Exam 4 Review Flashcards
Diagram the process of thrombogenesis including the platelet phases and the roles of
the various mediators (PGI2, collagen vWF, ADP, TXA2, 5-HT)
Thrombogenesis begins with vascular injury, exposing collagen and von Willebrand factor (vWF) beneath the endothelium. Platelets adhere to these exposed elements via receptors (GP Ia for collagen and GP Ib for vWF). Adhesion activates platelets, causing them to release ADP, thromboxane A₂ (TXA₂), and serotonin (5-HT), which recruit and activate additional platelets. ADP and TXA₂ enhance aggregation, while 5-HT promotes vasoconstriction, helping to reduce blood flow to the area. Platelets link together through fibrinogen binding to GP IIb/IIIa receptors, forming a platelet plug. Thrombin then converts fibrinogen to fibrin, creating a stable clot. Prostacyclin (PGI₂), released from intact endothelial cells, inhibits platelet aggregation in uninjured areas, keeping the clot localized.
Intrinsic coag pathway
Collagen exposure → Factor XII → XIIa → Factor XI → XIa → Factor IX → IXa (+ Factor VIII and Ca²⁺) → Factor X.
Extrinsic coag pathway
Tissue damage → TF + Factor VII → VIIa → Factor X.
Common coag pathway
Factor X → Xa (+ Factor V and Ca²⁺) → Prothrombin (II) → Thrombin (IIa) → Fibrinogen (I) → Fibrin → (+ Factor XIII) Stable Fibrin Clot.
Describe the causative factors of DVT and the difference between white and red thrombi/thromboemboli.
Causes: Stasis (immobility), hypercoagulability, endothelial inury.
White: formed in high pressure arteries, mainly composed of platelets/fibrin.
Red: Forms in low-pressure veins with trapped red cells around a fibrin-platelet core, with a tail that can detach and cause embolism.
List the risk factors for DVT
Inherited conditions such as antithrombin III deficiency, protein C/S deficiency, sickle cell anemia, activated protein C resistance.
Acquired risks: bedridden, surgery/trauma, obesity, estrogen use, malignancies, chronic venous insufficiency.
DIC, include causes and treatments
DIC: disseminated intravascular coagulation, overstimulation of clotting leads to excessive clot formation, depletion of platelets, and bleeding.
Causes: massive tissue injury, malignancy and sepsis.
Tx involves plasma transfusion and addressing underlying cause.
HIT, Include causes and treatments
Heparin-induced thrombocytopenia
Immune response to heparin resulting in low platelet count and increased bleeding risk. Treatment includes discontinuation of heparin and possibly using alternative coags.
TTP, Include causes and treatments
Thrombotic thrombocytopenic Purpura
Widespread platelet aggregation and small clots in microcirculation, leading to thrombocytopenia and hemolytic anemia. Tx involves plasma exchange.
Draw the pathway for fibrinolysis including the mediators involved
t-pa, urokinase, streptokinase binds to plasminogen -> converts it into plasmin -> plasmin breaks down fibrin into fibrin degradation products (FDPs) including D-dimers.
List the four classes of coagulation modifier drugs, and examples of each.
Anticoagulants: warfarin, heparin
Antiplatelet drugs: aspirin, clopidogrel
Thrombolytics: Streptokinase, urokinase
Hemostatic/antifibrinolytic drugs: Aminocaproic acid, Tranexamic acid
Differentiate the indirect and direct thrombin inhibitors and briefly describe how each function to inhibit thrombin.
indirect: heparin and LMWH, enhance antithrombin activity, inactivating thrombin and Factor Xa.
Direct: bind directly to thrombins active sites, inhibiting thrombin without needing antithrombin.
Explain the difference between HMW, LMW, and Fondaparinux heparins, and the use of each.
High molecular weight: broad activity, less specific for factor Xa
LMW: more specific for factor Xa with fewer side effects
Fondaparinux: synthetic, selectively inhibits factor Xa, useful in HIT patients with less bleeding risk
List the toxicity and contraindications of HMW heparin and treatment
Toxicity: bleeding and thrombocytopenia
Contraindications: active bleeding, hemophilia, severe hypertension, intracranial hemorrhage, TB, hepatic disease
Tx: d/c heparin, use of protamine sulfate for reversal
Describe the laboratory testing for coagulation pathways and normal values.
prothrombin time: assesses extrinsic and common pathways, normal INR = 0.8 - 1.2
advanced partial thromboplastin time (aPTT): evaluates intrinsic and common pathways, normal = 35-45 seconds
List the oral anticoagulants, their MOA, and treatment considerations.
warfarin: blocks vitamin k recycling, reducing clotting factor synthesis. Requires close monitoring of INR and dosage adjustments.
