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The exposure of tissue factor (TF) to the circulation. The expression of TF determines when and where coagulation begins. It is important to recognize that the production and expression of TF is evanescent. In the absence of persistent stimulation, TF levels may return to normal within hours of trauma, for example. Subsequent steps in clotting are independent of TF expression.
-Converting fibrinogen to fibrin (cleaves fibrinogen)
-Activating platelets via two members of the protease-activated receptor (PAR) family
-Activating protein C, which isresponsible for limiting the extent of thrombin formation
Tissue factor forms complexes with single chain Factor VII (FVII), which has a small amount of enzymatic activity, as well as with the fully active two chain form of the molecule, Factor VII (FVIIa).
Factors X and IX. The end products of the reaction are FXa and FIXa, respectively. The FXa pathway is is currently believed to be the initial pathway by which thrombin is formed. The FIXa pathway is currently viewed as a critical reinforcing step that accelerates formation of additional FVIIa.
Factors Va, Xa, Ca++ and phospholipids form a machine (the “prothrombinase complex”), which catalyzes the cleavage of prothrombin to thrombin.
The co-factors orient FXa with respect to prothrombin, accelerating the velocity of the reaction almost 10,000 fold.
TFPI is an endogenous inhibitor of the tissue factor pathway. It shuts down theTF/VIIa/Xa complex.
When prothrombin is cleaved, a small peptide is released, known as F-1.2. The concentration of F-1.2 in plasma canbe measured immunologically and is sometimes used as a sensitive marker of thrombin formation, T or F?
A transglutaminase, FXIIIa, which makes the stabilizes the polymers and makes the clot more resistant to proteolysis.
The PT is reported in seconds with a normal range that varies from lab to lab and with the reagents used, but is typically 9-11 sec.
Pathway #2 allows thrombin generation to continue when TFPI blocks the TF/VIIa/X complex. Thus, thrombin production can be reinforced.
Factor VIII is a scaffold protein that binds Factor IXa and greatly accelerates the conversion of Factor X to Xa. The complex is known as the “intrinsic ten-ase” because it cleaves Factor ten (X).
Two critical steps in the primary reinforcement clotting pathway, pathway 2, use co-factors to accelerate the reactions. What are those cofactors?
An additional way cleave and activate Factor IX in vivo is by the protease, Factor XIa. There are two ways to cleave and activate Factor XIa. One way involves thrombin, T or F?
A second way to convert Factor XI to XIa is by the contact factor or intrinsic pathway, T or F?
The primary pathway for blood coagulation begins with the formation of the TF/VIIa complex, which leads to thrombin generation through the combined effects of activating Factor X directly or activating Factor IX, which then cleaves and activates Factor X. Factor Xa then cleaves and activates prothrombin (Factor II) to form thrombin (Factor IIa). This pathway is called the extrinsic pathway because it is initiated by tissue factor, which is extrinsic to the blood.
FXII, PK and HMWK are collectively known as contact factors because they are responsible for the clots that form when blood or plasma that has not been anticoagulated sits in contact with a charged surface.
People who do not make FXII, PK or HMWK have a bleeding disorder, T or F?
Factor XIIa is a protease. Once FXIIa is produced by by PK and HMWK, it cleaves coagulation factor XI. Factor XIa, in turn, activates Factor IX to form FIXa, leading to FXa and thrombin formation.
The aPTT test test reflects the level of many coagulation proteins including FXII, HK, PK, FXI, FIX, FVIII, FV, FX, prothrombin and fibrinogen, T or F?
Thus, the most markedly prolonged aPTT times (>100 sec) may be found in people with factor VIII or factor IX deficiency (hemophilia A and B), T or F?
Serine proteases, such as IIa, VIIa, IXa, Xa, XIa, and XIIa are prime targets for endogenous regulators and anticoagulant drugs, T or F?
The INR is the ratio of the patient’s PT to the mean control PT in the lab at the same time. The ratio is then adjusted by an exponential constant that is empirically determined by the manufacturer of the batch of TF- containing reagent in use in the lab that same day. In other words, the INR is intended to minimize the effects of determining the PT in different labs and with different reagents and devices.
Tissue factor pathway inhibitor (TFPI)
Activated protein C cleaves and inactivates Factors Va and VIIIa, slowing thrombin production.
-Limits clot size.
-Degrades clots when no longer required.
Plasmin degrades the clot, ideally when you no longer need it
D-dimers are FXIII-crosslinked fragments of polymerized fibrin.
Thrombin converts fibrinogen to fibrin
FXIII cross-links fibrin
Plasmin cleaves fibrin into discrete fragments
D-dimers are FXIII-crosslinked fragments of polymerized fibrin.
D-dimer levels are increased in patients with thrombosis and DIC.
What are some major causes of cellular injury?
What four cellular systems are particularly susceptible to injury by many cellular insults?
Provide an example of free radical damage.
Differentiate between hypoxia and ischemia.
What are 4 ways in which cells adapt to non-lethal stimuli.
What are some characteristics of coagulative necrosis?
Distinguish between apoptosis and necrosis.
Describe the role of the following activators of apoptosis and be able to identify where in the apoptosis pathway they act: BH3-only Bcl-2-family proteins, Bax, Bak, Cytochrome c, Apaf-1, initiator caspases, and executioner caspases.
List an anti-apoptotic member and a pro-apoptotic member of the Bcl-2 family of proteins and explain why the ratio of these different members is important in apoptosis.
Multi-domain anti-apoptotic: Bcl-2, Bcl-XL, and MCL-1 each contain four “BH” (Bcl-2 Homology) domains, BH1, BH2, BH3, and BH4.
