Lecture 4.1 (unfinished) Flashcards

Question

1) What is ecchymoses? 2) Where does it occur? 3) What is the mechanism?

Answer 1

1) Bruises 2) Under sub-q 3) RBCs are degraded by macrophages Hemoglobin goes from blue  bilirubin (blue-green)  hemosiderin (golden brown)

Answer 2

Massive hemorrhage – blood loss, hypovolemic shock, exsanguination, death Hematoma – compression of tissues/compartments Compartment syndrome, (worst-case scenario for a hematoma)

Answer 3

Intracerebral hemorrhage – stroke, death Chronic hemorrhage – slow blood loss  iron deficiency anemia

Answer 4

1) Arteriolar vasoconstriction: Stop the flow! Local response (endothelin) won’t last long 2) Primary hemostasis: platelet plug

Answer 5

1) When the endothelium is broken > von Willebrand factor (vWF) is released 2) This promotes platelet activation  shape change! 3) Platelets release granules that recruit more platelets 4) This leads to platelet aggregation  primary hemostatic plug

Answer 6

Secondary hemostasis: fibrin clot Tissue factor is exposed from basement membrane  clotting cascade Thrombin turns fibrinogen into a fibrin clot

Answer 7

Clot stabilization and resorption Fibrin makes a solid, permanent scaffolding that stops further clotting Counterregulatory mechanisms come into play to limit too much clotting Tissue plasminogen activator tPA Plasmin breaks down fibrin Resorption and repair – mediated by interactions with endothelial cells

Answer 8

Clinical Testing A sign that clotting has been going on occurs when breakdown products of fibrinogen appear in the blood “fibrin-split products” One of these products, called D-dimer, is measurable This is what the “D-dimer” blood test is looking for

Answer 9

PT/INR addresses extrinsic pathway PTT addresses the intrinsic pathway *Note there are several “feedback loops” that amplify the sequence

Answer 10

Heparin-Like Molecule Activates antithrombin! Binds to thrombin  No more turning fibrinogen into a fibrin clot!

Answer 11

In their passive state are anticoagulant in the factors they emit After endothelial injury, they become procoagulant – for a time

Answer 12

Then they revert to anticoagulant to keep a balance They become anticoagulant by releasing tissue factor VIIa complexes that block VII activity

Answer 13

Thrombomodulin and endothelial protein C receptor Together, these bind thrombin and protein C in a complex on the endothelial surface This robs thrombin of the ability to “feedback” and activate coagulation factors and platelets – also keeps thrombin from forming clot Instead, thrombin activates Protein C

Answer 14

Protein C and its cofactor protein S are anticoagulants that disrupt the clotting pathway (Inhibits Va and VIIIa which are secondarily Vitamin K dependent)

Answer 15

Make you clot [taking away the anticoagulant will make you clot]

Answer 16

tPA made by endothelium Becomes active when bound to fibrin Given as medicine to break up clot Comes with a risk of bleeding

Answer 17

Prostacyclin (PGI2), nitric oxide, (both inhibit platelets) adenosine diphosphatase (degrades ADP: this affects clotting because ADP promotes platelet aggregation)

Answer 18

Acts by inhibiting vitamin K and depletes its reserves in the body The Liver uses vitamin K to synthesize factors II, VII, IX, and X This inhibits the extrinsic pathway and its effect is measured by PT/INR It is a notoriously unstable steady state and is often “tinkered with” in clinic Reversed, as you can imagine, by giving vitamin K

Answer 19

Made by the liver Activates antithrombin Inhibits thrombin Also given as medicine to prevent clotting It can be quickly reversed by giving Protamine Sulfate, which is soluble in the blood – binds to heparin

Answer 20

Xa inhibitors: Novel Oral Anticoagulants (anticoagulant) Act directly on Xa clotting factor Some reversal agents have been developed

Answer 21

Aspirin (antiplatelet) Binds irreversibly to platelets and inactivates them

Answer 22

P2Y12 inhibitors (antiplatelet) Block the receptor for ADP on platelets This inhibits the ability of ADP to activate platelets and promote clot

