunosuppression
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)
