Pathologies Flashcards
1
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Essential Thrombocytosis
A
Pathogenesis: Neoplastic proliferation of mature myeloid cells, mostly plateletsGenetics: JAK2 mutation Clinical Presentation: Increased risk of thrombosis*no risk of gout
2
Q
Mastocytosis
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Pathogenesis: Neoplasm of mast cellsGenetics: activating c-KIT mutation, CD117+, tryptase+Clinical Presentation: Urticaria pigmentosa or systemic mastocytosisHisto: Increased morphologically abnormal mast cells in various tissuesLabs: + metachromatic stains (toluidine blue)
3
Q
Acute Myeloid Leukemia (AML)
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Pathogenesis: Proliferation of myeloid cells without maturation (blasts/precursors)Genetics: t(15;17), t(8;21), inv(16), or 11q23 abn, Monosomy 7Clinical Presentation: Anemia (weakness, fatigue, pallor), Thrombocytopenia (bleeding), HepatosplenomegalyHisto: Blasts and Auer rodsLabs: Sudan black B+, MPO+, TdT-, CD34+*20% of all leukemias and 85% of adult leukemias
4
Q
Acute Promyelocytic Leukemia (PML)
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Pathogenesis: Type of AML. Proliferation of myeloid cells without maturation (blasts/precursors)Genetics: t(15;17). This disrupts retinoic acid receptor (RARα) geneClinical Presentation: Frequently associated with DICHisto: Abnormal promyelocytes with multiple Auer rodsLabs: Sudan black B+, MPO+, TdT-, CD34+Tx: ATRA
5
Q
Acute Myelomonocytic Leukemia
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Pathogenesis: Type of AML. Proliferation of myeloid cells without maturation (blasts/precursors)Genetics: inv(16) or t(16;16)Clinical Presentation: Anemia (weakness, fatigue, pallor), Thrombocytopenia (bleeding), Hepatosplenomegaly. Usually infiltrate the gumsHisto: Abnormal promyelocytes with multiple Auer rodsLabs: Sudan black B+, MPO-, TdT-, CD34+
6
Q
Myelodysplastic Syndrome
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Pathogenesis: Ineffective hematopoiesisGenetics: Monosomy 7Clinical Presentation: Peripheral cytopenia and Hypercellular BMHisto: Ringed sideroblasts, hypo-lobated neutrophils, and macrocytic anemia
7
Q
Langerhans Cell Histiocytosis
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Pathogenesis: neoplastic proliferation of Langerhans cellsHisto: Birbeck granules, admixed eosinophils, plasma cells, and neutrophilsSubtypes: Eosinophlic granuloma, Hand-Schuller-Christian Disease, Letterer-Siwe Disease
8
Q
Eosinophilic Granuloma
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Pathogenesis: Neoplastic proliferation of Langerhans cellsHisto: Birbeck granules, admixed eosinophils, plasma cells, and neutrophilsClinical Features: Bone pain, lung nodules M:F = 4:1,5-30 y.o.Prognosis: Self limited
9
Q
Hand-Schuller-Christian DIsease
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Pathogenesis: Neoplastic proliferation of Langerhans cellsHisto: Birbeck granules, admixed eosinophils, plasma cells, and neutrophilsClinical Features: Diabetes insipidus, membranous bone defects, proptosis M:F = 1:1 2-5 y.o.Prognosis: indolent
10
Q
Letterer-Siwe Disease
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Pathogenesis: Neoplastic proliferation of Langerhans cellsHisto: Birbeck granules, admixed eosinophils, plasma cells, and neutrophilsClinical Features: Dermatitis, organomegaly M:F = 1:1, < 2 y.o.Prognosis: Poor
11
Q
Acute Lymphocytic Leukemia/Lymphoblastic Lymphoma (ALL)
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Pathogenesis: Accumulation of lymphoblasts in the blood and bone marrow. 85% are B cell type. Neoplasm of lymphoid stem cell (lymphoblast)Genetics: Hyperdiploidy is a favorable prognosis, t(4;11) and/or t(9;22) is a bad prognosis, t(12;21) is a favorable prognosisImmunophenotype: TdT+, sIg- (no surface immunoglobulin), CD10+, CD29+Clinical Presentation: Bone pain, anemia*most common malignancy of childhood
12
Q
Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia (CLL)
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Pathogenesis: Accumulation of mature B-lymphocytesGenetics:mutated (7 years) > unmutated (3 years)Immunophenotype: CD5+, CD19+, CD20+, sIg+Clinical Presentation: Asymptomatic, anemia, thrombocytopenia, lymphadenopathy, lymphocytosisLymph Node: diffuse infiltrate of small, round lymphocytesHisto: Smudge cellsComplications: Richter transformation to diffuse large B-cell lymphomain 5-10%, Autoimmune Hemolytic Anemia, Hypogammaglobulinemia*most common leukemia in the US, seen in older adults
13
Q
Hairy Cell Leukemia
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Pathogenesis: Mature B-lymphocytes with villous cytoplasmic projectionsClinical Presentation: Hepatosplenomegaly (red pulp), Pancytopenia, InfectionsGenetics: BRAF mutationImmunophenotype:CD11c+, CD25+, CD103+, Annexin A1+, TRAP+Histo: “Hairy cells” - lymphocytes with villous cytoplasmic projections. Absolute monocytopeniaBone Marrow: Increased retculin fibrosis
14
Q
Follicular Lymphoma
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Pathogenesis: Neoplastic proliferation of small B cellsClinical Features: Generalized lymphadenopathy and hepatosplenomegalyGenetics: t(14;18) leading to overexpression of Bcl-2 which prevents apoptosisImmunophenotype: CD19+, CD20+, CD10+, CD5-, sIg+Lymph node: Nodular infiltrate of small, cleaved lymphocytes with admixed large cells. Markedly diminished/absent mantle zones*very common lymphoma in the US
15
Q
Diffuse Large B-Cell Lymphoma
