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Path-Polycyth. Vera
| Question | Answer |
|---|---|
| A patient presented an association of erythrocytosis with leukocytosis, thrombocytosis, and splenomegaly, the diagnosis would most likely be? | Polycythemia Vera |
| Define Polycythemia | characterized by an increase in absolute quantity of red cells or total RBC volume; contrast, anemia is a decrease in absolute quantity of red blood cells. Polycythemias are best expressed in terms of hematocrit |
| Define Relative polycythemia | is characterized by an apparent increased of the total red blood cell mass in the blood, the underlying cause being reduced blood plasma, i.e. hemoconcentration. It is a disturbance of plasma volume regulation |
| In what two categories are polycythemias categorized (hint: blood volume)? | (1) relative or spurious, or (2) absolute |
| In what two categories are polycythemias categorized? | Polycythemias are classified into primary and secondary. |
| The most common primary polycythemia is ... | polycythemia rubra vera (polycythemia vera), a clonal neoplastic disorder |
| What distinguishes primary from secondary polycythemia? | Polycythemia vera is characterized by increases in the number of red cells and granulocytes and platelets and by splenomegaly. And secondary polycythemias result from either appropriate or inappropriate increases in the red cell mass |
| Relative or spurious polycythemia | an elevation of the hematocrit level due to abnormally low levels of fluid (plasma). |
| Polycythemia vera - the commonest primary polycythemia - is caused from | the acquired somatic mutations in a single hematopoietic stem cell leading to clonal hematopoiesis. |
| When erythropoietin binds to what receptors proliferation into erythroblasts and reticulocytes occurs. | BFU-E and CFU-E |
| Master regulator of hypoxia sensing and hypoxic response | HIF-1 transcription system |
| Erythropoietin (EPO) is controlled by | the relative supply of oxygen to the kidney, the major site of erythropoietin synthesis |
| Erythropoietin secretion is ____________ in patients with secondary | Increased |
| HIF-1 is composed of | HIF-1alpha, HIF-1bravo |
| Erythropoietin secretion is always ______ in patients with polycythemia vera, this disorders is not a result of erythropoietin overproduction | Subnormal |
| Describe hypoxia pathway | accum of HIF-1α creates response w/o transc/transl mach. Tgting/polyub of HIF-1α req (VHL) protein, which binds to hydroxylated HIF-1a and becomes rec. comp. of ubiq/lig complex, lds to degra of HIF-1a, nondegra w HIF-β and inc transc of hypox.-induc gene |
| Primary familial or congenital polycythemia (PCFP) is | an uncommon disorder which is inherited as an autosomal dominant trait |
| PCFP is characterized by | (a) increased red blood cell mass without increased granulocyte or platelet counts, (b) normal hemoglobin-oxygen dissociation curve, (c) low serum erythropoietin levels and (d) in vitro hypersensitivity of erythroid progenitors to erythropoietin. |
| The cause of PCFP is | germline gain-of-function mutations of EPO receptor that lead to a loss of its neg regulatory domain. Interaction of (EPO) w (EPO rec)leads to its homodim resulting in (a) stim of cell div, (b) diff by induction of eryth-spec gene exprss, (c)apo prev |
| The cytoplasmic domain of the EPO receptor can be divided into two major regions | ~half of the cytoplasm domain (part nearest the pm), is the pos reg domain, req for generating the signals for proliferation and diff like in globin synthesis. The remaining half is the neg reg domain (not req for signaling) which acts to dampen sig |
| What are the hereditary primary polycythemias? | Primary familial and congenital |
| What is the mechanism for unbridled erythroid proliferation and elevated red cell mass in familial and congenital polycythemia? | EPO binds and sig transduction is activated by change of config of receptor dimer, but because no structure (neg reg domain) for HCP to bind to, receptor remains in activated position |
| When STAT5 is activated by the phosphorylation, it does what? | translocates to the nucleus, and initiates transcription of its target gene that ultimately results in erythroid progenitor proliferation and differentiation. |
| HCP is... | hematopoietic cell phosphatase (HCP) bind to the carboxyterminal of EPO receptor, which is its neg regulatory domain. This interaction dephosphorylates the receptor and turns off the signaling, resulting in cessation of erythroid progenitor proliferation. |
| Patients with Hereditary Primary Polycythemia have gain-of-function mutations resulting in... | EPO receptor gene lack the carboxyterminal portion of the receptor that contains the negative regulatory domain. |
| Polycythemia vera (PV) is | a clonal, chronic, prog. myeloproliferative disorder char. by erythrocytosis, and usually by granulocyte leukocytosis, thrombocytosis, splenomegaly. Bone marrow displays an excessive proliferation of erythroid, myeloid and megalokaryocytic elements. |
| What is the most common polycythemia? | Polycythemia Vera |