Answer 23

Because warfarin inhibits production of Protein C and S, causing a temporary procoagulant state, before the clotting cascade is fully blocked

Answer 24

What can go wrong? Factor V Leiden Mutation Protein C and S deficiency Antithrombin III deficiency Von Willebrand's disease

Answer 25

How do we intervene on other pathology with medicines that act on hemostasis? Blood Clots and Cardiovascular Disease Anticoagulate with heparin or NOAC now called (DOAC) Use ASA or P2Y12 inhibitors for antiplatelet therapy Lyse clot with tPA

Answer 26

1) Endothelial injury is most important 2) Abnormal blood flow? Turbulent flow irritates endothelium and leads to. . . . . . Endothelial injury 3) Hypercoagulability: (Well yeah)

Answer 27

Factor V Leiden mutation Anti-thrombin III deficiency Protein C and S deficiency Immobility! Cancer! Surgery! Tissue injury! Prosthetic valves Anti-phospholipid antibody syndrome Smoking Atrial fibrillation! Pregnancy and postpartum Oral contraceptives (esp. if smoking over 35)

Answer 28

Think endothelial injury or turbulent flow “Mural thrombi” – those occurring in aortic lumen and heart chambers Thrombi on heart valves are called “vegetations”

Answer 29

When deep these are called DVT When superficial they are called superficial thrombophlebitis Venous thrombi – almost invariably occlusive

Answer 30

1) Attach to underlying vascular surface and grow toward the heart 2) Arterial thrombi grow retrograde and venous extend with blood flow 3) Propagating portion

Answer 31

Emboli in circulation

Answer 32

1) intracardiac mural thrombi 2) Left ventricular wall infarcts Dilated left atria secondary to mitral valve defects Aortic aneurysm Atherosclerotic plaque

Answer 33

Arteriolar embolization often causes tissue infarction Major sites for venous emboli are lower extremities

Answer 34

1) Risk: Propagation It enlarges through addition of platelets and fibrin 2) Risk: Embolization It may move elsewhere in part or whole

Answer 35

1) Risk: Propagation 2) Risk: Embolization 3)Dissolution 4)

Answer 36

Dissolution Fibrinolytic factors may lead to its shrinkage Heparin will prevent spread

Answer 37

Organization and recanalization Old thrombi become organized by new endothelial cells, smooth muscle, and fibroblasts Capillary channels are formed The original lumen is restored (at least in part)

Answer 38

1) White Infarct (anemic): Arterial occlusion or Solid tissues 2) Red infarct (hemorrhagic): Venous occlusion

Answer 39

1) Anatomy of the vascular supply: Is there an alternative path? 2) Rate of occlusion: Did this develop abruptly? Is there time to divert to collateral blood supply? 3) Tissue vulnerability for hypoxia Ex: Is this the brain or skeletal muscle?

Answer 40

Autosomal dominant with incomplete penetrance Exacerbated by environmental factors Low incidence in Black and Asian and higher among Whites Physical exam DVT Possible PE

Answer 41

Factor V accelerates clotting Inheritance Risk One parent carries mutant allele 50% risk of child getting it 10% penetrance 5% lifetime risk

Answer 42

Heparin induced thrombocytopenia (HIT) Up to 5% of patients who get heparin Autoantibodies bind to complexes of heparin and platelet membrane protein and endothelial surfaces This results in platelet activation, aggregation, and consumption  also causes endothelial injury This leads to a PROTHROMBOTIC state! For this reason: PT/INR PTT always required for baseline before starting heparin

Answer 43

It occurs in some severe sepsis / shock, obstetric complications, advanced malignancy This is wide-spread clotting in the microcirculation all over the body At the same time, fibrinolytic mechanisms are activated Leads to profuse bleeding

Answer 44

Either by decreased cardiac output or decreased circulating blood volume – tissues are not being perfused Either something’s wrong with the pump or something’s wrong with the pipes Bad news Initially, cellular injury is. . . Reversible Until it passes the point of no return

Answer 45

1) In response to microbial infection; MC = Gram positive, then negative, then virus and fungi Cytokines release endothelial tight junctions and vessels leak Activated endothelium upregulates nitrous oxide and other vasoactive mediators Smooth muscle relaxes

