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Myeloid Neoplasms, Myeloid Neoplasms Chronic Myeloproliferative Disorders -Increased production of terminally diff-ated myeloid cells -all w/ EM hematopoiesis, SPLENOMEGALY -due to neoplastic spread to spleen -terminate in spent phase -can all progress to acute leukemia -most w/ elevated LAP (except CML) Essential Thrombocytosis-LEAST COMMON MPD -inc. prolif/production of megas -platelet count exceeds 600K -MUST EXCLUDE other Dzs w/ thrombocytosis -also exclude reactive conditions (inflam, asplenism, Fe def.) -THUS, MUST EXAMINE MARROW -mild to moderately increased cellularity -MANY megakaryocytes, ABNLly LARGE -some reticulin deposits maybe, no fibrosis PERIPH-ABNLly LARGE PLATELETS -mile leukocytosis CLINICAL-thrombosis, hemorrhage -long (-)Sx periods, w/ occasional throm/hem crises -survival 12-15 years, Myeloid Neoplasms Myelodysplastic Syndromes Ineffective hematopoiesis, ass'd cytopenias Maturation Defects-risk of transforming AML -bone marrow replaced by mutant mutipotent stem -can still dff'ate to RBC, grans, plts -but ineffective/disordered Bone Marrow-hyper- or normocellular, even hypo- Periph blood-PANCYTOPENIA PATHOGENESIS-maybe doesn't crowd out NL cells -arises out of stem cell dmg(?) XRT or alkylating CTX-monosomy/deletions 5(q), 7(q) risomy 8, deletions of 20q MORPHOLOGY-disordered/dysplastc lineages (all 3) Erythroid-RINGED SIDEROBLASTS(iron-laden mito) -megaloblastoid maturation (like B12/folate def) -nuclear budding ABNLities Neutrophils-dec. secondary granules -toxic granulations, DOHLE BODIES -Pseudo-Pelger-Huet Cells (2 nuc lobes) Megakaryocytes-single lobe, multiple nuclein (Pawn Ball) Myeloblasts may be increased, but ណ% of marrow % of periph leukocytes CLINICAL- ptsᡴyo -weakness, infx, hemorrhages -50% (-)Sx-found after incidental blood tests Median Survival 9-29 mo, some ɱyr Progression to AML in 10-40%, more clonal changes Can succomb to bleeding, infx TREATMENT-bone marrow x-plant if younger -supportive Tx if older (infx, bleeding support), Myeloid Neoplasms Acute Myelogenous Leukemia Accum. of immature myeloid cells in marrow Primarily adults 15-39 yo 20% of childhood leukemias Mostly acquired genetic alterations Replication rate of tumor cells slower than NL -IMPT FEATURE-lack of diff'ation (commitment) Immature cells accumulate and suppress NL marrow ->anemia, neutropenia, thrombocytopenia ->manifestations-sim to ALL CHROMOSOMAL-in 90% of AML -if de novo w/ no risk factors-balanced translocation -post-MDS AML-deletions/monosomies in 5,7, no translocations -trans if following topoisomerase II-inhibitors->MML gene 11q23 MANIFESTATIONS -fever-infx (oral, skin, lungs, kidneys, bladder, colon) -often from opportunists (Pseudomonas, fungi, commensals) -fatigue, -bleeding-most striking-petechiae/ecchymoses, serosal bleeds -Procoagulants released by leukemic cells(M3)->DIC Mild LN, organomegaly if any Monocytic-skin and gingiva infiltration maybe Less common CNS spread TREATMENT -cytotoxic drugs or overcoming diff'ation block (vit A deriv, AsO3) -more and more w/ bone marrow xplantation -60% complete remission w/ CTX (most relapse w/in 5 yr) Good prognosis-t(8;21), chrom 16 inversion Poor-t(9;22) (Phila), translocation w/ chrom 11q23 Dismal-AML arising from MDS or after genotoxic Tx -chrom 5 or 7 monosomies/deletions Classification: 8 types (M0-M3-degree of maturation M4-M7-lineage) MORPHOLOGY-Dx based on ᡖ% myeloid blasts in marrow Periph will 10K-100K cells, even none->must do marrow Bx, Chronic Myelogenous Leukemia- 25-60yo Genetics-BCR-ABL fusion t(9;22)(q34;q11)-Phila chrom-Ph1 