| PV is the result of | neoplastic proliferation of hematopoietic cells |
| Is red cell production in PV associated with excessive EPO production. | No,erythroid progenitor cells in this disease proliferate even in absence or presence of minimal amounts of EPO. |
| Describe molecular pathogenesis of PV. | Single point mutation in JAK2 causes subs. of aa (codon 617) w/in the JH2 of JAK2, lds to V617F mutation and autoinhibition of this reg domain. Tyr kinase of JH1 domain is act., phosph. STAT5, sig. transd. mol. act downstream of EPO rec. lds to neo prolf |
| JAK2 tyrosine kinase is encoded | by a gene in the 9p chromosome |
| Where is the JAK2 V617 mutation located? What is the result? | In the pseudokinase region; disrupts the autoinhibition of this regulatory domain and consequently the tyrosine kinase corresponding to the JH1 domain is constitutively activated |
| What mutation is sufficient for erythrocytosis in PV? | JAK2 V617F |
| What are some symptoms of PV? | Nonspec-headache, dizziness, vertigo, tinnitus, vis. disturbances, paresthesias, excessive sweating, epigastric distress(due inc histamine), joint pain (from uric acid), pruritus (inc hista.), wt loss. Phys-ruddy cyanosis, conjunctiva plethora, spl/hepmeg |
| What is a char symptom of PV? | ruddy cyanosis |
| Describe the clinical course of polycythemia vera? | (1) An initial erythrocytotic or plethoric phase (plethora is a Greek term denoting an excess of blood); and (2) A “spent” phase associated with cytopenia. |
| Describe the plethoric phase of polycythemia vera? | occurs first, char by hyperproliferation of marrow cell components and inc. red cell mass. Erythrocytosis, thrombocytosis, and leukocytosis. Mild splenomegaly too. Symptoms of hyperviscosity-headache, pruritus, dizziness or a thrombotic event. |
| Describe the spent phase of polycythemia vera? | progressive bone marrow fibrosis, gradual abatement of erythrocytosis and extramedullary hematopoiesis in spleen (hepatomegaly). Peripheral blood smear demonstrates anemia, thrombocytosis and granulocytosis. Transfusion may be required. Clinical prob. |
| PV related myelofibrosis is characterized by | the presence of teardrop red blood cell in the peripheral blood film. |
| Patients with PV-related myelofibrosis are at high risk for the development of | acute myeloid leukemia. |
| Increased viscosity of blood leads to... | reduced oxygen transportation |
| The thrombotic tendency in PV is primarily a direct consequence of | the expansion of red cell mass, |
| Von Willebrand factor (vWF) is | a high molecular weight glycoprotein produced by endothelial cells, which plays an important role in hemostasis by interacting with platelet membrane receptors |
| Qualitative platelet abnormalities are frequently present, and platelet aggregation studies and bleeding times are frequently abnormal in PV patients, high platelet counts can be indicative of... | acquired Von Willebrand syndrome - vWF sticks to the cut in the blood vessel and creates a plug. This plug prevents further bleeding and stays there until the damaged blood vessel heals; def leads to bleeding tendency |
| What is PV-related myelofibrosis? | abnormal bone marrow stem cells are replaced by a fibroblast cell proliferation and fibrosis with production of collagen fibers possibly due to release of growth factors, like PDGF,FGF, TGF from megakaryocytes or platelets present bone marrow of PV pts |
| Secondary polycythemias are due to | circulating factors (such as erythropoietin) that act on erythroid progenitors. Secondary polycythemias can be either hereditary or acquired |
| Conditions leading to hypoxia that may result in acquired polycytemia mediated by inc levels of EPO include | such as high altitude, congenital heart disease with right-to-left shunts, or chronic lung disease |
| Hereditary polycythemias may result from either | (a) inherited mutations of the hemoglobin which confer the molecule an increased affinity for oxygen or (b) inherited mutations of the Von Hippel Lindau gene resulting in defects in hypoxia sensing. |
| Describe hereditary high affinity hemoglobin polycythemias. | lead to increased oxygen affinity and thus decreased delivery and compensatory polycythemia; mutations involve either the α- or β-globin chains. High affinity hemoglobin variants are transmitted as autosomal dominant traits |
| Describe hereditay polycythemias due to Von Hippel Lindau gene. | elevated hematocrit and red cell counts,with norm leukocyte and platelets, and elevated serum EPO. Autosomal recessive. (VHL) in hypoxia-sensing pathway binds to proline-hydroxylated form of HIF-1α and mediates ubiq/proteosomal degrad; def lds to inc EPO |
| What are some acquired sec polycythemias? | Rt-lt shunt, Chronic pulm dis, hypoventilation syndromes(obstructive sleep apnea and obesity hypoventilation/Pickwickian syndrome), high alt, neonatal polycythemia, smoker's polycythemia, and post-transplant erythrocytosis, kidney/liver disease, steroids |
| When excess angiotensin is produced by the native kidney, this hormone modulates the release of | erythropoietin. |
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