Discuss treatment considerations and pharmacogenomics of warfarin treatment.
Considerations: start low and adjust based on INR, drug interactions, risk of bleeding.
Pharmacogenomics: variability in warfarin metabolism due to genetic differences can influence dosing and response.
List non-warfarin anticoagulant drugs and their targets.
Factor Xa inhibitors: apixaban, rivaroxaban
Direct thrombin inhibitors: dabigatran
List the various fibrinolytic drugs.
Streptokinase, urokinase, tPA (alteplase) activate plasminogen to plasmin, leading to fibrin clot breakdown
Describe the targets for the antiplatelet aggregation drugs aspiring, Plavix, Ticlid, and
abiciximab.
aspirin: inhibits thromboxane A2, reducing platelet aggregation.
Clopidogrel (plavix) and Ticlopidine (Ticlid): inhibit ADP receptors on platelets, preventing aggregation.
Abciximab: monoclonal antibody blocking the llb/llla receptor on platelets
Describe how bleeding disorders can be treated with Vit. K, plasma fractions,
desmopressin, aminocaproic acid, and tranexamic acid
Vit K: essential for clotting factor production
Plasma fractions: used to treat clotting factor deficiencies
Desmopressin: increases Factor VIII in mild hemophilia and von willebrand disease
Aminocaproic acid and TXA: inhibit plasminogen activation, reducing fibrinolysis in bleeding conditions.
Describe the exocrine and endocrine functions of the pancreas.
exocrine: pancreas acts as an exocrine gland by producing digestive enzymes, which are released into the duodenum to aid in the breakdown of proteins, fats, and carbs.
Endocrine: Involves the islets of langerhans, which contain different cell types, including beta cells that release insulin and alpha cells that release glucagon. These hormones regulate blood glucose in the body.
Contrast the roles of insulin and glucagon on blood glucose levels.
Insulin: released from pancreatic beta cells in response to high blood glucose levels, insulin facilitates glucose uptake by cells, thus lowering blood glucose. It also promoted glycogen storage in the liver.
Glucagon: secreted by pancreatic alpha cells when BG levels are low, glucagon increases blood blucose by stimulating glycogen breakdown in the liver (Glycogenolysis) and glucose production.
List the four main types of diabetes mellitus.
I: insulin dependent, caused by destruction of beta cells, leading to severe insulin deficiency. Auto-immune.
II: Non-insulin-dependent, commonly associated with insulin resistance and often linked to obesity.
III: Secondary to other conditions like pancreatitis, drug therapy.
IV: Gestational diabetes, during pregnancy due to insulin resistance from pregnancy hormones.
List the three cardinal symptoms of diabetes.
Polydipsia (Thirst), polyuria (urination), polyphagia (Hunger)
Describe the sorbitol pathway, and why it leads to peripheral neuropathy and blindness.
Conversion of excess glucose into sorbitol anf fructose. High BG levels lead to increased sorbitol in cells such as those in the lens, nerves, RBCs, resulting in osmotic stress as water is drawn in. Causes cell damage, contributing to peripheral neuropathy and blindness due to cellular swelling and rupture.
Differentiate the two types of diabetes tests.
Fasting BG test: measures BG after overnight fast to assess baseline glucose levels
Glucose tolerance test: after fasting, consumes high glucose drink, and blood samples are taken every hour over several hours to measure glucose tolerance.
Describe the structure of insulin, and the role of insulin secretagogues in its release.
Structure: peptide hormone with an alpha and beta chain connected by disulfide bonds. Inactive form (Proinsulin) it includes a C-peptide that is cleaved to activate insulin.
Secretagogues: glucose, certain amino acids, and incretins that stimulate insulin release by depolarizing the beta cell membrane, allowing calcium influx and vesicle fusion to release insulin.
- Delineate the insulin receptor pathway and the various types of glucose transporter
(GLUT).
Pathway: insulin binds to receptor, a tyrosine kinase, initiating phosphorylation that leads to multiple intracellular signaling cascades. This action results in GLUT translocation to the cell membrane, allowing glucose uptake.
GLUT2: found beta cells and liver; low affinity, active at high glucose levels.
GLUT 4: Common in muscle and adipose tissue; moderate affinity, responsive to insulin.
GLUT1/3: high affinity, found in brain and RBCs, enables uptake under low-glucose conditions.
List the four types of insulin preparation, and examples of each.