Increased neoplastic granulocytic precursors in marrow -w/ BCR-ABL (also in Bs, Ts, myeloids) -fewer NL cells in background -thus, TRANSFORMATION IN PLURIPOTENT STEM MORPHOLOGY-marrow 100% cellular -mostly grans, somtimes megas, NL RBC # -SCATTERED STORAGE HISTIOCYTES-sea-blue cyto -increased reticulin fiber deposition, but no fibrosis Peripheral -LEUKOCYTOSIS K cells -mostly neutrophils, metamyelocytes, myelocytes, % blasts -EOSINPHILIA, BASOPHILIA -Thrombocytosis in 50% EM Hem in red pulp->splenomegaly->focal infarction ->hepatomegaly, mild lymphadenopathy CLINICAL-insidious onset, nonspecific Sx -mild anemia, hypermetabolism->fatigue, wt loss, anorexia -dragging sens in LUQ due to splenomegaly/infarction to DIFFERENTIATE-find BCR-cABL -very little Leukocyte Alkaline Phosphatase (LAP)-also in PNH W/out Tx-3 year survival-ᡪ% to 'accelerated phase' -accel phase-inc. anemia, thrombocytopenia, basophilia -add'l chrom ABNLities-trisomy 8, iso 17q, duplicated Ph1. Terminates resembling ACUTE LEUKEMIA (BLAST CRISIS) -50% straight to blast crisis w/out accel. -70% pts look like myeloblasts -30%-blasts w/ TdT, CD10, CD9 (early B lineage) TREATMENT-low-dose CTX->still progresses to blast crises -best Tx-bone marrow xplant-cure in 75% pts -also IFN-a suppresses CML progenitors->NL take over -or culture NL cells, then cytotoxic Tx, then inplant 100% Progression Primarily adults 15-39 yo 20% of childhood leukemias Mostly acquired genetic alterations Replication rate of tumor cells slower than NL -IMPT FEATURE-lack of diff'ation (commitment) Immature cells accumulate and suppress NL marrow ->anemia, neutropenia, thrombocytopenia ->manifestations-sim to ALL CHROMOSOMAL-in 90% of AML -if de novo w/ no risk factors-balanced translocation -post-MDS AML-deletions/monosomies in 5,7, no translocations -trans if following topoisomerase II-inhibitors->MML gene 11q23 MANIFESTATIONS -fever-infx (oral, skin, lungs, kidneys, bladder, colon) -often from opportunists (Pseudomonas, fungi, commensals) -fatigue, -bleeding-most striking-petechiae/ecchymoses, serosal bleeds -Procoagulants released by leukemic cells(M3)->DIC Mild LN, organomegaly if any Monocytic-skin and gingiva infiltration maybe Less common CNS spread TREATMENT -cytotoxic drugs or overcoming diff'ation block (vit A deriv, AsO3) -more and more w/ bone marrow xplantation -60% complete remission w/ CTX (most relapse w/in 5 yr) Good prognosis-t(8;21), chrom 16 inversion Poor-t(9;22) (Phila), translocation w/ chrom 11q23 Dismal-AML arising from MDS or after genotoxic Tx -chrom 5 or 7 monosomies/deletions Classification: 8 types (M0-M3-degree of maturation M4-M7-lineage) MORPHOLOGY-Dx based on ᡖ% myeloid blasts in marrow Periph will 10K-100K cells, even none->must do marrow Bx, Myeloid Neoplasms Chronic Myeloproliferative Disorders -Increased production of terminally diff-ated myeloid cells -all w/ EM hematopoiesis, SPLENOMEGALY -due to neoplastic spread to spleen -terminate in spent phase -can all progress to acute leukemia -most w/ elevated LAP (except CML) Chronic Myelogenous Leukemia- 25-60yo Genetics-BCR-ABL fusion t(9;22)(q34;q11)-Phila chrom-Ph1 Increased neoplastic granulocytic precursors in marrow -w/ BCR-ABL (also in Bs, Ts, myeloids) -fewer NL cells in background -thus, TRANSFORMATION IN PLURIPOTENT STEM MORPHOLOGY-marrow 100% cellular -mostly grans, somtimes megas, NL RBC # -SCATTERED STORAGE HISTIOCYTES-sea-blue cyto -increased reticulin fiber deposition, but no fibrosis Peripheral -LEUKOCYTOSIS K cells -mostly neutrophils, metamyelocytes, myelocytes, % blasts -EOSINPHILIA, BASOPHILIA -Thrombocytosis in 50% EM Hem