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Pathogenesis: Neoplastic proliferation of large B cells that grow diffusely in sheetsGenetics: some cases associated with EBV and KSHV/HHV8Immunophenotype: CD19+, CD20+, CD10+/-, CD5-, sIg+Lymph Node: diffuse infiltrate of large, non-cleaved lymphocytes*most common lymphoma in the US
16
Q
Plasma Cell Myeloma (Multiple Myeloma)
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Pathogenesis: Multifocal destructive infiltration of plasma cells in the bone marrowClinical Features: Punched out bone lesions, Hypercalcemia, Renal disease, Anemia, Primary AmyloidosisBlood: Monoclonal (M) Ig or light chain spike on SPEP/UPEP, Rouleaux formation on blood smear, Increased IL-6Bone Marrow: Nodules or diffuse sheets of plasma cellsUrine: Bence Jones protein (monoclonal free light chain)
17
Q
Solitary Osseous Plasmacytoma
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Pathogenesis: Neoplasm of terminally differentiated, Ig secreting B lymphocytes. Plasma cell proliferation and M componentClinical Features: Single destructive bone lesion
18
Q
Extraosseous Plasmacytoma
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Pathogenesis: Neoplasm of terminally differentiatied, Ig secreting B lymphocytes. Plasma cell proliferation and M componentClinical Features: Extramedullary soft tissue mass
19
Q
Monoclonal Gammopathy of Undetermined Significance (MGUS)
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Pathogenesis: Increased serum protein w/ M spike on SPEP/UPEP but other features of multiple myeloma are absent* commonly in elderly* 1% of pts. w/ MGUS develop multiple myeoma each year
20
Q
Waldenstrom Macroglobulinemia
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Pathogenesis: B-cell lymphoma with monoclonal IgM productionClinical Features: Generalized LAD (lytic bone lesions absent), increase serum protein w/ M spike on SPEP/UPEP, visual and neurologic deficits (b/c of stroke/hemorrhage from increased viscocity of blood)Tx: plasmapheresis and/or Ibrutinib
21
Q
Heavy Chain Disease
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Heavy chains produced withought light chains
22
Q
Burkitt Lymphoma/Leukemia
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Pathogenesis: Neoplastic proliferation of intermediate-sized B cellsGenetics: Associated with EBV,t(8;14), c-MYC oncogene translocated to Ig heavy chain locusImmunophenotype: CD19+, CD20+, CD10+, CD5-, sIg+, TdT-Clinical Features: Classically presents as an extranodal mass in a child or YA (African = jaw Sporadic = abdomen)Lymph Node: DIffuse infiltrate of medium-sized, non-cleaved lymphocytes. Tingible body macrophages present = “starry sky pattern”
23
Q
Mantle Cell Lymphoma
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Pathogenesis: Neoplastic proliferation of small B cells that expands the mantle zoneClinical Features: Presents in late adulthood w/ painless LAD. Most are advanced stage and have BM involvementGenetics: t(11;14)(q13;q32) in 70-75% of casesImmunophenotype: CD19+, CD20+, CD10-, CD5+, sIg+, CyclinD1+
24
Q
Extranodal Marginal Zone B-Cell Lymphoma of MALT tissue
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Pathogenesis: Neoplastic proliferation of small B cells that expands the marginal zone (post-germinal center B cells)Clinical Features: GI tract, lumg, head and neck, eye skin. Associated w/ chronic infection (H. pylori) and AI disorders (Hasimoto’s thyroiditis, Sjogrens, etc.)Tx: remove infection
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Mycosis Fungoides
Pathogenesis: Neoplastic proliferation of mature CD4+ T cells that infiltrate the skin, producing localized skin rash, plaques, and nodules. Aggregates of neoplastic cells in the epidermis are called Pautrier microabscesses Immunophenotype: CD4+, Dermal infiltrate of atypical lymphocytes *Can spread to the blood (Sezary Syndrome). These cells will have characteristic cerebriform nuclei (Sezary cells) on blood smear
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Adult T-Cell Leukemia/Lymphoma
Pathogenesis: Neoplastic proliferation of mature CD4+ T cellsEpidemiology: Associated w/ HTLV-1; most commonly seen in Japan and the Caribbean Clinical Features: Rash, generalized LAD, hepatosplenomegaly, lytic (punched-out) lesions, hypercalcemia
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Anaplastic Large Cell Lymphoma
Pathogenesis: Neoplasm of large T cellsGenetics: t(2;5) - rearrangement of ALK gene in children is a good prognosis. No ALK rearrangement in older adults is a bad prognosisHisto: Large anaplastic cells (Hallmark cells) w/ horseshoe shaped nucleus
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Peripheral T-Cell Lymphoma, Unspecified
Pathogenesis: Neoplastic proliferation of mature T cells. T cell receptor gene rearrangement Immunophenotype: CD2+, CD5+, CD3+, TCR-αβ or γδLymph Node: Architectural effacement and vascular proliferationCourse: Poor prognosis
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Nodular Sclerosis Hodgkin Lymphoma
Pathogenesis: Neoplastic proliferation of Reed-Sterberg (RS) cells in a polymorphous mixed background. RS cells are large B cells with mutilobed nuclei and prominent nucleoli ("owl-eye nuclei"). RS cells arise from germinal center B cells. The transformed cells escape from apoptotic pathways to proliferate. Ig gene rearrangements in most cases. No detectable Ig.Immunophenotype: CD15+ and CD30+ (negative for most B and T cell markers) Clinical Features: LAD, constitutional "B" symptoms (fever, night sweats, and weight loss) Other: Broad bands of fibrous tissue. Numerous lacunar variant of Reed-Sterberg cells in a mixed cellular background Course: Excellent prognosis. 90% cure rate*Most common malignancy in 10-30y.o. age group in US