Multi-domain pro-apoptotic: Bax and Bak lack the BH4 domain, but contain BH1, BH2, and BH3 domains.
BH3-only pro-apoptotic: Bad, Bid, Bim, and Noxa/Puma contain only the BH3 domain.
The ratio of pro- to anti-apoptotic proteins sets the threshold of susceptibility to apoptosis for the intrinsic, or mitochondrial, pathway.
Describe why permeability of the outer mitochondrial membrane is important in the intrinsic pathway of apoptosis.
List two general types of signals that can initiate apoptosis.
Hypoxia tends to injure tissue more rapidly than ischemia, T or F?
Graves’ Disease. Autoimmune disease associated with HLA-B8 and HLA-DR3. The female-to-male ratio is approximately 7 to 1. Very common, affecting up to 1.5% of women in the U.S. Usually mild, but sometimes deadly.
Etiology: Autoantibodies that bind to the Thyroid Stimulating Hormone (TSH) receptor.
Pathogenesis: Anti-TSH-receptor antibodies mimic TSH, and induce increased thyroid hormone synthesis.
Morphologic changes: Thyroid hyperplasia.
Clinical significance: Hyperthyroidism.
Thyroidhormone is pre-synthesized and stored as a colloid called thryoglobulin orthyroid colloid. What you see above is several “lakes” of stored thyroglobulin. The darkdots are the nuclei of the thryoid cells, which line the “shorelines” ofthe colloid lakes. Red blood cells are evident in the capillaries in the “isthmuses”between the lakes.
Transversesections of the heart showing cardiac hypertrophy secondary to hypertension(lower right). Note the thickness of the ventricle walls, and the ratio ofthose thicknesses to the size of the ventricular lumens. When the heart mustpump against higher pressures, the individual cells increase in size inresponse to the increased demand for function.
Thisslide shows a normal anterior horn of the spinal cord. Note the prominent cell bodies (large darkblobs) of the motor neurons.
Etiology:Mutations in the Survival Motor Neuron 1 (SMN1)gene, which encodes a protein involved in RNA processing.
Pathogenesis:Loss of SMN1 protein function results in abnormal RNA processing. Motor neuronscannot tolerate this and die.
Morphologicchanges:Denervation atrophy of skeletal muscle.
Skeletal muscle, Atrophy:
Theupper left is normal and the lower right is atrophic. Note the obviousdifference in cross-sectional areas of the cells. (Partial nerve damageaccounts for the two distinct populations of muscle cells in this micrograph.)
Aftersmoking for a time, the normal bronchial epithelium starts undergoing squamousmetaplasia. Note how the epithelial cells are layering and flattening out, andthe absence of cilia.
Free radicals are atoms with an unpaired electron, which makes them very highly reactive.
Free radicals can be generated by:
Parkinson's; protein misfolding
A)a normal substantia nigra(dark crescents), B) de-pigmented substantia nigra inidiopathic (cause-unknown) PD, and C) Lewy bodies in a substantia nigraneuron (bright pink circles).
Parkin is an E3 ubiquitin ligase, with alpha synucleinamong its substrates; loss of Parkin function leads to an increase in misfoldedalpha-synuclein
Proteinmisfoldingplays an important role in PD.
Thearea of necrosis in the center bottom is surrounded by a red, hyperemic border.Red blood cells are piling up since their entry into the necrotic area isimpaired.
Thisis the area of necrosis secondary to ischemia. Note that you can still seewhere the glomerulus was, as well as where several tubules were. Maintenance oftissue architecture is characteristic of coagulativenecrosis, in which proteins denature and coagulate. Note also that the nucleiare essentially absence, which is also characteristic.
-hydrolytic enzymes predominate over protein denaturation.
-rapid softening with loss of cell outlines (in contrast to coagulative necrosis).
-characteristic of brain tissue necrosis and after some inflammatory reactions (pus).
-Ex: Cardiac abscess secondary to bacterial endocarditis.
Thespace just left of center in the coronal brain section shown above was filledwith liquefactivenecrosis fluid. The lesion was caused by ischemia secondary to an embolus, asin the example of coagulativenecrosis in the kidney. Same inciting cause, different tissue, differentpattern of necrosis.
-Combination of coagulative and liquefactive necrosis
-Principally associated with Tuberculosis (Tb).
-Cells are not totally liquefied, but their outlines are not preserved
-Necrotic area is classically surrounded by a granulomatous inflammatory wall
-Material in the center is typically referred to as 'cheesy'.
Clinicalsignificance:Primary lesions of the lung can undergo fibrosis and calcification.Reactivation and/or dissemination, due to high virulence or susceptibility(AIDS, for example), can be deadly
Notethe delicate, lacy appearance of the alveoli in the normal lung.
Immunohistochemistryfor bcl2 Protein
Left,Follicular Lymphoma; Right, Normal
Inimmunohistochemistry, cells are treated with a protein-specific antibodycovalently linked to an enzyme that converts a substrate into a coloredproduct. Note that follicular B cells normally express very little Bcl-2protein, whereas Bcl-2 expression in the follicles from the lymph node withfollicular lymphoma is very high, as indicated by the dark staining.
Which of the following is generally more characteristic of necrosis than apoptosis?
a. Loss of membrane integrity and release of intracellular contents.
b. Involvement of only a single cell.
c. Activation of caspases.
d. The absence of an inflammatory response.
Whichone of the following is associated with activated apoptosis?
a.Decreased transcription of a BH3-only Bcl2-family protein.
b.Up-regulation of Bcl2.
c.Multimerization of Bak and Bax in the outer mit. mem.
d. Decreased permeability of outer mit. mem.