in red pulp->splenomegaly->focal infarction ->hepatomegaly, mild lymphadenopathy CLINICAL-insidious onset, nonspecific Sx -mild anemia, hypermetabolism->fatigue, wt loss, anorexia -dragging sens in LUQ due to splenomegaly/infarction to DIFFERENTIATE-find BCR-cABL -very little Leukocyte Alkaline Phosphatase (LAP)-also in PNH W/out Tx-3 year survival-ᡪ% to 'accelerated phase' -accel phase-inc. anemia, thrombocytopenia, basophilia -add'l chrom ABNLities-trisomy 8, iso 17q, duplicated Ph1. Terminates resembling ACUTE LEUKEMIA (BLAST CRISIS) -50% straight to blast crisis w/out accel. -70% pts look like myeloblasts -30%-blasts w/ TdT, CD10, CD9 (early B lineage) TREATMENT-low-dose CTX->still progresses to blast crises -best Tx-bone marrow xplant-cure in 75% pts -also IFN-a suppresses CML progenitors->NL take over -or culture NL cells, then cytotoxic Tx, then inplant, Primarily adults 15-39 yo 20% of childhood leukemias Mostly acquired genetic alterations Replication rate of tumor cells slower than NL -IMPT FEATURE-lack of diff'ation (commitment) Immature cells accumulate and suppress NL marrow ->anemia, neutropenia, thrombocytopenia ->manifestations-sim to ALL CHROMOSOMAL-in 90% of AML -if de novo w/ no risk factors-balanced translocation -post-MDS AML-deletions/monosomies in 5,7, no translocations -trans if following topoisomerase II-inhibitors->MML gene 11q23 MANIFESTATIONS -fever-infx (oral, skin, lungs, kidneys, bladder, colon) -often from opportunists (Pseudomonas, fungi, commensals) -fatigue, -bleeding-most striking-petechiae/ecchymoses, serosal bleeds -Procoagulants released by leukemic cells(M3)->DIC Mild LN, organomegaly if any Monocytic-skin and gingiva infiltration maybe Less common CNS spread TREATMENT -cytotoxic drugs or overcoming diff'ation block (vit A deriv, AsO3) -more and more w/ bone marrow xplantation -60% complete remission w/ CTX (most relapse w/in 5 yr) Good prognosis-t(8;21), chrom 16 inversion Poor-t(9;22) (Phila), translocation w/ chrom 11q23 Dismal-AML arising from MDS or after genotoxic Tx -chrom 5 or 7 monosomies/deletions Classification: 8 types (M0-M3-degree of maturation M4-M7-lineage) MORPHOLOGY-Dx based on ᡖ% myeloid blasts in marrow Periph will 10K-100K cells, even none->must do marrow Bx Myeloblastomas, Granulocytic Sarcomas, Chloromas Myeloblastomas, Granulocytic Sarcomas, Chloromas -myeloblastic masses w/ no marrow, periph involvement, Myelofibrosis w/ Myeloid Metaplasia- ᡴyo -neoplastic transformation of multipotent myeloid stem -HALLMARK=EARLY PROGRESSION TO MYELOFIBROSIS -identical to 'spent' phase of other chronic MPDs -suppresses hematopoiesis->periph cytopenias ->neoplastic extramedullary h'poiesis in liver,spleen, LN PATHOPHYSIOLOGY-collagen deposition from non-CA fibroblasts - due to excess PDGF, TGF-b release from CA megakaryocytes -due to leakage from ABNL cells or after death -PDGF, TGF-b-fibroblast mitogens -TGF-b-promotes fibrosis, cause angiogenesis displaced stem cells from marrow->stem cells seed spleen, liver MORPHOLOGY Early-hypercellular marrow w/ all lineages in excess -most NL, but mega'cytes large, dysplastic, clustered -minimal fibrosis Progression-hypocellular, diffusely fibrotic, clusters of ABNL megas Late-marrow largely converted to bone-->'osteosclerosis' SPLENOMEGALY-up to 4000gm, firm, red-gray, no white pulp -multiple subcapsular infarcts, sinusoidal then cord foci -3 lineages of hematopoiesis-big, clustered megas predominate Hepatomegaly-sinusoidal foci of hematopoiesis LN-some extramed hematopoiesis, but no enlargement Periph blood-Inappropriate release of nucleated RBCs and early granulocytes