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Mixed Cellularity Hodgkin Lymphoma
Pathogenesis: Neoplastic proliferation of Reed-Sterberg (RS) cells in a polymorphous mixed background. RS cells are large B cells with mutilobed nuclei and prominent nucleoli ("owl-eye nuclei"). RS cells arise from germinal center B cells. The transformed cells escape from apoptotic pathways to proliferate. Ig gene rearrangements in most cases. No detectable IgImmunophenotype: CD15+ and CD30+ (negative for most B and T cell markers) Clinical Features: LAD, constitutional "B" symptoms (fever, night sweats, and weight loss) Other: Numerous RS cells in a mixed cellular background *Most common malignancy in 10-30y.o. age group in US
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Lymphocyte Depletion Hodgkin Lymphoma
Pathogenesis: Neoplastic proliferation of Reed-Sterberg (RS) cells in a polymorphous mixed background. RS cells are large B cells with mutilobed nuclei and prominent nucleoli ("owl-eye nuclei"). RS cells arise from germinal center B cells. The transformed cells escape from apoptotic pathways to proliferate. Ig gene rearrangements in most cases. No detectable IgImmunophenotype: CD15+ and CD30+ (negative for most B and T cell markers) Clinical Features: LAD, constitutional "B" symptoms (fever, night sweats, and weight loss) Other: Rare. Classic RS cells w/ scant lymphocytes *Most common malignancy in 10-30y.o. age group in US
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Lymphocyte Rich Hodgkin Lymphoma
Pathogenesis: Neoplastic proliferation of Reed-Sterberg (RS) cells in a polymorphous mixed background. RS cells are large B cells with mutilobed nuclei and prominent nucleoli ("owl-eye nuclei"). RS cells arise from germinal center B cells. The transformed cells escape from apoptotic pathways to proliferate. Ig gene rearrangements in most cases. No detectable IgImmunophenotype: CD15+ and CD30+ (negative for most B and T cell markers) Clinical Features: LAD, constitutional "B" symptoms (fever, night sweats, and weight loss) Rarely seen
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Nodular Lymphocyte Predominance Hodgkin Lymphoma
Immunophenotype: Lymphocytic and histiocytic cells - CD19+, CD20+, CD15-, CD30-Other: Predominance of small lymphocytes in the background. Lacks classic Reed-Sternberg cellsCourse: Good prognosis*Most common malignancy in 10-30y.o. age group in US
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Aplastic Anemia
Pathogenesis: A disorder of the myeloid stem cell resulting in decreased production of red cells, white cells, and platelets Genetics: Mutations in telomere repair complex genes, Fanconi anemiaImmunologic Factors: Autoreactive CD8 T cells Environmental Factors: Drugs such as ChloramphenicolClinical Features: Pancytopenia, hypocellular bone marrow, normocytic and normochromic
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Pure Red Cell Aplasia
Definition: A disorder of the erythroid progenitor cell resulting in decreased red cell productionPathogenesis: Immunologic factors (thymoma) and environmental factors (parvovirus B19) Clinical Features: Pallor, weakness, fatigueOther: Normocytic anemia. Intranuclear inclusions in B19 infectionTx: Thymectomy, anti-thymocyte globulin, plasmapheresis, supportive therapy
36
Iron Deficiency Anemia
Definition: Anemia caused by absent total body iron stores which results in deficient heme synthesis Pathogenesis:
* ↓ iron intake - infants, poverty
* ↓ iron absorption - celiac, gastritis, H. pylori
* ↑ iron loss - GI or GU bleeding
* ↑ iron utilization - preganancy
Clinical Features: Fatigue, weakness, Pica, atrophic glossitisOther: Microcytic hypocytic anemia. Anisocytosis Serum: ↓ ferritin, ↓ iron, ↑ transferrinPlummer-Vinson syndrome: iron def anemia + glossitis + esophageal webs
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Anemia of Chronic Disease
Definition: Anemia due to chronic inflammatory cytokines that ultimately impair the release of iron from the BM storage sites (macrophages) Pathogenesis: Hepcidin - usually prevents iron release from macrophages, blocks ferroportin, and decreased EPO secretionOther: Normocytic or microcytic anemiaSerum: ↑ ferritin, ↓ iron, ↓ transferrin*associated w/ cancer, infection, and AI diseases
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Beta Thalassemia
Definition: Inherited anemia caused by decreased synthetic rate of Hb β Pathogenesis: Point mutation in 1 or 2 beta genes leading to decreased beta chain production, aggregation of alpha chains, intramedullary hemolysis, and peripheral blood hemolysisGenetics: Heterozygous - mild anemia. Elevated HbA2; Homozygous - severe anemia in infancy. Facial and cranial bone enlargement, splenomegaly, and secondary hemochromatosis. Elevated HbFOther: Microcytic anemiaHisto: Target cells, basophilic stippling
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Alpha Thalassemia
Definition: Inherited anemia caused by decreased synthetic rate of HbαPathogenesis:
* 1 def gene - silent carrier, no anemia
* 2 def gene - α thalassemia trait, mild anemia
* 3 def gene - HbH disease, moderate anemia
* 4 def gene - HbBarts disease, severe anemia
Other: Microcytic anemia Histo: Target cells, basophilic stippling
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B12 Deficiency
Definition: Anemia caused by vitamin B12 deficiency which results in defective thymidine synthesis and ultimately defective DNA synthesis Pathogenesis: Defect in DNA synthesis caused by delayed or blocked erythroblast division in the bone marrow.