Answer 46

Sepsis alters the expression of clotting factors, and it favors coagulation Cytokines (TNF and IL-1) increase tissue factor production TNF  Initiates clotting cascade Inhibits tissue factor pathway inhibitor, thrombomodulin, and protein C  hypercoagulable Also, dampens fibrinolysis! Vascular leakage diminishes the “washout” of activated coagulation factors One of the ways that clotting is regulated in normal physiology

Answer 47

Cytokines (TNF and IL-1) upregulate stress hormones glucagon, growth hormone, cortisol  this drives gluconeogenesis At the same time inflammatory cytokines suppress insulin release and promote insulin resistance in the liver Leads to hyperglycemia (added complication  Hyperglycemia decreases neutrophil function) So, the ability to fight infection is diminished After this phase, if enough time passes, there can be a respondent adrenal insufficiency and deficit of glucocorticoids

Answer 48

Leads to hyperglycemia

Answer 49

As the cells continue bearing the brunt of shock (inadequate perfusion) they become increasingly hypoxic, and lactic acid is produced, leading to lactic acidosis Blood pH drops

Answer 50

Systemic hypotension, interstitial edema and small vessel thrombosis all decrease oxygen and nutrients to tissues Mitochondria start to take damage due to oxidative stress Myocardial contractility starts to diminish Reducing cardiac output Increased vascular permeability leads to ARDS Finally, kidneys, liver, lungs, heart are all catastrophically effected, leading to death * Note well: severe shock by other means still leads to poor perfusion which can cause most of this to occur

Answer 51

The primary threat to life is the underlying initiating event, though cardiac, cerebral, and pulmonary changes aggravate the situation Prognosis varies with origin and duration

Answer 52

Organized into 3 concentric layers (more apparent in larger arteries Intima Media Adventitia

Answer 53

Clog the pipe Weaken the pipe Born with bad pipes

Answer 54

1) 2) 3) Congenital anomalies

Answer 55

Berry aneurysms

Answer 56

abnormal connections between arteries and veins that bypass capillaries May be benign, may cause abnormal shunting of blood into venous system Done intentionally for dialysis

Answer 57

irregular thickening of walls of medium to large sized arteries as a result of medial and intimal hyperplasia – results in luminal stenosis (clogged pipe) Seen in young women

Answer 58

1) Generalized: All arteries 2) Localized: Cerebral, Coronary, Aortic

Answer 59

Soft lipid core covered by firm fibrous cap Protrudes into lumen, obstructing flow (stenosis) Weakens underlying media (arterial wall) Plaque ruptures in vessel, thrombus forms Vessel wall expands – aneurysm and rupture

Answer 60

1) True, saccular: wall focally bulges 2) True, fusiform: circumferentially bulges 3) False: wall is ruptured, collection of blood bounded by extravascular tissues 4) Dissection: blood has entered wall of vessel and separated layers Tunica intima from media

Answer 61

1) Obstruction of branch vessel 2) Iliac, renal, mesenteric 3) Compression of adjacent structure 4) Abdominal mass 5) Rupture into peritoneal cavity – usually fatal

Answer 62

Atherosclerotic aneurysms occur most frequently in the abdominal aorta and common illiac

Answer 63

Left: Aortic aneurysm that ruptured (arrow) Right: Opened view with probe in rupture tract; wall of aneurysm is thin, lumen filled with thrombus

Answer 64

Aortic Sudden onset of excruciating pain Type A aortic dissection more common and more dangerous Most common cause of death is rupture into pericardial, pleural, peritoneal spaces

Answer 65

An autosomal dominant genetic disorder that affects the skeletal system, cardiovascular system, and eyes Individuals are tall and thin, with long arms and legs, and thin fingers Caused by a loss-of-function mutation in the fibrillin 1 (FBN1) gene Major component of microfibrils in ECM; scaffold for elastin

Answer 66

Peripheral resistance is mostly controlled by arterioles Neural and humoral factors Vasoconstrictors Vasodilators