from marrow, extramedullary sites ='LEUKOERYTHROBLASTOSIS' -Teardrop RBCs (dacrocytes) in periph (both also in granulomatous dz, metastatic CA) -ABNLly large platelets, basophilia CLINICAL-can be preceded by PCV, CML -progressive anemia, splenice enlargement (fullness in ULQ) -fatigue, wt loss, pm sweats due to inc. metabolism from inc. stems -hyperuricemia, 2ndary gout LAB-normochromic, normocytic anemia w/ leukoerythroblastosis -WBC NL, reduced or high (during early phase) -platelets NL, elevated, or LOW w/ dz progress -marrow Bx w/ reticulin/fibrosis necessary for Dx 5-20% transform to AML (can arise in LNs, soft tissues) -infx, bleeding threaten life 1-5 year median survival ង% Progression Primarily adults 15-39 yo 20% of childhood leukemias Mostly acquired genetic alterations Replication rate of tumor cells slower than NL -IMPT FEATURE-lack of diff'ation (commitment) Immature cells accumulate and suppress NL marrow ->anemia, neutropenia, thrombocytopenia ->manifestations-sim to ALL CHROMOSOMAL-in 90% of AML -if de novo w/ no risk factors-balanced translocation -post-MDS AML-deletions/monosomies in 5,7, no translocations -trans if following topoisomerase II-inhibitors->MML gene 11q23 MANIFESTATIONS -fever-infx (oral, skin, lungs, kidneys, bladder, colon) -often from opportunists (Pseudomonas, fungi, commensals) -fatigue, -bleeding-most striking-petechiae/ecchymoses, serosal bleeds -Procoagulants released by leukemic cells(M3)->DIC Mild LN, organomegaly if any Monocytic-skin and gingiva infiltration maybe Less common CNS spread TREATMENT -cytotoxic drugs or overcoming diff'ation block (vit A deriv, AsO3) -more and more w/ bone marrow xplantation -60% complete remission w/ CTX (most relapse w/in 5 yr) Good prognosis-t(8;21), chrom 16 inversion Poor-t(9;22) (Phila), translocation w/ chrom 11q23 Dismal-AML arising from MDS or after genotoxic Tx -chrom 5 or 7 monosomies/deletions Classification: 8 types (M0-M3-degree of maturation M4-M7-lineage) MORPHOLOGY-Dx based on ᡖ% myeloid blasts in marrow Periph will 10K-100K cells, even none->must do marrow Bx, Polycythemia Vera- 60 yo median age -multipotent myeloid stem cell neoplasm ->inc. production of all 3 lineages ->erthrocytosis (polycythemia) ->granulocytosis, thrombocytosis RED CELL MASS->CLINICAL Sx PATHOPHYSIOLOGY- -extremely small EPO, other GF amts needed ->thus virtually no serum EPO -diff'ate from 2ndary polycythemias MORPHOLOGY -hypercellular marrow, some fat -increase in all 3 lineages -10% pts have marrow reticulin fibers Early-mild organomegaly early on via congestion -minimal extramed hematopoiesis Late-SPENT phase-fibrosis fills intratrabecular space -fibrosis displaces hematopoietic cells ->more prominent organomegaly via extramed. hem. Can transform to typical AML CLINiCAL-inc. Hct, inc. total blood volume ->vasc distention/stasis -most excess blood trapped in venous side (distended) ->pts plethoric, cyanotic due to stagnation 70% hypertensive; HA, dizziness, GI Sx -Intense PRURITUS, likelihood of peptic ulceration -due to basophil histamine release (?) -High cell turnover->hyperuricemia, gout in 5-10% -ABNL blood flow->bleeding, thrombotic episodes Thromb in hepatic vv. (Budd-Chiara), portal, mesenteric, venous sinuses of brain ->strokes, infarction Hgb high, Hct high, Elevated platelets, WBCs(12K-50K) LAP elevated Chronic bleeding -> Fe-deficiency->lowers Hct (CAUTION) Platelets-Giant megakaryocytic fragments, agg. defects No TX->death w/in months from bleeding/thrombosis Tx-phlebotomies->survival ~10yr 10-15%->myelofirbosis w/ myeloid metaplasia after 10yrs -great splenomegaly due to EM