* Decreased intake - vegans
* Decreased absorption - pernicious anemia, gastrectomy, ileum disease.
* Increased utilization - Diphyllothrium botrioides (fish tape worm)
Clinical Features: Neurologic deficits - spastic paraparesis, sensory ataxia, paresthesis, dementia. Brain and spinal cord demyelinationOther: Macrocytic anemia, pancytopeniaHisto: Macro-ovalocytes, hypersegmented neutrophilsSerum: low B12, high methylmalonic acid, high homocysteine
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Folic Acid Deficiency
Definition: Anemia caused by folic acid deficiency which results in defective thymidine synthesis and ultimately defective DNA synthesisPathogenesis:
* Decreased intake - poor nutrition, alcoholism
* Decreased absorption - jejunum disease, phenytoin
* Increased utilization - pregnancy, hemolytic anemia
Clinical Features: Anemia and pancytopenia. NO NEUROLOGIC DEFICITS Other: Macrocytic anemia, pancytopeniaHisto: Macro-ovalocytes, hypersegmented neutrophilsSerum: Low folic acid levels, high homocyteine levels
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Sickle Cell Disease
Definition: Hereditary hemoglobinopathy causing RBC structural change to sickle form Pathogenesis: AR inheritance. Homozygous for 6glu-->val mutation in beta globin chain. HbS precipitation under deoxy state. Hemolysis is due to splenic trapping of poorly deformable sickle cells and increased mechanical fragility of sickle cells. Microvascular occlusion is due to increased stickiness of sickle cells for vascular endotheliumClinical Features: Pain, organ infarction (autosplenectomy), increased infections due to hyposplenism, hemolytic and aplastic crisisLabs: Sickel cells, target cells, elevated HbS on electrophoresis *more common in AA
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Sickle Cell Trait
Definition: Hereditary hemoglobinopathy causing RBC structural change to sickle form Pathogenesis: AR inheritance Heterozygous for 6glu-->val mutation in beta globin chain. Clinical Features: No hemolysis or vaso-occlusive cirsis. Hematuria (5%) *more common in AA*protective against Malaria
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Hereditary Spehrocytosis
Definition: Hereditary hemolytic anemia caused by cytoskeletal protein defect. AD inheritancePathogenesis: Mutation of ankyrin, spectin, or band 3. Loss of biconcave structure. Splenic trapping or poorly deformable spherocytes Clinical Features: Anemia, splenomegaly, cholelithiasisLabs: Hemolysis, elevated MCHC, spherocytes on blood smear, increased osmotic fragility due to low ionic strength
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Paroxysmal Nocturnal Hemoglobinuria
Definition: Acquired hemolytic anemia caused by a deficiency in glycosyl-phosphatidylinositol (GPI) linked glycoproteins. GPI usually anchor DAF to RBCs which protects them from complementPathogenesis: Mutation in phosphatidylinositol glycal A gene. Deficiency in CD55 (DAF) and CD59 (MIRL). Complement deposition on RBCs, white cells, platelets (C5b-9 complex, C3b) leading to complement meditated hemolysisClinical Features: Hemolysis most noteable in the morning, venous thrombosis, transformation to AMLOther: Normocytic anemiaLabs: + urine hemoglobin, + urine hemosiderin, Fe deciciency
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Glucose-6-Phosphate Dehydrogenase Deficiency
Definition: Hereditary hemolytic anemia caused by erythrocyte G6PD deficiency. X-linked recessive Pathogenesis: Cells sensitive to oxidative stress because they cannot produce NADPH or RIbulose-5-Phosphate from the HMP shunt. NADPH is necessary for the oxidative burst in neutrophils (O2 ---NADPH oxidase---> O2- ---SOD---> H2O2 ---MPO---> HOCL)Histo: Heinz bodies (precipitated denatured Hgb) and Bite cells (phagocytic removal of Heinz bodies by splenic macrophages)*precipitated by drugs (Dapsone and anti-malarials) and toxins (Fava beans)
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Warm AI Hemolytic Anemia
Definition: Acquired hemolytic anemia caused by IgG autoAbs against RBC membrane antigensPathogenesis: IgG autoAbs bind specific RBC antigens (usually Rh). Binding is optimal at 37 degrees C (warm temp). IgG coated RBCs bind splenic macrophage Fc receptors. Loss of RBC membrane by partial phagocytosis RBCs turn into spherocytes, which have poor deformability and are removed in the spleen (extravascular hemolysis)*Can either be primary (50%) or secondary from: 1. Hematopoietic neoplasms (CLL), 2. AI disease (SLE), or 3. Drugs (alpha-methyldopa)Clinical Features: anemia, splenomegalyLabs: + Direct Coombs test for IgG bound to pts. RBCs and for complement C3 in 70% of casesHisto: Spherocytes on blood smear
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Cold AI Hemolytic Anemia