An untreated bacterial urinary tract infection spreads to the kidney. An absess forms, and a portion of the kidney is destroyed by hydrolytic enzymes, leaving behind only pus. This is most characteristic of which type of necrosis?
Liquefactive necrosis (check with someone else to see if correct)
(Clinically aka “clot” or “blood clot”;
implies clot formed before death)
Platelets arise through an incompletely understood process from megakaryocytes located within the bone marrow.
In addition to serving as a site for normal platelet destruction, the spleen also serves as a site where platelets are transiently sequestered, T or F?
At any given time under normal conditions, what percentage of platelets are located in the spleen?
2. The phospholipids in the platelet plasma membrane form a surface which greatly accelerates the reactions that leading to thrombin generation and fibrin formation, including the activation of factor X to factor Xa and the conversion of prothrombin (factor II) to thrombin.
B. Interaction w/ a variety of circulating molecules that bind to receptors on the platelet surface. The most important is thrombin. B/c thrombin is an end-product of clotting cascade, blood clotting and platelet aggregation are synergistic.
C. ADP and TxA2 can also activate platelets
Platelets arrest on and adhere to 1 or more components of the connective tissue, including collagen. This process is facilitated by von Willebrand's factor (VWF), a high molecular weight multimeric protein that is synthesized by endothelial cells and megakaryocytes. The importance of von Willebrand's factor in this process is indicated by the fact that people who lack VWF have a bleeding disorder called von Willebrand's disease. Adhesion initiates platelet activation.
Activated platelets stick to each other because intracellular signaling in response to platelet agonists causes a necessary conformational switch in alpha 2b beta 3 integrins, allowing the integrin to bind fibrinogen. Shape change isn't required and granule secretion helps to the extent that it makes additional agonists available.
The phospholipids in the platelet plasma membraneform a surface which greatly accelerates the reactions that leading to thrombin generation andfibrin formation, including the activation of factor X to factor Xa and the conversion of prothrombin (factor II) to thrombin.
Glanzmann’s thrombasthenia is a rare bleeding disorder in which platelets fail to express the two proteins (glycoproteins IIb and IIIa, currently better known as the integrin IIb3) that form the fibrinogen receptor, rendering them unable to aggregate, T or F?
As the count drops,less TPO is bound to circulating platelets,leaving more free TPO to stimulate megakaryopoiesis in the bone marrow. This regulates the platelet count. T or F?
Ecchymoses and petechiae in a child with ITP
Immune destruction/ increased destruction of platelets.
Idiopathic thrombocytopenic purpura(ITP): A common autoimmune disorder,
especially in young women which is due to the production of antibodies that bind to the patients platelets. In children this is an acute, self-limiting disease. Inadults it is usually chronic and requires treatment with steroids, -globulin and splenectomy.
- 6y.o. girl with easy bruising and frequent nose bleeds. Neg. family hx.
-Flow cytometry: diminished surface expression of aIIbb3 (GP IIb-IIIa).
-Western blot: Decreased expression of aIIb and b3.
-Sequencing: Deletion in the mRNAtranscripts for aIIb.
Diagnosis: Glanzmann’s thrombasthenia (fibrinogenreceptor deficiency) resulting in a failure of platelet aggregation.
Clinical implications: Easy bruising. Epistaxis. Menorrhagia (heavy periods) as anadult. Platelet transfusions before surgery and for bleeding. Gene therapy?
Aggregation studies reflect hisuse of aspirin, but are otherwise normal.
Diagnosis: Platelet activation in the wrong place due toa combination of vascular wall disease and the platelet sensitizing effects ofdyslipidemia.
Clinical implications: Control of dyslipidemiaand hypertension. Lifestyle changes. Additional anti-plateletagents. Angioplasty?
A trigger for platelet destruction is prod. of ITP autoantibodies.Abs to platelet glycoprotein IIb/IIIa complex and other autoantigens bind to platelets, and mediateuptake by reticuloendothelial (spleen and liver) macrophagesthrough Fcγ receptors. Platelet proteins are degradedand displayed on the macrophage cell surface in a complex w/ CD154.
Macrophages are antigen-presenting; Autoantibodiesperpetuate the cycle of platelet destruction.
1) the Bernard-Soullier syndrome,the platelets lack the receptor for VWF,
2) Glanzmann's thrombasthenia, platelets lack receptors for fibrinogen and therefore cannot aggregate,
3) storage pool deficiency, one or more types of secretory granules is missing
4) procoagulant activity (PF3) deficiency, the platelet surface is unable to promote clotting.
5) von Willebrand's disease which is due to quantitative or qualitative defects in von Willebrand's factor (not rare)
Onthe left, one sees a vessel packed with red cells. This is an example of congestion or stasis. On the right we see the process of margination. Neutrophils have settled out of thecirculation, and are lining up against the endothelium of the blood vessel.
-Mediated by histamine, bradykinin, leukotrienes
Leakiness can also be induced by direct injury to blood vessels, such as in burns or infections.
Likewise, leakiness can be induced by leukocytes themselves, mediated by toxic oxygen species and proteolytic enzymes.
Thisis an example ofedema involving an organ, in this case the kidney. On the left is a normal kidney. The renal tubules are closely packed together(“back to back”). On the right is anexample of severe edema. This is from atransplanted kidney undergoing rejection, with marked interstitial edema. Due to the increased fluid in the interstitium, thetubules are widely separated from each other by edema fluid (which stains pinkdue to its protein content).
A transudate has a low specific gravity (Robbins defines a transudate as a fluid with a SG of less than or equal to 1.012). An ultrafiltrate of plasma, it is typically clear to straw colored, like a glass of tea. Think cyst.