hematopoiesis 2%->AML, 15% w/ alkylating drugs or XRT ALL transformation RARE 10-15% Myelofibrosis w/ Myeloid Metaplasia- ᡴyo -neoplastic transformation of multipotent myeloid stem -HALLMARK=EARLY PROGRESSION TO MYELOFIBROSIS -identical to 'spent' phase of other chronic MPDs -suppresses hematopoiesis->periph cytopenias ->neoplastic extramedullary h'poiesis in liver,spleen, LN PATHOPHYSIOLOGY-collagen deposition from non-CA fibroblasts - due to excess PDGF, TGF-b release from CA megakaryocytes -due to leakage from ABNL cells or after death -PDGF, TGF-b-fibroblast mitogens -TGF-b-promotes fibrosis, cause angiogenesis displaced stem cells from marrow->stem cells seed spleen, liver MORPHOLOGY Early-hypercellular marrow w/ all lineages in excess -most NL, but mega'cytes large, dysplastic, clustered -minimal fibrosis Progression-hypocellular, diffusely fibrotic, clusters of ABNL megas Late-marrow largely converted to bone-->'osteosclerosis' SPLENOMEGALY-up to 4000gm, firm, red-gray, no white pulp -multiple subcapsular infarcts, sinusoidal then cord foci -3 lineages of hematopoiesis-big, clustered megas predominate Hepatomegaly-sinusoidal foci of hematopoiesis LN-some extramed hematopoiesis, but no enlargement Periph blood-Inappropriate release of nucleated RBCs and early granulocytes from marrow, extramedullary sites ='LEUKOERYTHROBLASTOSIS' -Teardrop RBCs (dacrocytes) in periph (both also in granulomatous dz, metastatic CA) -ABNLly large platelets, basophilia CLINICAL-can be preceded by PCV, CML -progressive anemia, splenice enlargement (fullness in ULQ) -fatigue, wt loss, pm sweats due to inc. metabolism from inc. stems -hyperuricemia, 2ndary gout LAB-normochromic, normocytic anemia w/ leukoerythroblastosis -WBC NL, reduced or high (during early phase) -platelets NL, elevated, or LOW w/ dz progress -marrow Bx w/ reticulin/fibrosis necessary for Dx 5-20% transform to AML (can arise in LNs, soft tissues) -infx, bleeding threaten life 1-5 year median survival, Chronic Myelogenous Leukemia- 25-60yo Genetics-BCR-ABL fusion t(9;22)(q34;q11)-Phila chrom-Ph1 Increased neoplastic granulocytic precursors in marrow -w/ BCR-ABL (also in Bs, Ts, myeloids) -fewer NL cells in background -thus, TRANSFORMATION IN PLURIPOTENT STEM MORPHOLOGY-marrow 100% cellular -mostly grans, somtimes megas, NL RBC # -SCATTERED STORAGE HISTIOCYTES-sea-blue cyto -increased reticulin fiber deposition, but no fibrosis Peripheral -LEUKOCYTOSIS K cells -mostly neutrophils, metamyelocytes, myelocytes, % blasts -EOSINPHILIA, BASOPHILIA -Thrombocytosis in 50% EM Hem in red pulp->splenomegaly->focal infarction ->hepatomegaly, mild lymphadenopathy CLINICAL-insidious onset, nonspecific Sx -mild anemia, hypermetabolism->fatigue, wt loss, anorexia -dragging sens in LUQ due to splenomegaly/infarction to DIFFERENTIATE-find BCR-cABL -very little Leukocyte Alkaline Phosphatase (LAP)-also in PNH W/out Tx-3 year survival-ᡪ% to 'accelerated phase' -accel phase-inc. anemia, thrombocytopenia, basophilia -add'l chrom ABNLities-trisomy 8, iso 17q, duplicated Ph1. Terminates resembling ACUTE LEUKEMIA (BLAST CRISIS) -50% straight to blast crisis w/out accel. -70% pts look like myeloblasts -30%-blasts w/ TdT, CD10, CD9 (early B lineage) TREATMENT-low-dose CTX->still progresses to blast crises -best Tx-bone marrow xplant-cure in 75% pts -also IFN-a suppresses CML progenitors->NL take over -or culture NL cells, then cytotoxic Tx, then inplant Progression Myelofibrosis w/ Myeloid Metaplasia- ᡴyo -neoplastic transformation of multipotent myeloid stem -HALLMARK=EARLY PROGRESSION TO MYELOFIBROSIS -identical to 'spent' phase of