Definition: Acquired hemolytic anemia caused by IgM autoAbs against RBC membrane antigens Pathogenesis: IgM Ab bind specific RBC Ag. Binding is optimal at 0-4 degrees C (cold temp). IgM coated RBCs fix complement onto RBC membrane. C3b coated RBCs are cleared by liver and spleen macrophages via C3b receptor (extravascular hemolysis). C9 membrane attack complex causes intravascular hemolysis. IgM is multivalent and causes red cells to agglutinate.*Can be primary or secondary: 1. Hematopoietic neoplasms (NHL), 2. Bacterial infection (Mycoplasma pneumoniae-big I Ag), 3. Viral infection (EBV-little i Ag)Clinical Features: Anemia, cyanosis of fingers and toes, hemoglobinuriaLabs: + Direct Coombs test for C3b bound to pt. RBCs + cold agglutining titerHisto: Clumped RBCs on blood smear
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Paroxysmal Cold Hemoglobinuria
Definition: Acquired hemolytic anemia caused by IgG autoAbs against the P blood group antigen that bind at cold temperatures (Donath-Landsteiner Ab)Pathogenesis: IgG Ab bind P Ag at cold temperature (0-4 degrees C) in fingers, toes Complement is fixed when RBCs circulate to central warm blood vessels. Massive complement mediated intravascular hemolysis. Clearance of Hb in urineClinical Features: Episodes of anemia and hemoglobinuria following cold exposure*can be caused by infections (syphilis, measles, mumps, chickenpox) Donath-Landsteiner Test:1. 37 degrees C x 60 minutes = no hemolysis 2. 4 degreees C x 30 minutes and 37 degrees C x 30 minutes = hemolysis
50
Macroangiopathic Hemolysis
Definition: RBCs are damaged when passing through obstructed or narrowed vessel lumen. Seen with mechanical heart valvesHisto: Schistocytes on blood smear
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Microangiopathic Hemolysis
Definition: RBC fragmentation in partially occluded capillaries. DIC (fibrin strands), TTP (vWF strands), HUSHisto: Schistocytes on blood smear
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Acute Blood Loss
No immediate change in Hb level. Hypovolemic shock. Slow fluid shift from interstitial space to intravascular space causes low Hb. Slow recovery of RBC mass.
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Chronic Blood Loss
No anemia until absent iron stores --> Iron deficiency anemia
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Relative Erythrocytosis
Males: Hct > 54%Females: Hct > 47%Associated Dz's: PV, Waldenstrom macroglobulinemia Clinical Features: Hyperviscosity syndrome. Decreased blood flow at Hct > 60%. Visual dysf(x) - HA, dizziness, deafness, stuporPathologic Features: Normal red cell mass. Decreased plasma volume. Dehydration, tobacco smoke
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Absolute Erythrocytosis
Males: Hct > 54%Females: Hct > 47%Pathogenesis:Primary - PV, low EPO levelsSecondary - Due to high EPO levels.
* Appropriate causes - tissue hypoxia (lung Dx, heart Dz, high altitude, high affinity Hgb).
* Inappropriate causes - Local kidney hypoxia (kidney cyst, hydronephrosis), EPO secreting tumors (RCC, hepatocellular carcinoma, cerebellar hemangioblastoma, uterine leiomyoma)
Associated Dz's: PV, Waldenstrom macroglobulinemia Clinical Features: Hyperviscosity syndrome. Decreased blood flow at Hct > 60%. VIsual dysf(x) - HA, dizziness, deafness, stuporPathologic Features: Increased RBC mass, primary and secondary causes
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Hereditary Hemorrhagic Telangiectasia
Definition: Hereditary disorder caused by weak venules, resulting in recurrent bleedingPathogenesis: Mutation in endoglin gene or activin-receptor-like kinase 1 gene. Thickened smooth muscle layer and absent elastin fibers in venule wallClinical Features: Epistaxis, telangiectasias of skin and mucus membranes, rectal bleeding, dyspnea, and intracranial bleeding Pathologic Features: Telangiectasias, AV malformations in various organs (nasal mucosa, skin, GI tract, lung and brain)
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Henoch-Schonlein Purpura
Definition: Acquired disorder of immune complex vasculitis (IgA) Epidemiology: Viral infection, drugsClinical Features: Petechiae, GI bleeding, renal failure, palpable purpuraPathologic Features: Leukocytoclastic vasculitis (neutrophil infiltration of vessel wall). Fibrinoid necrosis of vessel wall
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Immune Thrombocytopenic Purpura
Pathogenesis: Platelet destruction caused by Ab against platelet Ag. Epitope - GP IIB-IIIa, GP Ib-IXEpidemiology: Viral infection, collagen vascular disease, malignancy lymphomaClinical Features: Skin bleeding - petechiae, ecchymosis. Mucosal bleeding - epistaxis, gingival, GI, GU, intracranial Pathologic Features: Increased megakaryocytes on BM biopsy, thrombocytopenia, prolonged bleeding time (manual and automatic), anti-platelet IgG in serumTx: Glucocorticoids, spenectomy, RituximabPrognosis: Acute - < 6mo (children); Chronic - > 6mo (adults)
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Thrombotic Thrombocytopenic Purpura
Definition: Bleeding and thrombotic disorder caused by widespread platelet agglutinationPathogenesis: Deficiency of vWF metalloprotease (ADAMTS-13). Inherited (10%) due to gene mutation. Acquired (90%) due to Ab Endothelial injury --> release of large vWF multimers --> failure to degrade ULVWF --> microvascular platelet agglutinationPrecipitating Factors: Collagen vascular Dz (lupus), drugs (clopidogrel), infetions (HIV), pregnancy, HSC transplantClincial Features: fever, neuro deficits (stroke, seizure, coma), renal failure, bleeding (petechiae, purpura) Pathologic Features: Hyaline microthrombi w/in arterioles and capillaries (platelet-rich, no fibrin), schistocytes on blood smear, thrombocytopenia, elevated serum LDH, elevated serum creatinineClassic pentad:
* Microangiopathic Hemolysis
* Thrombocytopenia
* Fever
* Neurologic deficit
* Kidney failure
Tx: Urgent plasma exchange with fresh frozen plasma replacement. Rituximab (anti-CD20)
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Hemolytic Uremic Syndrome
Definition: Bleeding and thrombotic disorder caused by platelet aggregation in the kidney microvasculaturePathogenesis: Infection by bacteria that produce Shiga-like toxin (E. Coli O157:H7), glomerular endothelial injury Clinical Features: Usually children, acute diarrhea, bleedingPathologic Features: Hyaline microthrombi w/in arterioles and capillaries (platelet-rich, no fibrin), schistocytes on blood smear, thrombocytopenia, elevated serum LDH, elevated serum creatinine
61
Bernard-Soulier Syndrome
Definition: GP Ib/V/IX deficiency.Autosomal Recessive Pathogenesis: Defective platelet adhesionEpidemiology: Dx by platelet adhesion testing. No platelet adhesion/aggregation response to ristocetin
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Glanzmann Thrombasthenia
Definition: GPIIb/IIIa Deficiency.Autosomal RecessivePathogenesis: Defective platelet aggregationEpidemiology: Dx'd by platelet aggregation testing. No platelet aggregation response to epinephrine, ADP, collagen, arachidonic acid, thrombin. Normal platelet aggregation response to ristocetin.
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Alpha Storage Pool Disease
Definition: Deficiency of alpha granules (Fibrinogen, vWF, Platelet Factor 4) Pathogenesis; Defective platelet aggregationEpidemiology: Dx'd by electron microscopyClinical Features: Bleeding in mild to moderate
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Delta Storage Pool Disease
Definition: Deficiency/defective delta granules (ADP, Ca2+, Serotonin) Pathogenesis; Defective platelet aggregationEpidemiology: Dx'd by platelet aggregation testing Clinical Features: Bleeding in mild to moderate
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Medication Derived Platelet Disorder
Platelet aggregation inhibitors: COX inhibitors (aspirin, ibuprofen), ADP receptor inhibitors (clopidogrel)
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Kidney Failure Platelet Disorder
Pathogenesis: Defective platelet aggregation. Increased blood levels of platelet inhibitors (prostacyclin I2, NO, phenolic acids)Tx: Reversible w/ hemodialysis
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Hemophilia A
Pathogenesis: Factor VIII deficiency. X-linked recessive Epidemiology: Males 1/10,000Clinical Features: Hemarthrosis, hematomas, ecchymoses, degenerative arthritis, severity of bleeding is similar between generations Pathologic Features: Elevated PTT, normal PT, corrected PTT 1:1 mixing study, normal bleeding time, decreased factor VIII activityTx: Recombinant FVIII, cryoprecipitate, recombinant FVIIaPrognosis: Severe (<1%) - spontaneous bleeding. Moderate (2-5%) - bleeding after trauma/surgery. Mild (>5%) - bleeding after trauma/surgery
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Hemophilia B
Pathogenesis; Factor IX deficiency. X-linked recessive Epidemiology: Males. 1/60,000Clinical Features: Hemarthrosis, hematomas, ecchymoses, degenerative arthritisPathologic Features: Elevated PTT, normal PT, corrected PTT 1:1 mixing study, normal bleeding time, decreased factor IX activity
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Factor XIII Deficiency
Autosomal recessive bleeding disorderPathogenesis: Defective fibrin cross-linking and an unstable fibrin clotClinical Features: Bleeding and delayed wound healingPathologic Features: Normal PT, normal PTT, normal bleeding time, abnormal urea solubility test
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Von Willebrand Disease
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Pathogenesis: 3 types
* Partial quantitative deficiency (AD)
* Qualitative deficiency
* Complete quantitative deficiency (AR)
Clinical Features: Mucocutaneous bleeding (petechiae, ecchymoses, prolonged bleeding after tooth extraction). Hemarthrosis and hematomas in type 3Pathologic Features: Prolonged bleeding time, prolonged PTT, decreased vWF activity, decreased vWF antigen (type 1 and 3), normal vWF antigen (type 2)Tx: Cryoprecipitate and ADH (Desmopressin)
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Acquired Factor VIII Inhibitor
Pathogenesis: Idiopathic (elderly), Secondary (AI dz - SLE, RA, postpartum, hemophilia A), Specificity against FVIIIClinical Features: Mild-severe bleeding. Spontaneous resolution or chronicPathologic Features: Prolonged PTT, normal PT, non-corrected PTT 1:1 mixing study, normal bleeding time, decreased factor VIII activity Tx: Recombinant FVIIIa, Immunosuppressive drugs, (prednisone, cyclophosphamide)