Rapid: lispro, aspart, glulisine
Short: regular insulin (humulin, novolin)
Intermediate: Neutral protamine hagedorn (NPH)
Long: glargine, detemir
Describe the types of insulin dosing regimens.
intensive: basal + bolus, using long acting for baseline and rapid acting for meal coverage.
Conventional: premixed insulin (70:30 mix) for less precise but easier dosing.
Insulin pump: provides continous subcutaneous insulin for tight control, adjusting for basal and bolus needs.
Calculate the units of insulin required given an example scenario.
If a patient is consuming 60g of carbs, and 1 unit of rapid acting insulin covers 15g of carbs, they need 4 units of insulin.
Correction factor: if glucose is 200mg/dL, and each unit lowers it by 50mg/dL, administer 2 units to reach target of 100mg/dL
List problems and treatments for hypoglycemia.
Problems: anxiety, blurred vision, sweating, slurred speech, shakiness, confusion.
Tx: 3-4 glucose tablets, 1/2 can of soda, glucagon injection if severe. (1mg IM, IV, SQ, repeat if needed)
List the eight classes of oral antidiabetic medications, their MOA, potential side effects, and examples of each.
Biguanides: Reduces hepatic glucose production. Example: Metformin. Side effects: GI upset.
Insulin Secretagogues: Increase insulin release by blocking potassium channels. Examples: Sulfonylureas, Meglitinides. Side effects: Hypoglycemia, cardiovascular risks.
Thiazolidinediones (TZDs): Enhance insulin sensitivity via PPAR activation. Example: Rosiglitazone. Side effects: Risk of MI.
Alpha-glucosidase Inhibitors: Delay carbohydrate absorption. Example: Acarbose. Side effects: GI issues.
Bile Acid Binding Resins: Reduce glucose reabsorption. Example: Colesevelam. Side effects: GI upset.
Amylin Analog: Suppress glucagon, reduce blood glucose. Example: Pramlintide. Side effects: Nausea.
Incretin-based Therapies: Enhance insulin release and inhibit glucagon. Examples: GLP-1 agonists (e.g., Semaglutide), DPP-4 inhibitors. Side effects: Risk of pancreatic issues.
SGLT2 Inhibitors: Increase glucose excretion in urine. Examples: Dapagliflozin, Canagliflozin. Side effects: Dehydration, weight loss.
Describe adjunctive therapies that may be useful in pre-diabetes.
lfiestyle modifications (diet control and exercise)
medications such as metformin
CV protection: blood pressure control with ACE inhibitors or ARBs
Lipid management: statins for LDL control, dietary fiber, and omega-3 fatty acids.
Diagram a treatment algorithm for patients with Type II diabetes.
initial step: lifestyle interventions
First line med: metformin
Second-line: sulfonylurea, TZD, or DPP-4 inhibitor
Third line or combo therapy: Add SGLT2 inhibitor, GLP-1 agonist, basal insulin
Regular monitoring of A1C, adjust treatment as necessary based on glucose levels and patient response.
Diagram the process of atherogenesis.
Endothelial injury: damage caused by things like high LDL, smoking, hypertension, diabetes
Lipid entry: LDL enters vessel wall and oxidizes
Monocyte activation: monocytes migrate, turn into macrophages, and engulf oxidized LDL to form foam cells
Fatty streak: foam cell accumulation creates early lesions
Smooth muscle migration: smooth muscle cells move to the intimate, proliferate, and form a fibrous cap
Plaque formation: a lipid core and fibrous cap reduce the vessel lumen
Plaque rupture: Cap rupture exposes the core, leading to thrombus formation and potential blockage.
Describe the difference between triglycerides and cholesterol.
Triglycerides: energy storage molecule made of glycerol +3 fatty acids, stored in adipose tissue. They are broken down into free fatty acids and glycerol for energy during fasting or in between meals.
Cholesterol: sterol used as precursors for cell membranes, hormones, bile acids, vitamin D. Not used as energy but is vital for structural and metabolic functions.
Differentiate free and esterified cholesterol.
Free: active form found in cell membranes and blood plasma. Helps maintain membrane fluidity.
Esterified: Cholesterol combined with fatty acids for storage and transport
List the two sources of cholesterol, and key elements of the mevalonate pathway.
Dietary (eggs, meat, dairy) which are absorbed in the intestine and transported via chylomicrons.
Also, liver synthesis (de novo).