On the other hand, an exudate has a high specific gravity (greater than 1.020), reflecting more protein, and even the presence of blood cells. They tend to be thicker and cloudier, like these milkshakes. Think abscess.
This isanother example ofsuppurative inflammation: purulent meningitis.
Theimage on the left is from an autopsy case of meningococcal meningitis. Theunderside of the brain is coated with a dirty yellow purulent exudate.
On the right is the microscopicappearance of acute meningitis. Note the acute inflammatory infiltrate (neutrophils) within themeninges, overlying the cortex.
Here is an example of a gastriculcer.
The histologic image demonstrates that the inner lining,or mucosa of the stomach, normally lined by tall glands) has totally eroded,leaving a deep ulcer crater.
Selectins help mediate leukocyte adhesion, T or F?
Chemotactic substances include N-formylmethionine (a bacterial wall product), complement component C5a, leukotriene B4 and chemokines (cytokines that affect leukocyte movement), T or F?
Leukocyte activation allows leukocytes to effectively attaintheir full defensive capability. Some ofthese important functions include:
Degranulation and secretion of lysosomalenzymes, and generation of the oxidative burst, which refers to the production ofpowerful oxygen radicals (microbe killers) during phagocytosis.
Modulation of leukocyte adhesion molecules.
Secretion of cytokines (proteins that modulate the function ofother cell types and fine-tune the inflammatory response).
An important mechanism for killing microbes is the production of the hypochlorous radical, generated from hydrogen peroxide by the enzyme myeloperoxidase, through an oxygen dependent pathway, T or F?
Leukocytes have O2 independent pathways to kill microbes, largely through increasing membrane permeability. Important substances w/in lyosomal granules include:
-BPIP: bactericidal permeability increasing protein
-Major Basic Protein: found in eosinophils, kills parasites
Major roles of complement components in inflammation:
Deficiency of one an antiprotease (alpha-1-antitrypsin) is a leading cause of emphysema, and is also a cause of liver cirrhosis (which is fibrosis of the liver), T or F?
Thediagnosis is established by the use of a special silver stain that demonstratesthe corkscrew-like spirochetes within the lesion.
Notsurprisingly, joint damage (arthritis),is the principle focus of this disease. Illustrated here on the left is normal synovium. Synoviumis the usually thin membrane which lines and lubricates our joints. Note how the surface on the L is flat, and there arevery few inflammatory cells.
Thephotomicrograph on the right was obtained from a patient with silicosis, anddemonstrates a dense scar cuffed by chronic inflammatory cells. Silica, when ingested by macrophages, causesrelease of a number of mediators, of which TNF is perhaps the most important incausing fibrosis.
Thesebright red large granules, as you can see in this circulating eosinophil,contain major basic protein, which is toxic to parasitic worms, but also verytoxic to mammalian tissue, causing tissue damage.
Thisand the following slide demonstrate the histologic appearance of granulomas.The arrows are pointing to epithelioid macrophages. Note the abundant pinkcytoplasm.
Noclear cell borders
Thesephotomicrographs demonstrate granulomas with giant cells. Note that the nuclei in the giant cells inthe left panel have a wreath-like arrangement (these are Langhansgiant cells). The right hand paneldemonstrates a giant cell with haphazardly arranged nuclei (foreign body-typegiant cells).
Notethe epithelioidmacrophages which make up the majority of the cells in both images.
The rise in plasma fibrinogen serves as the basis of a useful clinical test for inflammation, the ESR, or erythrocyte sedimentation rate, T or F?
-Facilitates platelet adhesion to injured endothelium
-Binds and carries coagulation Factor VIII in plasma
Von Willebrand Disease (bleeding)
VWFwithin Weibel-Palade bodies in endothelial cells
VWF is made by endothelial cellsand megakaryocytes. cv
Treatment options for vWFD are
Factor VIII deficiency.
In hemophilia, the most common sites of bellying are :
Why are hospitalized patients at risk for venous thrombosis and pulmonary
-Medications and abnormal proteins in blood may interfere w/ clotting
-Pts may have conditions (cancer) that increase risk of clotting
-Pts may have laboratory abnormalities due to interfering substances or antiphospholipid antibodies that do not reflect pts' bleeding or clotting risk
Prophylaxis reduces risk
How does disseminated intravascular coagulation (DIC) occur and why is it a dangerous
-DIC occurs when there is ongoing stimulation of coagulation that overwhelms the normal regulatory mechanisms which keep coagulation in check. It is thought to be initiated by exposure of the blood to tissue factor (TF).
-Induction of coagulation w/ fibrin formation stimulates release of plasminogen activators, resulting in fibrinolysis. As both coagulation and fibrinolytic systems remain stimulated, clotting and inhibitory factors consumed faster than produced.
Can have abnormal lab w/o symptoms. 2 options:
1) changes are mild
2) something interferes w/ lab. assay that has no clinical consequence, eg. lupus anticoagulant. Lupus anticoagulants are antibodies against phospholipid-binding proteins, or occasionally phospholipids directly, that interfere w/ phospholipid-dependent coagulation testing in vitro. They are usually not associated with underlying disease. Most common sign is a prolonged aPTT. Risk factor for thrombosis.
Pregnancy increases the risk of VTE 5-6 fold, with a greater day-to-day risk in the 6-8 weeks following delivery.
Thrombotic risk is further increased in women who are at bed rest; have delivered by C-section; w/ inherited thrombophilia.
When thrombosis occurs it is usually in L leg or L iliac venous system. The predominance of L side may be due to compression of L iliac vein by R iliac artery, as the artery (w/ increased flow) crosses the vein.