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Disseminated Intravascular Coagulation
Definition: An acquired hemorrhagic and/or thrombotic disorder caused by excessive release of tissue factor into the blood, leading to over activation of the coagulation system and secondary fibrinolysis Pathogenesis: Release of tissue factor into the blood. Excess thrombin and plasmin generation. Clotting factor and platelet consumptionRisk factors: Bacterial sepsis, massive trauma, acute promyelocytic leukemia, carcinoma, placental abruption, retained dead fetusClinical Features: Bleeding (rectal, hematuria, petechiae, venipuncture sites), Arterial thrombosis (stroke, extremity infarction), Venous thrombosis (leg veins, pulmonary embolism)Pathologic Features: Hyaline microthrombi of micro vessels, platelet and firbrin rich thrombi, thrombocytopenia, prolonged PT and/or PTT, decreased fibrinogen, elevated D-dimer, microangiopathic hemolysis (schistocytes on blood smear) Tx: Treat underlying condition
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Vitamin K Deficiency
Pathogenesis: Decrease in Vitamin K leading to decrease in Vitamin K dependent proteins Epidemiology: Antibiotics, malnutrition, malabsorption, newbornsClinical Features: Mild-severe bleeding Pathologic Features: Increased PT only early. Increased PT and increased PTT late
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Liver Disease Coagulation Disorder
Pathogenesis: Decrease in all clotting proteins Epidemiology: Hepatocellular damageClinical Features: Mile-severe bleeding Pathologic Features: Increased PT only early. Increased PT and increased PTT late.
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Deep Vein Thrombosis
Definition: Thrombosis or thrombotic emboli within any location in the venous system, usually legPathogenesis: Virchow's triad - hypercoagulability, venous stasis, vessel damageEpidemiology: Increases with ageClinical Features: Unilateral leg pain or leg swelling. Calf pain on ankle dorsiflexion (Homan sign). Palpable cord in calf. Symptoms and signs are very nonspecific. 50-85% of pts w/ clinical features have no DVT on objective testing Dx: Compression ultrasound of proximal leg veins - if possible (confirmed), if negative - repeat test in 1 wk. D-dimer + compression ultrasound - if both negative, no need for repeat testing. Venography of proximal leg veins - if positive, confirmed
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Post Thrombotic Syndrome
Epidemiology: 60% risk after 2 years DVTClinical Features: Chronic symptoms in the thrombosed leg - pain, swelling, ulcerationTx: 50% risk reduction by wearing compression stockings for 2 years
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Pulmonary Embolism
Definition: Thrombosis or thrombotic emboli within the pulmonary venous systemPathogenesis: Virchow's triad - hypercoagulability, venous stasis, vessel damageClinical Features: Dyspnea, wheezing, chest pain, hemoptysis, R sided heart failure, hypoxemiaDx:
* Spiral CT scan - High PPV (if +, confirms dx)
* D-dimer - High NPV (if -, no clot)
* Negative CT and D-dimer excludes PE
* Ventilation-Perfusion Scan - High NPV
* Pulmonary Angiography - High PPV and NPV
Prognosis: Mortality - 15% at 3 month; Cause of death = right ventricular failure
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Chronic Pulmonary Hypertension
Pathogenesis: Increased pulmonary vascular resistance due to embolic obstructionEpidemiology: 4% risk after 2 years PE
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Factor V Leiden
Pathogenesis: Point mutation at position 506Arg-->Glu of FV. Mutated Fva is resistant to proteolytic inactivation by APC. Unopposed FVa activity leads to increased thrombin generation --> hypercoagulability Epidemiology: High prevalence in caucasians (5%). Low prevalence in African and Asian ethnicity (0.5%)Clinical Featurs: Heterozygotes - 5x increased risk of VT; Homozygotes - 50x increased risk of VT; Increased risk of MI in young womenDx:
* Activated Protein C Resistance Test - PTT is measured in absence and presence of added APC. APC causes prolongation of PTT in normals. APC causes less prolongation of PTT in FVL. Low cost, high sensitivity (screening test)
* Mutation Analysis by PCR - Used as a confirmatory test when APC resistance test is +. Distinguishes heterozygotes/homozygotes
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Prothrombin G20210A Mutation
Pathogenesis: Point mutation in 3'-untranslated region of gene. Increased stability of prothrombin mRNA. Causes 30% increase in prothrombin levels in plasma. Mechanism of hypercoagulability may result from increased thrombin generation due to increased prothrombinase complex activity.Clinical Features: Heterozygotes - 2.5 increased risk of VTDx: Mutation analysis by PCR
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Protein C Deficiency
Pathogenesis: Impaired inactivation of Factor Va and Factor VIIIaEpidemiology: Other causes of low platelet counts - liver dz, Warfarin, Vitamin K deficiency, DICClinical Features:
Heterozygotes - adult presentation, 10x risk of VT. Warfarin-induced skin necrosis;
