Anti Phospholipid Syndrome (APS or APA)

Anti Phospholipid Syndrome (APS or APA)

associated with SLE vs. primary APS (PAPS) / PAPS has higher incidence of TMA

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  prolonged aPTT does not correct with normal serum
  
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  APS pts usu. have baseline platelets of 100-160
  
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  anticardiolipin antibody (IgG elevated ~30%, IgM ~20%, both decreased ~50%, and IgA not considered important)
  
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  Russell viper venom test (RVVT), but you have to make sure the lupus anticoagulant is there as well (can get elevated RVVT but not significant)
  
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  low titre false positive RPR
  
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  anti-B₂-glycoprotein Ab’s (B₂GPI), can be the only positive lab (and tends to correlate more directly with actual disease activity, so definitely get this test if others are negative and clinical suspicion is high [this is a send-out lab]
  

livedo reticularis [pic] and CNS ischemic events (usu. associated with APA syndrome) with broken circles, it’s livedo racemosa [pic]

CNS lesions (association with APA syndrome) / diffuse white matter (WM) lesions and a scattering of lacunar infarcts in the basal ganglia and WM

160+ mutations / Type I vs. Type II / decreased degradation of V, VIII / decreased clot/fibrinolysis / nephropathy form / also decreased in acute clotting / because C and S also dependent on vitamin K, levels can decrease before other factors leading to warfarin induced skin necrosis [pic][pic]

Cofactor for APC / same mechanism as Protein C / nephropathy form

1 % prevalence / can be from nephrotic syndrome in children (but is usually only symptomatic in children, adults) / can also occur secondary to massive thrombus with APA syndrome / congenital form? / long term use of heparin (increased clearance of heparin-ATIII complexes)

AD or acquired (liver disease, hepatoma, AIDS, lymphoproliferative / < 1 % prevalence / dysfunctional or deficient fibrinogen (a constellation of different defects) / even a severe deficiency produces mild, rare bleeding episodes (usu. noticed after surgery)

10-50% prevalence / impractical to measure because normal range varies a lot

some say loss of anti-clotting factors (several smaller molecular weight ones)

others say activation of platelets
Leukemia
acute leukemia anemia, infection, hemorrhage / 30% or more blasts in bone marrow

high or low peripheral WBC / identical twins have 1 in 20 chance

children and young adults / 85% of childhood leukemias

up to 85% remission (not with adult ALL) 85% L1 / 15% L2 / L3 (Burkitt’s - worst) / CNS common site of relapse / 80% B-cell origin (CALLA marker) / T-cell present in thymus / 60% have cytogenetic abnormalities hyperdiploidy (good) / Philadelphia chromosome (poor prognosis) and others (t8:14, c-myc)

Complications: 10-30% rate of hyperleukocytosis or blast crisis

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  CNS: stupor, headache, dizziness, tinnitus, visual changes, confusion, coma
  
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  Lungs: respiratory distress, hypoxemia, progressive respiratory failure
  

most common chronic leukemia in U.S. / 50 - 70 yrs / males 2:1

95% B-cell origin [pic] / incompetent lymphocytes in marrow, nodes, spleen

Presentation: usually type B symptoms (weakness, fatigue, etc.), lymphadenopathy (66%), enlarged liver/spleen (10-40%)

Diagnosis: 40% in marrow required for Dx (historically, not sure if still true) / can now do flow cytometry on blood and detect monoclonal B-cell line (e.g. CD5⁺ B-cells) / bone marrow biopsy gives prognostic information (nodular, interstitial, mixed, diffuse)

Labs: may or may not have absolute lymphocytosis at diagnosis (usu. 40-150K) [pic], anemia (15-20%), thrombocytopenia (10%), Coomb’s positive (10%), may have increased M fraction

Course: usually indolent but can develop number of late complications

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  bone marrow failure or pure red cell aplasia (slow progression)
  
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  fulminant transformation (Richter’s syndrome)
  

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  severe adenopathy obstructing esophagus, ureters, GI tract, lymphatics
  
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  pleural effusions, ascites, leg edema
  
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  opportunistic fungal, viral, gram negative and encapsulated organisms (due to low IgG)
  
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  increased incidence of MALT or mantle cell leukemia (also has translocation of chromosome 11 and 14 and expression of cyclin D1)
  

fulminant prolymphocytic form of CLL / marked splenomegaly, minimal lymphadenopathy

rare / mature B-cells / CD25+

Myeloproliferative Disorders

Acute Myelocytic Leukemia (AML)

onset 15 - 40 yrs / only 15-20% of childhood leukemias

Histology: myeloblasts contain Auer rods [pic] and myeloperoxidase / lymphocytes contain TdT

Markers: Philadelphia chromosome 9:22 - poor prognosis for M1 / 8:21 is good prognostic sign for M2

Complications: 3-13% incidence of hyperleukocytosis

Treatment: chemotherapy with allopurinol to prevent renal calculi, bone marrow transplant
Chloroma [pic][pic][pic]

leukemic infiltrate of skin / reddish-blue (the green is usually hidden by the blood)

Maturation (M1-M3)