Conditions ass. w/ DIC: tissue damage, infections, neoplasia, and obstetrical conditions.
Treatment of the DIC includes treatment of the underlying cause and replacement of the factors being consumed. This is usually done with transfusions of platelets and fresh frozen plasma (FFP), which will replace the clotting factors. If the fibrinogen remains low despite FFP treatment, the blood product cryoprecipitate, which is enriched in fibrinogen is used.
DIC can show:
Arterial embolism can occur through a Patent foramen oval (PFO)
ANTITHROMBIN (Anti- thrombin III) protein is responsible for 80% of thrombin neutralization in your blood. It is the a major inhibitor of thrombin and Factor Xa.
In the general population, 0.2 - 0.4% have some degree of deficiency, which can cause thrombophilia.
T or F?
Testing: Do NOT measure antithrombin levels right after the patient had a clot:
-Antithrombin levels decrease by 30% while the patient is heparinized.-Antithrombin is consumed during an acute episode
Higher doses of heparin (heparin cofactor II binds heparin and inhibits thrombin), warfarin, purified ATIII concentrates (not great), or anabolic steroids.
Proteins C and S are Vit. K dependent anticoagulants that together inhibit Factors Va & VIIIa. Deficiency of protein C is relatively common. Deficiency causes thrombophilia, typically venous clots.
T or F?
Protein C deficiency:
-Can present as newborns with purport fulminates
-Coumadin-induced skin necrosis typically occurs in protein C-deficient heterozygotes during first several days of coumadin (warfarin) therapy
For both: Test w/ functional assay. But, do NOT test during an acute event - they are consumed by body's efforts to limit clot formation. Nor during coumadin therapy, since both require Vitamin K dependent gamma carboxylation for synthesis.
Fully anti-coagulate with heparin prior to initiation of coumadin. Consider purified Protein C concentrates or anabolic steroids.
Most APC Resistant Plasma Contain Factor V Leiden
Test: Resistance of aPTT to activated protein C is often unreliable, genetic testing for the point mutation is better. Genetic test unaffected by clotting events; can test at any time.
Rx: Higher risk of clotting than gen. pop., but lower than APC, APS, ATIII. Unclear whether to treat longer after thrombus or prophylactically.
The molecular mechanism is thought be due to increased prothrombin mRNA stability and hence increased prothrombin protein synthesis or it may merely be genetically linked to the real reason.
Can do genetic test.
Treat like other patients w/ anticoagulation. Unclear whether to treat longer after thrombus or prophylactically.
Unfractionated heparin (UFH):
-large heparin molecules in UFH can inhibit thrombin and factor Xa.
·Given IV or SQ
-short half life
-smaller molecule, shorter range
-molecules large enough to bind to (and activate) AT-III, but not large enough to bind to thrombin
-effective against Xa, but NOT against thrombin (IIa).
-longer half-life (give less frequently)
-fewer risks (bleeding, thrombocytopenia)
-dosed by weight
-aPTT 1.5-2 x baseline (typically 55-80 sec).
-heparin assay: 0.2 -0.4 u/ml
-Monitor Increased PT ( and sometimes aPTT) with target International Normalized Ratio (INR) of 2-3
-Toxicity causes bleeding (from vit. K depletion), embryopathy during 1st trimester, skin necrosis
-Tissue-type plasminogen activator (tPA)
-Plasminogen goes to plasmin
-Plasmin cleaves fibrinogen and fibrin
Antiplatelets are drugs that work either by inhibiting thrombin or Factor Xa or by decreasing the level of competent prothrombin and other zymogens, T or F?
Antiplatelet agents - Inhibit platelet plug formation by inhibiting platelet activation or preventing platelets from sticking to each other.
Fibrinolytic agents - Accelerate degradation of existing fibrin clots, T or F?
1) inhibit platelet activation by blocking agonist receptors on the platelet surface, especially ADP receptor antagonists (Clopidogrel (Plavex), Prasugrel)
2)inhibit platelet activation by blocking signaling mechanisms inside the platelet (aspirin, dipyridamole)
3) Drugs that prevent activated platelets from binding fibrinogen by blocking the fibrinogen binding site on the integrin IIb3. Examples include Abiciximab (ReoPro), Integrilin and Tirofiban.
Heparin-associatedthrombocytopenia with thrombosis (HATT)
Mechanism: antibodies that recognize the heparin/PF4 complex bind to platelet Fc receptors, triggering platelet activation. These antibodies may also activate macrophage, yielding TF-bearing micro particles.
What can happen when you are taking broad-spectrum antibiotics and not eating?
Can run out of vitamin K
The major source of vitamin K is food, particularly green leafy vegetables. A secondary source is gut bacteria. Under normal circumstances, all of us store approximately a one week supply of vitamin K in our livers.
Bound warfarin binds to albumin in blood; The free form of warfarin gets into liver
In liver, Cytochrome p450 system gets rid of drugs and toxins. However, other drugs can outcompete warfarin for binding spots on albumin. Drugs that displace warfarin from albumin increase the amount of free warfarin, making warfarin levels seem to go up.
Drugs that increase P450 expression decrease the effects of warfarin.
Drug interactions can result in too big or too small effect
Warfarin-induced skin necrosis
B/c of the risk of this, you should never start coumadin (warfarin) without first starting heparin. AKA, therapy in transition (heparin followed by coumadin)
Since Coumadin can be taken orally, it can be given easily to outpatients provided the dosage is closely monitored. Typically, coumadin is given to patients with venous or arterial thrombosis as a follow-on to heparin in order to prevent recurrence. Other common indications include atrial fibrillation, the presence of a mechanical prosthetic heart valve, prophylaxis of venous thrombosis in certain high risk situations and for poisoning rats.