other chronic MPDs -suppresses hematopoiesis->periph cytopenias ->neoplastic extramedullary h'poiesis in liver,spleen, LN PATHOPHYSIOLOGY-collagen deposition from non-CA fibroblasts - due to excess PDGF, TGF-b release from CA megakaryocytes -due to leakage from ABNL cells or after death -PDGF, TGF-b-fibroblast mitogens -TGF-b-promotes fibrosis, cause angiogenesis displaced stem cells from marrow->stem cells seed spleen, liver MORPHOLOGY Early-hypercellular marrow w/ all lineages in excess -most NL, but mega'cytes large, dysplastic, clustered -minimal fibrosis Progression-hypocellular, diffusely fibrotic, clusters of ABNL megas Late-marrow largely converted to bone-->'osteosclerosis' SPLENOMEGALY-up to 4000gm, firm, red-gray, no white pulp -multiple subcapsular infarcts, sinusoidal then cord foci -3 lineages of hematopoiesis-big, clustered megas predominate Hepatomegaly-sinusoidal foci of hematopoiesis LN-some extramed hematopoiesis, but no enlargement Periph blood-Inappropriate release of nucleated RBCs and early granulocytes from marrow, extramedullary sites ='LEUKOERYTHROBLASTOSIS' -Teardrop RBCs (dacrocytes) in periph (both also in granulomatous dz, metastatic CA) -ABNLly large platelets, basophilia CLINICAL-can be preceded by PCV, CML -progressive anemia, splenice enlargement (fullness in ULQ) -fatigue, wt loss, pm sweats due to inc. metabolism from inc. stems -hyperuricemia, 2ndary gout LAB-normochromic, normocytic anemia w/ leukoerythroblastosis -WBC NL, reduced or high (during early phase) -platelets NL, elevated, or LOW w/ dz progress -marrow Bx w/ reticulin/fibrosis necessary for Dx 5-20% transform to AML (can arise in LNs, soft tissues) -infx, bleeding threaten life 1-5 year median survival, Myeloid Neoplasms Chronic Myeloproliferative Disorders -Increased production of terminally diff-ated myeloid cells -all w/ EM hematopoiesis, SPLENOMEGALY -due to neoplastic spread to spleen -terminate in spent phase -can all progress to acute leukemia -most w/ elevated LAP (except CML) Polycythemia Vera- 60 yo median age -multipotent myeloid stem cell neoplasm ->inc. production of all 3 lineages ->erthrocytosis (polycythemia) ->granulocytosis, thrombocytosis RED CELL MASS->CLINICAL Sx PATHOPHYSIOLOGY- -extremely small EPO, other GF amts needed ->thus virtually no serum EPO -diff'ate from 2ndary polycythemias MORPHOLOGY -hypercellular marrow, some fat -increase in all 3 lineages -10% pts have marrow reticulin fibers Early-mild organomegaly early on via congestion -minimal extramed hematopoiesis Late-SPENT phase-fibrosis fills intratrabecular space -fibrosis displaces hematopoietic cells ->more prominent organomegaly via extramed. hem. Can transform to typical AML CLINiCAL-inc. Hct, inc. total blood volume ->vasc distention/stasis -most excess blood trapped in venous side (distended) ->pts plethoric, cyanotic due to stagnation 70% hypertensive; HA, dizziness, GI Sx -Intense PRURITUS, likelihood of peptic ulceration -due to basophil histamine release (?) -High cell turnover->hyperuricemia, gout in 5-10% -ABNL blood flow->bleeding, thrombotic episodes Thromb in hepatic vv. (Budd-Chiara), portal, mesenteric, venous sinuses of brain ->strokes, infarction Hgb high, Hct high, Elevated platelets, WBCs(12K-50K) LAP elevated Chronic bleeding -> Fe-deficiency->lowers Hct (CAUTION) Platelets-Giant megakaryocytic fragments, agg. defects No TX->death w/in months from bleeding/thrombosis Tx-phlebotomies->survival ~10yr 10-15%->myelofirbosis w/ myeloid metaplasia after 10yrs -great splenomegaly due to EM hematopoiesis 2%->AML, 15% w/ alkylating drugs or XRT ALL transformation RARE