Acute promyelocytic leukemia (M3)

greater risk for DIC with hemorrhage / this may be the rare time when heparin is given to treat DIC

Differentiation (M4-M7)
Monoblastic component (M4-M5)

tissue infiltration / increased muramidase and hypokalemia erythroleukemia

Radiation and toxin-induced leukemia (M6)
Megakaryocytic leukemia (M7)

Down’s / follows myeloproliferative disorders
Chronic Myelogenous Leukemia (CML) (poor prognosis)

7-20% of leukemias / onset in 40s (but children can get it too) / mutated tyrosine kinase (unregulated signal transduction) / Philadelphia chromosome (95%) (9:22 translocation), BCR, ABL

Presentation: 40% asymptomatic at time of diagnosis / fatigue, weight loss, weakness, fever, splenomegaly (50%), hepatomegaly / rarely has CNS invasion or lymphadenopathy

Diagnosis: bone marrow full of WBCs (high M:E), basophilia very indicative, wide variety of myeloid precursors [pic] / very low leukocyte alkaline phosphatase (low LAP), distinguishes from leukemoid reaction (such as with Tb in marrow) / elevated B₁₂ due to increased transcobalamin I

Labs: leukocytosis, thrombocytosis, 10% blasts with promyelocytes / can follow therapy by testing quantitative t(9;22) BCR-ABL by PCR (7/09)

Course: chronic phase 3-5 yrs / acute phase (blast crisis) 3 to 6 months with > 30% blasts in marrow, myeloid crisis does not respond to chemotherapy

Treatment:

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  Imatinib (Gleevec)  preliminary findings show response of 60-90%
  
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  rIFN- plus low-dose cytarabine early stage / low response rate (5-20%), but some survival benefit
  
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  HU  alternative conventional chemotherapy with reduced benefit but less toxicity; response rate following IFN roughly 50%
  
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  BMT  best within 1-2 yrs of diagnosis, increased short term risks, increased chance of remission, lack of evidence based support / previous chemotherapy may reduce success of subsequent BMT; only 30% find donors
  
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  Under Investigation: anti-RAS drugs
  

Primary Thrombocythemia or Essential Thrombocytosis

primary thrombocytosis causes severe bleeding or thrombosis / secondary thrombocytosis common in CML and PRV / rarely may be associated w/ myeloid metaplasia

Treatment: ASA + platelet pheresis when count exceeds 1 M / hydroxyurea, alkylating agents, 6-MP

Diagnosis: historically diagnosis of exclusion but JAK2 V617F PCR now available (high sensitivity, very specific in distinguish reactive/secondary thrombocytosis from myeloproliferative disorder)

Secondary thrombocytosis: infection, inflammatory conditions, malignancy, iron deficiency, hemorrhage, post surgical states, other myeloproliferative (CML, myelofibrosis), myelodysplastic syndromes (e.g. 5q syndrome), rebound (correction of B12 or folate deficiency or cessation of chronic alcohol use)
Polycythemia Rubra Vera (PRV)

Presentation: ruddy cyanosis, headache, dyspnea or orthopnea, dizziness, eye complaints, epigastric discomfort / thrombosis (because of erythrocytosis, not thrombocytosis) / high Hb, dark, viscous blood / accompanied by leukocytosis and thrombocytosis (releases K causing “spurious hyperkalemia”)

Complications: 20% get CML

Diagnosis: JAK2 V617F PCR

Treatment:

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  phlebotomy (can give ASA but no evidence that ASA reduces incidence of thromboses if asymptomatic and normal Hct 1/07)
  
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  chemotherapy for symptomatic splenomegaly (increased risk of leukemogenesis with use of hydroxyurea)
  

Secondary PRV due to low oxygen saturation state (lung disease, intracardiac shunt, hypoventilation, AV malformation, altitude), elevated carboxyhemoglobin (smoking, CO poisoning), high-affinity hemoglobinopathy, some tumors (RCC, HCC, uterine leiomyoma), hormonal disorders

high erythropoietin / usually not splenomegaly and immature cells in peripheral blood

Leukemoid Reaction

usually no anemia, thrombocytopenia as in leukemia / mature WBCs / transient / high LAP

Myelodysplastic syndrome

clonal proliferation (can affect any of three cell lines) / 5 subtypes (RA, RARS, RAEB, RAEB-T, CMML) / elderly / male>female / macrocytic anemia, mild thrombocytopenia or neutropenia may precede diagnosis of MDS for years / 20% have splenomegaly / development of secondary AML (30% of de novo MDS and 50% of chemo-related MDS) is highly refractory to chemotherapy (poor prognosis)

Presentation: based on affected cell lines

Diagnosis: must distinguish CMML from CML

Labs: may have dimorphic RBC populations, macrocytosis, punctate basophilia, WBCs with pseudo-Pelger-Huet abnormality or hypersegmentation and/or Dohle bodies, increased or decrease platelet count, neutropenia / %myeloblasts distinguishes RA
Treatment: refer to hematologist (treatment and new classifications are constantly changing) / meanwhile, treat supportively, replace RBC, platelets as needed

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