A. Aqueous (passive) Diffusion
B. Lipid Diffusion
C. Special carrier mechanism
A. Aqueous Diffusion
B. Lipid Diffusion
C. Special carrier mechanism
-Division of parenchymal cells in intact stromal environment (liver after carbon tetrachloride)
-Compensatory division of parenchymal cells in remaining structure (after partial hepatectomy)
- Stem cell division and differentiation of progeny (satellite cells in skeletal mus.
Regeneration occurs readily in highly proliferative tissues (“labile cells”), like the GI epithelium, Epidermis, and Bone marrow. It can be more limited in tissues that normally divide at low rates, such as liver, kidney, and vascular endothelium, T or F?
Note the wavy, disorganized collagenfibrils in this two-week old wound.
Trichrome stains, showing collagen in blue,of A: Granulation tissue with blood vessels, edema, and a loose ECM containingoccasional inflammatory cells; minimal mature collagen can be seen at thispoint; and B: Mature scar, showing densecollagen, with fewer and more intact blood vessels. Granulation tissue contains substantialamounts of type III collagen, which is replaced by type I collagen in themature scar.
Which one of the following is required for proper
assembly and crosslinking of collagen?
a) glutamate oxidase
b) vitamin A
c) vitamin C
d) factor XIII
Which one of the following is a principal component of granulation tissue?
b) leaky capillaries
d) Schwann cells
Which one of the following is most critical for proper scar remodeling?
a) collagen proteolysis
b) elastin crosslinking
c) fibrin degradation
d) FGF glycation
a) collagen proteolysis
Hyperemia: Local increased blood volume
- Active process
- Increased arterial inflow blood due to arteriolar dilation
- “Redder” tissue (↑ oxgenated blood), (erythema)
Congestion: Local increased blood volume
Paradoxical: venous thrombus goes into systemic arterial circ.
- inflammation, trauma, hematologic disorders
-solid organs w/ one blood supply
-Apex points towards occluded vessel
-infarct in organ with 2 blood supplies, (lung, liver)
-white infarct with repercussion (eg. MI treated w/ thrombolytic agents)
-infarction in organs with a single venous drainage (ovary, testis)
DVT: Congestion & Edema
Theseimages show 2 examples of lower extremity DVTs associated with congestion andedema in the affected leg. Not all DVTsare this dramatic appearing.
Congestion& edema often occur together
Nutmegliver – centrilobular congestion (dark red) and periportalfatty change (yellow) = chronic passivecongestion of the liver
2. Hypercoagulability (Genetic, Acquired)
3. Abnormal Blood Flow
Hypoxic EC injury
↑ Conc. Activated Factors
Depletion of inhibitors
EC shear stress
Coronaryartery with occlusive thrombus
Arterialthrombi are generally occlusive. Here isone in a coronary artery.
Shouldbe a lumen; filled here with red plaque
longitudinally opened femoral vein running through skeletal muscle
Arterial thrombi propagate away from the heart.and when they embolize they embolize farther downstream, away from the heart.
left side of heart goes to systemic arterial circulation
Organized& recanalized thrombus
Organizationconverts the thrombus to a fibrous plug. The fibrous plug may be incorporated into the wall of the vessel. Or,blood vessels may grow into the fibrous tissue (a process calledrecanalization) and partially restore blood flow.
Infarctsin solid organs (except the heart) are generally wedge shaped with the apexpointing to the thrombosedvessel. Arterial occlusion usuallyresults in a white (anemic) infarct due to obstruction of the blood flow to thearea.
Apexpoints towards occluded vessel
Thetop left: MI, white infarct
Bottom right: Another MI with reperfusion – converts tohemorrhagic infarct
Microcyticanemia. The size of the RBCs is smaller than the nucleus of a lymphocyte (leftpanel).
Normocytic(normal sized) anemia. The size of the RBCs is normal (middle panel).
Macrocyticanemia. The size of most RBCs is larger than the nucleus of a restinglymphocyte (right panel).
Normalblood showing a neutrophilic granulocyte (neutrophil, or “poly” or PMN, for polymorphonuclear leukocyte, or “seg”, for segmented), with itssegmented nucleus and faint pink granules (upper nucleated cell), and a smallresting lymphocyte, with condensed nuclear chromatin and scant lightlybasophilic cytoplasm (lower nucleated cell).
Themature RBC is small (about the size of a mature resting lymphocyte – greenarrow), fully hemoglobinized (with pink cytoplasm), and hasextruded its nucleus.
Normal myeloid maturation sequence:
1. myeloblast (purple arrows)
2. promyelocyte (blue arrows)
3. myelocyte (green arrow)
4. metamyelocyte (red arrow)
Notethis single megakaryocyte’s huge size compared to othermarrow elements, its multilobed nucleus, and its abundant granularpurple-grey cytoplasm. Platelets are formed by “budding” of the cytoplasm from the cell surface.
Whilesubtypes of a receptor will recognize a common physiological agonist, subtledifferences in structure and sometimes large differences in anatomic distributionprovide unique pharmacological points of attack.
-DifferentGPCR subtypes yield different responses
-Samereceptor subtype in different tissue gets different results
-Knowingthis information you can identify compounds that will selectively targetreceptor
Mosteffective: a and b
Neoplasia: increased cell # , colonal, genetic alterations, irreversible
Hyperplasia = increased cell #, polyclonal, response to injury/stimulus, reversible
Abnormalon L, large nuclei, little cytoplasm, glands have no space between them
Hereare two sarcomas-one leiomyosarcoma, asarcoma of smooth muscle tissue and liposarcoma, asarcoma of adipose tissue. The cells of leiomyosarcoma tendto be spindle and form bundle mimic the normal smooth muscle tissue. The cells in liposarcoma tend to contain lots of lipid contentmimic normal adipocyte.