Key pathway elements: Acetyl-CoA formation is the starting point -> HMG-CoA synthase converts acetyl-coa into HMG-CoA -> HMG-CoA reductase converts HMG-CoA into mevalonate (reductase is the target for statins)
Lastly, Mevalonate is processed into isoprenoids and squalene. Squalene is cyclized to form lanosterol, which is then converted into cholesterol.
Describe the different types of lipoproteins including their structure, how they are formed, and their role in lipid transport.
Chylomicrons: Largest lipoprotein. formed in intestinal cells called enterocytes, transport dietary triglycerides/cholesterol to tissues.
VLDL: formed in liver, transport glycerides to tissues
IDL: derived from VLDL after triglyceride delivery. Intermediate form; precursor to LDL
LDL: formed from IDL, “cholesterol rich” bad cholesterol; delivers cholesterol to tissues
HDL: synthesized in liver/intestines, protein rich, good cholesterol, removes cholesterol to the liver for excretion
Calculate coronary artery disease risk using the LDL/HDL ratio.
LDL divided by HDL = CAD risk.
Males:
1.0 = low risk
3.55 = moderate risk (average)
6.25 = high risk (twice the average)
7.99 = Very high risk (3 times average risk)
Females:
1.47 = low risk
3.22 = moderate risk
5.03 = high risk
6.14 = very high risk
List target levels of total cholesterol, HDL, LDL, and triglycerides.
Total: <200
LDL: <130
HDL: men >40, women >50
Triglycerides: <120
Differentiate between primary hypercholesterolemias and secondary causes.
Primary: Genetic mutations (familial caused by LDL receptor mutations). Key feature is extremely high LDL levels from birth, resulting in early-onset atherosclerosis
Secondary: Result of conditions or lifestyle factors, such as:
-Obesity
-DMII
-Hypothyroidism
-CKD
-Meds such as steroids or beta-blockers
Explain why dietary control of lipid intake may not be sufficient to lower cholesterol, and some dietary strategies.
Reason: liver compensates by increasing endogenous cholesterol synthesis when dietary cholesterol is reduced.
Strategies for dietary management:
-increase soluble fiber such as oats and legumes to reduce cholesterol absorption.
-consume omega-3 fatty acids (fish, flaxseed) to lower triglycerides
-Limit saturated fats and trans fats to reduce LDL protection
-Plant sterols and stanols, which will compete with cholesterol for absorption
List the six hyperlipidemia drug classes, their MOA, examples, and side effects of each.
Statins: inhibit HMG-CoA reductase to decrease cholesterol synthesis. Ex: atorvastatin, rosuvastatin. SE: muscle pain, liver enzyme elevation.
Niacin (Vit B3): reduces VLDL and LDL synthesis; increases HDL. Ex: Niaspan. SE: flushing, GI upset, liver tox
Fibrates: Activate PPAR-alpha to enhance triglyceride metabolism. Ex: fenofibrate, gemfibrozil. SE: GI upset, gallstones
Bile acid resins: Bind bile acids in intestine, forcing liver to use cholesterol to produce more bile acids. Ex: cholestyramine, colestipol. SE: constipation, bloating
Cholesterol absorption inhibitors: Inhibit NPC1L1 transporter to block dietary cholesterol absorption. Ex: ezetimibe. SE: GI upset, rare liver tox
PCSK9 inhibitors: monoclonal antibodies prevent LDL receptor degradation, increasing LDL clearance. Ex: evolocumab, alirocumab. SE: injection site reactions
Explain the novel MOA of PCSK9 inhibitors.
PCSK9 binds to LDL receptors and promotes their degradation. So, the Inhibitors block PCSK9 activity, preserving LDL receptors on the livers surface, enabling more LDL to be removed from the bloodstream. LDL reduction up to 65% when combined with statins
List possible risks of hypocholesterolemia
-increased cancer risk due to impaired cell repair
-hemorrhagic stroke
-anxiety and depression (cholesterol needed for brain function)
-preterm birth and low birth weight
-impaired wound healing
Define NSAIDs and give examples.
Relieve pain, fever, inflammation by inhibiting cyclooxygenase enzymes. Aspirin, ibuprofen, naproxen, diclofenac, celecoxib
Diagram the major cell damage pathways (COX, LOX).
COX pathway: converts arichidonic acid to prostaglandins which mediate pain fever and inflammation.
LOX pathway: converts arachidonic acid to leukotrienes which are involved in bronchoconstriction and vascular permeability
Differentiate the two COX isoforms.
COX-1: constitutive, widely distributed, involved in homeostatic functions like gastric protection and platelet aggregation.
COX-2: inducible, expressed during inflammation, promotes inflammatory response.