Homozygotes - Neonatal presentation. Neonatal Purpura Fulminans
Dx: Decreased plasma levels of protein C function or free protein C antigen. Mutation analysis not required
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Protein S Deficiency
MOA: Impaired inactivation of Factor Va and Factor VIIIaClinical Features:
Heterozygotes - adult presentation, 10x risk of VT, Warfarin-induced skin necrosis;
Homozygotes - neonatal presentaiton, Neonatal Purpura Fulminans
Dx: Decreased plasma levels of protein S f(x) or free protein S
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Antithrombin III Deficiency
MOA: Impaired inactivation of serine proteases of coagulation cascade.Clinical Features:
Heterozygotes - adult presentation, 25x risk of VT, resistance to Heparin therapy, Warfarin induced skin necrosis
Homozygotes - incompatible w/ life
Dx: Decreased plasma levels of antithrombin III f(x)
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Antiphospholipid Antibody Syndrome
An acquired venous and arterial thrombotic disorder caused by autoAbs against phospholipid binding proteinsMOA: Primary autoantigen is β-2-glycoprotein-1 (B2GP1), a plasma protein that binds to a variety of ligands. B2GP1 binds to apolipoprotein E receptor 2 on platelets. Anti-B2GP1 autoAb cross-links apoER2-B2GP1 complex, leading to platelet activationClinical Features: Venous thrombosis, arterial thrombosis, recurrent spontaneous pregnancy loss, seen secondarily in SLEDx: anti-B2GP1 Ab, anti-cardiolipin Ab, lupus anticoagulant test - causes a prolonged PTT w/ a noncorrected 1:1 mixing study.Diagnostic Tests:
* Russell Viper venom time test
* Hexagonal phase phospholipid neutralization test
Tx: Anticoagulation and immunosuppression
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Heparin Induced Thrombocytopenia
A drug induced thrombotic disorder cause by Abs directed against the heparin-platelet factor 4 complexMOA: Incidence highest with unfractionated heparin. AutoAb-heparin-PF4 complex activated platelets leading to increased risk of thrombosisClinical Features: 4 T's Thrombocytopenia Timing - 5-10 days after Thrombosis - venous, arterial Thrombocytopenia Dx: ELISA for heparin-PF4 AbsTx: Discontinue Heparin. Start direct thrombin inhibitor*50% mortality if unrecognized
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Chronic Myeloid Leukemia
Pathogenesis: Neoplastic proliferation of mature myeloid cells, especially granulocytes and their precursors: basophils are characteristically increased.Clinical Features: Splenomegaly (red pulp) b/c of extramedullary hematopoiesisGenetics: t(9;22) aka BCR/ABL fusion aka Philidelphia chromosome. Histo: Marked granulocytosis including all stages of maturationBlood: Leukocytosis >20,000/uL mostly basophilia*The mutation is in the multipotential hematopoietic stem cell, so can have blast crisis where is transforms to >20% blasts (70% AML 30% ALL)Tx: Imatinib Mesylate (Gleevec)
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Polycythemia Vera
Pathogenesis: Neoplastic proliferation of mature myeloid cells, especially RBCs (granulocytes and platelets also increased)Genetics: Point mutation in pseudokinase domain of JAK2 (chomosome 9) Histo: Increased total body RBC massBlood: Elevated RBC, Hb, and Hct. Normochromic and normocytic RBCs. Low serum EPO. Decreased or absent Fe.
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Primary Myelofibrosis
Pathogenesis: Neoplastic proliferation of mature myeloid cells, especially megakaryocytes. Plateles produce excess pletelet derived growth factor (PDGF) causing BM fibrosisGenetics: JAK2 mutation in 50%, also MPL mutation in 1-5%Clinical Features: SplenomegalyBlood: Leukoerythroblastosis and extramedulary hematopoiesisHisto: Tear drop RBCs, nucleated RBCsBone Marrow: Reticulin and collagenous fibrosis and osteosclerosis
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Fibrinolytic Protein Deficiency
Epidemiology:
* AR - Plasminogen activator inhibitor 1 (PAI-1): usually inhibits tPA
* AD - Alpha-2-antiplasmin: usually inhibits plasmin
If you don't have downregulation of fibrinolysis, then overactivation of fibrinolysis leading to increased lysis of the clot and increased bleedingClinical Features: Mild-severe bleedingPathologic Features: Normal platelets, PT, and PTT
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Hemophilia C
Pathogenesis: Factor XI deficiencyAutosomal RecessiveClinical Features: Hemarthrosis, hematomas, ecchymoses, degenerative arthritis, severity of bleeding is similar between generations Pathologic Features: Elevated PTT, normal PT, corrected PTT 1:1 mixed study, normal bleeding time, decreased factor XI activityTx: Factor XI concentratePrognosis: Severe (<1%) - spontaneous bleeding. Moderate (2-5%) - bleeding after trauma/surgery. Mild (>5%) - bleeding after trauma/surgery
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Factor XII Deficiency
Deficiency in Factor XII of coagulation cascade (Extrinsic pathway)Clinical Presentation: Completely normal. No bleeding.Labs: Increased PTT with corrected mixing study