Assessment of morphologic and functional difference between a tumor and tissue of origin
It is focused on the degree of difference between tumor and the their corresponding normal tissue. The less the tumor looks like its normal tissue counterpart the worse the differentiation. In general, benign tumors are always well differentiated and malignant tumors can be well, moderate, poorly or undifferentiated.
Dysplasia - “disorderedgrowth”
*Does not necessarily progress to cancer*
“Hallmarks” refer to homeostatic mechanisms that are commonly disrupted by mutation during the development of cancer, T or F?
Oncogenes are typified by gain-of-function mutations in normal genes, whereas tumor suppressors are typified by loss-of-function mutations, T or F?
Most oncogenes and tumor suppressor genes encode proteins dedicated to sensing outside signals, or converting those signals into specific cellular responses (differentiation, division, survival, movement). Mutations in these genes promote cancer.
Oncogenes are derived from normal “proto-oncogenes” through gain-of-function mutations resulting in overexpression or constitutive activity of the encoded protein.
Oncogenes and tumor suppressors encode proteins involved in signal perception, transduction, or cellular responses, T or F?
Many prominent oncogenes and tumor suppressors regulate multiple downstream responses (cell division, differentiation, survival, movement), so that mutations in any one has great impact on cell, T or F?
List the molecular functions of PI3K, AKT, PTEN, and p53
An important, prominent example of a human oncogenic pathway is the PI3K signaling pathway. PI3K an enzyme that phosphorylates a specific lipid head group found on the cytoplasmic side of the plasma membrane. What is the signaling pathway involved/how does it become oncogenic?
P1P3 binds and activates PH domain AKT, a protein kinase that phosphorylates many cellular proteins and alters their fxns.
One clinical consequence of activated AKT in cancer cells is increased glucose transport and glycolysis
Hence, AKT activity contributes to the “Warburg effect”, the signature high glycolytic rate in many (but not all) human cancer cells
Overexpression of this pathway observed in many cancers (due to loss of PTEN fxn)
Compare and contrast mechanisms of action of two important human tumor suppressors: PTEN and p53
What activates PI3K?
Receptor Tyrosine Kinases (RTKs) bind and activate PI3K, generating increased levels of PIP3 in the plasma membrane.
PIP3 is a docking site for important signaling proteins containing “pleckstrin homology” or PH domains. PIP3 recruits PH-domain proteins to inner side of the plasma membrane…
The primary downstream effector of PI3K signaling is AKT, a serine/threonine kinase also known as “protein kinase B” (PKB), T or F?
PIP3 binds a PH domain in AKT, recruiting it to the plasma membrane, where it becomes phosphorylated on T308 and S473 (by two other kinases) – this phosphorylated form of AKT is now fully active.
AKT promotes cellular metabolism, cell growth, survival, and motility… very profound effects on cellular behavior.
Patients are given radioactively labeled (18F) deoxyglucose, which can be taken up by cells, but not broken down through glycolysis, so it accumulates. Therefore, any cell with high rates of glucose uptake (like cancer cells) can be visualized easily. It’s important to remember that not ALL cancers display the Warburg effect, so not all tumors light up in PET scans.
Loss of PTEN phosphatase activity results in higher overall PIP3 levels, and elevated AKT activity, thereby promoting cell growth, proliferation, survival, etc.
Normal cells have a tightly regulated balance between PI3K and PTEN activity, which is typically lost in cancer cells…
Classic example of loss of heterozygosity leading to cancer
Notice how the PTEN-deficientcells are bigger, less organized (note position of nucleus), and appear to bedividing inappropriately. See howmutation of a single gene can have profound effects…?
GADD45 – involved in DNA repair pathways, protecting genome
Bax, Puma, Noxa - pro-apoptotic proteins that induce cell death
MDM2 – ubiquitylates p53, targeting it for proteasomal degradation
Autoregulation - p53 transcribes its own negative regulator (MDM2) – an effective way of keeping downstream pathways under control
Succinylcholine is an example of non-competitive antagonism with the nicotinic receptor and ACH, T or F?
For which of the following is 12 g/dL considered anemia? (a) a newborn, (b) a woman aged 75 years, (c) a man aged 50 years, (d) a child aged 8 years.
The balance of expression between pro- and anti-apoptotic Bcl proteins can determine survival or cell death.
True. Bak sits in the OMM, where it can form pores to release cytochrome C; however, it is inhibited by Bcl-2. When Bax is activated by apoptotic signal, it migrates to the OMM and, together with Bak, forms pores, triggering cytochrome C release, caspase activation, and death…This occurs in the INTRINSIC pathway of apoptosis, aka the STRESS-INDUCED pathway.
Fas receptor (CD95, Apo1) sits in plasma membrane - when bound to ligand (FasL), trimeric receptor recruits FADD (Fas-associated-death-domain) protein. FADD then recruits initiator procaspases 8 or 10, which can autoactivate and trigger effector caspases (caspase 3,6,7) downstream, T or F?
1. over-expressing anti-apoptotic family members (Bcl-2, Bcl-XL)
True. Telomerase expression innormal human cells restrictedto embryonic tissues,adult stem cells,activated lymphocytes...Consequently,other cells can only divide so many times before they lose telomericsequences (“Hayflick limit”) –results in replicative senescence –permanent cell cycle arrest. Byactivatingtelomerase expression,incipient cancercells canpermanently stabilize chromosomes, although they are often highly aberrant…
Vascular Endothelial Growth Factor (VEGF)
VEGF stimulates endothelial cell (EC) division, survival, differentiation, movement, etc., considered master regulator of angiogenesis. There are multiple VEGF genes and isoforms, but the major one is “VEGF-A”.