Answer 67

Autoregulation comes from self protective response where vasoconstriction occurs from high blood flow to prevent hyperperfusion pH and hypoxia fine tune arterial tone to adjust perfusion of tissues

Answer 68

1) Giant-cell (Temporal) arteritis 2) Polyarteritis nodosa 3) Kawasaki disease 4) Thrombangiitis obliterans (Buerger disease)

Answer 69

Over 50-60 years of age Pain and tenderness 3) One-sided HA 4) Involves temporal artery Can involve ophthalmic artery and lead to blindness

Answer 70

Granulomatous inflammation with giant cells, lymphocytes, intimal fibrosis Possibly T-cell mediated autoimmune response to vessel wall antigen a) giant cells near fragmented internal elastic membrane Formed by fusion of epithelial cells and macrophages b) focal destruction of internal elastic membrane

Answer 71

Enlarged cervical lymph nodes, cheilitis, strawberry tongue, etc

Answer 72

Fever for 5 days + four of the following without other explanation: -Bilateral conjunctivitis -Oral mucous membrane changes -Peripheral extremity changes -Erythema of palms/soles, desquamation -Polymorphous rash -Cervical LAD at least 1 greater than 1.5 cm

Answer 73

Cause unknown Potential autoimmune component Appx 20% correlation with upper respiratory illness Now seen in SARS Covid 2 with “Kawasaki Like” illness Multisystem inflammatory syndrome

Answer 74

Affects medium-sized and small arteries, mainly of the extremities (especially tibial and radial arteries) Acute and chronic inflammation of the vessel wall, with luminal thrombosis Almost exclusively in heavy smokers, usually before 35 Cessation can be curative Thrombus typically contains microabscesses (arrow)

Answer 75

Superficial nodular phlebitis Cold sensitivity in the hands Pain in instep of foot Severe pain, even at rest Chronic ulceration of toes, feet, or fingers, which may be followed by gangrene

Answer 76

Most frequently associated with AIDs Forms of KS, similar viral pathogenesis Classic (European) Endemic (African) Transplant-associated (immunosuppression)

Answer 77

Particles with protein and phospholipid coats that transport cholesterol and other lipids in blood Low density lipoproteins (LDLs), 45% cholesterol High density lipoproteins (HDLs), 20% cholesterol

Answer 78

FH occurs among all races FH accounts for somewhat less than 5% of patients with hypercholesterolemia Familial hypercholesterolemia (FH) is a disorder of cholesterol and lipid metabolism caused by mutations in the low-density lipoprotein receptor (LDLR) gene

Answer 79

LDL receptor is expressed in the liver and adrenal cortex Hepatic LDL receptors clear half of intermediate-density lipoproteins and up to 80% of LDL from circulation by endocytosis Mutations occur through combination of large insertions, deletions and recombination involving Alu repeats Mutations in the LDLR gene disrupt production of LDL receptor and cause accumulation of plasma LDL

Answer 80

In heterozygotes, hypercholesterolemia usually manifests at birth and is the only finding in the first decade of life In heterozygotes of all ages, the plasma cholesterol concentration is twice as high in unaffected individuals In heterozygotes, arcus corneae and tendon xanthomas begin to appear by the end of the second decade

Answer 81

The development of coronary artery disease among heterozygotes depends on gender and age (e.g., at age 50, 50% of males have CAD and only 20% of females) Homozygous FH presents in the first decade of life with arcus corneae and tendon xanthomas. Plasma cholesterol concentration is twice that of heterozygotes and without aggressive treatment homozygotes will usually die by age 30.

Answer 82

Aggressive normalization of LDL cholesterol concentration is required to reduce the risk of CAD Rigorous adherence to a low-fat, high-carbohydrate diet usually produces only a 10-20% reduction in LDL cholesterol, which is usually insufficient Therefore, heterozygous patients receive bile acid sequestrants They block bile acid in your stomach from being absorbed in your blood Also they will be given statin drugs that inhibit hepatic cholesterol synthesis Also LDL apheresis Where LDL is filtered from the blood using a machine

Answer 83

Because FH is an autosomal dominant disorder, each child of an affected heterozygous parent has a 50% chance of inheriting the mutant LDLR allele