Week 2 Flashcards
Are gain-of-function or loss-of-function mutations more commonly the cause of thrombophilia? Which is the most common inherited thrombophilia mutation, and how does this biochemically change the protein?
Gain of function (in procoagulant genes) are more common causes of thrombophilia, though loss of function mutations in anticoagulant genes are stronger risk factors if present (rare). The most common mutation: Factor V leiden, which generates a FV which is resistant to proteolytic cleavage/inactivation by APC.
What are some of the risk factors for pulmonary embolism?
Risk factors include age > 50, HR > 100, O2 sat on room air <95, recent surgery/trauma, unilateral leg swelling, and hormone use (e.g. oral contraceptives). There are several clinical decision making tools which make use of these (and other) risk factors to assign a risk category or pre test probability to the patient, from which you would pursue either no testing or a D-dimer (low risk patients) or proceed to CT pulmonary angiography (high risk/pre test probability)
Why might a patient who does not eat leafy green vegetables and chronic antibiotic use have a bleeding diathesis? What is the biochemical mechanism?
Vitamin K is primarily obtained as a result of leafy green vegetable intake and via colonic bacteria production of K2. Vitamin K is a cofactor for the gamma-carboxylation reaction of many coagulation factors (II, VIII, IX, X, Protein C, Protein S) which is required for their proper function. Note that most of these factors are pro-coagulation.
Which clotting factors are affected by warfarin? Put them in order of first to disappear from plasma to last to disappear after starting warfarin. For an extra challenge, what is the approximate half life of the first and last factor?
In order, VII (~6h), protein C (~10h), X (24-40), protein S (40-60), prothrombin (II; 60-72). The half lives themselves are not that important, but it is important to understand that protein C will be largely depleted in a day, whereas three pro-coagulant factors will take many days to be depleted. This can lead to the hypercoagulable state which can predispose to warfarin necrosis, particularly in patients with a genetic protein C deficiency.
What is the difference between grading and staging? What are the three primary components of tumor staging (general) and which are the most important for colon cancer?
Grading generally assesses the histology of a tumor, for example, in breast carcinoma, architecture, mitotic rate, and nuclear grade are considered to yield a score ranging from well-differentiated (I; low) to poorly differentiated (III, high). Staging more so refers the degree of spread and generally has better prognostic value. The typical schema is TNM – tumor size, lymph node involvement, and metatstases (multifocality). For colon cancer, depth of tumor invasion and lymph node metastases are the most important factors in staging.
A 50 year old man presents with fatigue and abdominal discomfort. Workup reveals a primary blood malignancy characterized by increased levels of neutrophils and basophils. From your understanding of blood malignancy naming conventions, you can likely name the disease. Pick from the following: Acute/chronic, myeloid/lymphoblastic, lymphoma/leukemia
Chronic myeloid leukemia. Chronic, because the cells affected are appear to be more mature (versus the immature myeloid “blasts” of AML). Myeloid, because the myeloid lineage gives rise to neutrophils and basophils (versus lymphocytes in the lymphoid/lymphoblastic lineage). Finally, leukemia, because this is a primary blood malignancy (versus tissue-based disease, such as a lymphoma arising in the spleen or a lymph node).
The hallmark molecular abnormality in chronic myeloid leukemia is the Philadelphia chromosome, a translocation resulting in the BCR-ABL1 fusion protein. On the other hand, activating mutations in JAK2 are by far the most common causative mutation for non-CML myeloproliferative neoplasms. What therapies address these genetic abnormalities? Which of these drug(s) would you expect to have a greater effect on normal hematopoiesis?
Imatinib (and other tyrosine kinase inhibitors) target the constitutive tyrosine kinase signaling through the BCR-ABL fusion protein. Ruxolitinib (and other JAK2 inhibitors) target the constitutive JAK-STAT signaling. Because JAK-STAT signaling is integral to normal hematopoiesis, whereas tyrosine kinase signaling via the unnatural fusion protein BCR-ABL1 enables constitutive proliferation but is not specifically fundamental to hematopoiesis, JAK inhibitors will have a greater impact on normal hematopoiesis.
What is the most common molecular abnormality associated with lymphomas of geminal cell origin which show a follicular growth pattern? How does this enable tumorigenesis?
t(14;18), BCL2/IgH is present in ~80% of follicular lymphoma. Translocation of BCL2 (encoding a protein which opposes apoptosis) to the IgH locus, which results in constitutive transcription of BCL2 and allows the cell to grow despite stresses associated with uncontrolled growth (eg, DNA damage, protein misfolding) which would normally induce apoptosis
Which RNA retrovirus endemic to parts of Japan, the Caribbean, South America, and tropical Africa causes an adult T-cell lymphoma? Which virus is associated with Burkitt lymphoma, NK/T cell lymphoma, and angioimmunoblastic T-cell lymphoma?
1) HTLV-1 2) EBV
What are the symptoms of end organ damage in multiple myeloma? Hint: there are four major ones classically associated with multiple myeloma.
Hypercalcemia, renal failure, anemia/immune abnormalities, lytic bone lesions (often in the spine). A common case presentation will be a 50 yo with back pain and some of the CBC/BMP findings above.
What is the difference between autologous, allogeneic, and syngeneic hematopoietic stem cell transplants, and when are they used?
Autologous – patient’s own stem cells, typically harvested prior to intensive chemotherapy which will ablate the patient’s bone marrow (as a side effect). Thus can restore HSC and thus normal hematopoiesis with no concern of rejection. Allogeneic means from another person, who will be HLA-matched to the extent possible to reduce risk of rejection or severe graft vs. host disease. Syngeneic means from an identical twin. Allogeneic are used to provide long-term alloreactivity against a malignant process (graft vs. tumor effect).