VEGF binds and activates specific receptor tyrosine kinases on ECs (VEGFR1 and VEGFR2). Like EGFR and other RTKs, these receptors turn on important downstream signaling events.
Cancer cells metastasize through the blood and lymphatic systems. T or F?
Evidence of cancer cells in draining lymph nodes is an important indicator of invasive and/or metastatic disease.
-If you lack an immune system, you get cancer:
-Tumor infiltrating lymphocytes have been found in many human cancers.
-Immuno-suppression associated with increased risk of cancer
-Presence of intra-tumoral T cells correlates with patient survival in ovarian cancer
-Cytotoxic T-cell recognition of targets (leads to lysis of targets)
-Priming of CTL by antigen presenting cell
-Tumor cells drive T cells that are helpless/anergic
You can vaccinate against a T-cell antigen:
-Agonist anti-CD40 mAb can substitute for helper T cells
-Can CD40 activation reverse immune suppression and drive T cell immunity?
-Gemcitabine and agonist anti-CD40 mAb in chemo-naïve locally advanced or metastatic pancreatic carcinoma leads to increased survival in mice.
-Took out T cells from mice CD40 continued to shrink tumor
-BUT, No effect from CD40 if get rid of macrophages
-Can use immune system to alter inflammation around cancer
Can we both step on gas and cut the breaks?
A morphologically distinctive macrocytic anemia caused by impaired synchrony of nuclear and cytoplasmic maturation.
Megaloblastic anemias are usually treatable, thus recognition of them is essential. The majority will respond to B12/folate. More rarely, the cause of a megaloblastic anemia is due to a drug, malignant, or inborn error-induced suppression of DNA synthesis, T or F?
Absence of Intrinsic Factor (IF) is a specific feature of the most common cause of B12 deficiency, pernicious anemia (PA), T or F?gross rearrangements (usually translocations) of DNA, which lead to abnormal gene expression
-Pallor & Jaundice
-EpithelialLesions (Gums & Tongue, Gastric Mucosa, Cervical Lesions)
Eg: Subacute Combine Systems Disease; Paresthesias of Hands & Feet; Spastic Ataxia; Somnolence; Megaloblastic Madness)
The neurologic symptom is only seen with B12 deficiency, NOT folate deficiency or other causes of megaloblastic anemia.
AlsoResponds to High Dose Folate,EXCEPT FOR NEUROLOGIC SYMPTOMS
1) Deceased Intake (Poor Nutrition, Impaired Absorption (autoimmune))
2) Increased Requirements (Pregnancy, Increased Cell Turnover)
Treat with physiologic doses of folate. Dietary deficiency is the most common cause of folate deficiency.
Megaloblastic hypersegmentation means that a single neutrophil has6 or more lobes, or 5% have at least 5 lobes, or the average amount oflobes is greater than 4. Hypersegmented neutrophils are large andprobably result from omission of terminal division during thematuration of the neutrophil.
Low iron state: more transferrin (take into red cells), less ferritin
High iron state: more ferratin (storage), less transferrin
Smalland large cells, teardrops, too much paleness in center, pencil-like shape= typicalof iron deficiency anemia
TIBC=total iron binding capacity
A neoplasm is characterized by a clonal proliferation, in which every cell is identical to every other cell, T or F?
In general, the term leukemia refers to neoplasms that extensively involve the bone marrow and spill out into the peripheral blood; these are often but not always neoplasms of cells that are native to the marrow (blood forming elements: granulocytes, red cells, and megakaryocytes and their precursors), and immature lymphocytes (lymphoblasts).
Flow cytometry: on live cells, which produces the dot plot (or analogous readout)
Immunohistochemistry: tissue sections (containing fixed cells) are stained for antigen expression. These are evaluated by light microscopy.
TdT, CD1a, cCD3
CD2, sCD3, CD5, and CD7 are markers of mature T cells, T or F?
Why are mature B cell neoplasms more common than T cell lesions?
B cells (unlike T cells) are subjected to multiple rounds of controlled genomic damage (double-stranded DNA breaks and point mutations)
1. immunoglobulin gene rearrangement (bone marrow)
2. heavy chain class switching/somatic hypermutation (germinal center)
Lymphomas are generally derived from lymphocytes (not histiocytes), T or F?
Modern lymphoma diagnosis formally takes into account all of the following parameters except:
b. proposed cell of origin
d. gene expression profile
d. gene expression profile
Gene expression profile is important in prognosis, but not in classification
This is a mature B cell neoplasm
Expressingsurface immunoglobulin, so by definition mature
NOT a reactive lesion, a germinal center neoplasm, or a lymphoblastic lesion
Histologic and immunophenotypic studies of this patient’s lymph node show a nodular CD10+ BCL6+ BCL2+ neoplasm, which by cytogenetic studies is associated with the t(14;18) translocation. Which progenitor cell gave rise to this neoplasm?
Germinal center B cell
NOT intrafollicular T cell, tingible body macrophage, or lymphoblast
The O2 affinity of hemoglobin is reduced in the presence of phosphates, especially 2,3 BPG (2,3 DPG), T or F?
There are 3 functional a-like globin genes and 5 functional b-like globin genes, arranged in clusters on different chromosomes. The various a- and b- like globin genes are expressed in a developmental stage-specific sequence (II). What is the sequence for adults?
Adult: a2b2 + a2d2
(Hb A + Hb A2)