BL.2.6: Immunomodulators, Thrombotic Disorders Flashcards
What is immunomodulation?
The use of drugs, alone or in combination with other maneuvers, to change the function of all, or part, of the immune system.
Contrast NSAIDs with DMARDs:Mechanism of Action
NSAIDs: Cox1/2 InhibitorsDMARDs: variable…Methotrexate/Leflunomide are enzyme inhibitorsSulphasalazine is a NSAID and DMARD, no other detailsAntimalarials inhibit lysosome action which prevents peptide presentation by MHC in turn failing to stimulate T-cellsMinocyline mechanism is unclear
Contrast NSAIDs and DMARDs:Use on autoimmune and rheumatic diseases
Up to quite recently, most patients with rheumatoid arthritis (RA) got NSAIDs, but relatively few (perhaps 20%) also got DMARDs. Now almost all RA patients get DMARDs. Treatment of other autoimmune diseases is similar to RA, with emphasis on the most distressing symptoms, and then addition of specialized drugs for specific indications.
Contrast NSAIDs with DMARDs:Effect on rheumatic and autoimmune diseases
DMARDs can prevent the progression of symptoms and joint erosions. Studies are showing that they are less toxic than previously thought, and in combinations, often have even less toxicity, hardly more so than NSAIDs.
Define monoclonal antibodies, and describe in principle how they are made.
These antibodies are derived from the progeny of a single B cell, that has been fused with a multiple myeloma tumor cell; the resultant hybrid line can grow forever in culture like its tumor parent, but make the specific antibody of its B cell parent.
Discuss the use of monoclonal antibodies as anti-inflammatory agents.
Can use monoclonal antibodies to bind things like TNF alpha in rheumatoid arthritis, or IVIG can bind inhibitory Fc receptors on inflammatory cells.
Compare and contrast murine, chimeric, humanized, and human monoclonal antibodies.Discuss which might have disadvantages when used in human patients, and the reason for that.
The original monoclonals were made from immunized mice; such antibodies are murine [-omab] (e.g., ibritumomab).Some have been engineered to have the mouse VL and VH domains, but human C domains; these are chimeric, [-ximab] and less likely to be recognized by your patient’s own immune system.Going further, there are monoclonals which are humanized [-zumab]; only the CDR’s of the V domains are from the mouse.Finally, fully human [-umab] monoclonals have arrived.The more human the Ab are the longer it will take to make antibodies against them.
Discuss the use of growth factors in bone marrow transplantation.
If blood will be the source of the stem cells, the donor is often first treated with G-CSF or GM-CSF.Since the concentration of T cells in blood is high, the stem cells must be purified.Recovery is hastened by the use of G-CSF or GM-CSF
Identify the componenets of Virchow’s triad and their pathophysiologic contribution to thrombosis.
- Decreased blood flow (venous stasis)2. Inflammation of or near the blood vessels (altered vessels)3. Intrinsic alterations in the nature of the blood itself (altered coagulability)You could see how these could slow blood flow, increase viscosity, etc.
Describe at least three major clinical symptoms that occur when a patient suffers from an acute iliofemoral thrombosis of the leg, and indicate the pathophysiologic reason for each one (for example, dilated superficial veins of the calf due to obstruction of venous return in the occluded deep veins).
Complete obstruction of a proximal vein, such as a massive iliofemoral thrombosis, can produce nearly complete obstruction of venous outflow from an extremity, leading to a condition called phlegmasia cerulean dolens (an extremely swollen, blue, painful leg). Lesser degrees of obstruction can produce pain, pitting edema of the distal extremity, and a warm, dusky, reddish-blue discoloration of the skin caused by enhanced superficial venous blood flow.
Compare and contrast the cause and mechanism of a thrombus occurring in the arterial circulation (such as acute coronary artery thrombosis) from one that develops in a deep vein of the leg. Include the instigating factor(s) and composition of the clot.
Arterial: high shear stress, platelets are main component, looks whiteVenous: slow flow, fibrin + red cells, looks red
List three clinical clues suggesting an inherited hypercoagulable disorder.
First thrombosis < 50Family historyRecurrent episodes of thrombosisThrombosis at unusual sitesNeonatal thrombosisThrombosis w/o apparent antecedent thrombogenic event
Briefly describe at the molecular level the pathophysiologic reason that patients with deficiencies of antithrombin, protein C, protein S, factor V Leiden or the prothrombin gene mutation are likely to have thrombosis. Explain what tests are used to identify these patients.
Factor V leiden: Due to an autosomal dominant mutation of the factor V gene that leads to partial resistance to inactivation through proteolytic cleavage by protein C. Factor V Leiden is inactivated 10 times more slowly than normal factor Va. Resistance to inactivation leads to increased risk for thrombosis.Prothrombin mutation: The mutation appears to lead to elevated concentrations of plasma prothrombin.Protein C deficiency: Protein C is a vitamin K-dependent plasma protein that, when activated, inactivates factors Va and VIIIa to inhibit coagulation. Deficiency is inherited in an autosomal dominant fashionProtein S deficiency: Protein S is another vitamin K-dependent plasma protein that facilitates the anticoagulant activity of activated protein C. As with protein C, deficiency is inherited as an autosomal dominant traitAntithrombin deficiency: Antithrombin III regulates coagulation by inactivating thrombin as well as factors Xa, IXa, XIa and XIIa. AT-III deficiency is inherited in an autosomal dominant fashion
List and describe at least three acquired disorders that are associated with recurrent venous or arterial thromboembolism.
Clotting factors/inhibitors, PNH, myeloproliferative disorders, malignancy, vasculitic disorders, antiphospholipid syndrome
Describe the clinical features and criteria for diagnosis of antiphospholipid antibody syndrome.
In vitro prolonged PTT, in vivo thrombotic disordersClinical criteria:Vascular thrombosis (One or more clinical episodes of arterial, venous or small- vessel thrombosis of any organ or tissue)Complications of pregnancy including:One or more unexplained death of nl fetus ≥ 10 wksOne or more premature births of nl neonates ≤ 34 wksThree or more unexplained consecutive abortions < 10 wks
