Coagulation_Clinical Pathology Boards Review

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Coagulation_Clinical Pathology Boards Review
2014-09-21 01:49:16
Coagulation Clinical Pathology Boards Review Coag Clin Path CP

Coagulation Clinical Pathology Boards Review
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  1. What is normal platelet survival time?
    7-10 days
  2. What do these plt receptors bind to?
    1) GP Ia/IIa
    2) GP Ic/IIa
    3) GP Ib/V/IX (CD42 = GPIb)
    4) GP IIb (CD41)/IIIa (CD61)
    • 1) collagen (Bra and Brb)
    • 2) fibronectin
    • 3) vWF (def is Bernard Soulier)
    • 4) fibrinogen (def is Glanzmann)
  3. What RBC antigens do plts also have on their cell surface?
    ABO, P, I, i, Le
  4. All of the following are contained by α granules except:
    A) Fibrinogen
    B) PDGF
    C) ADP
    D) vWF
    E) P-selectin
    F) PF4
    G) FVa
    C - α granules contain the big molecules
  5. All of the following are contained by dense granules except:
    A) PF4
    B) ADP
    C) 5-HT (serotonin)
    D) Calcium
    E) ATP
    A - dense granules contain small molecules
  6. What are the intrinsic pathway factors? What activates the pathway?
    F8,9,11,12; negatively charged glass
  7. What are the extrinsic pathway factors? What activates the pathway?
    TF (F3) and F7; TF
  8. What are the common pathway factors?
    Small dollar bills: 1, 2, 5, 10
  9. What are factors I, II, III, IV, and VI?
    • I - fibrin
    • II - thrombin
    • III - Tissue Factor
    • IV - Calcium
    • VI = FVa or accelerin
  10. What drugs block the GPIIb/IIIa fibrinogen receptor? What do platelet aggregation studies look like?
    • Abciximab-Reopro, Eptifibatide (Integrilin), Tirofiban (Aggrastat)
    • Looks like Glanzamann (everything abnormal except Ristocetin)
  11. What are the Vitamin K dependent factors? Why does Coumadin require heparin bridging?
    10,9,7,2 + Prot C and S; Prot C and S are one of the first things to drop so you're initially hypercoagulable
  12. Where is vWF made?
    Endothelial cells (in Weibel palade bodies, which are in hemangioedotheliomas) & megakaryocytes
  13. What factor isn't made in the liver hepatocytes? Where is it made?
    F8; liver kupffer cells
  14. What bleeding disorders show the following PT/PTT findings:
    1) ↑PT, ↑PTT, nml plts
    2) ↑PT, nml PTT, nml plts
    3) ↑PTT, nml PT, nml plts
    4) nml PT, PTT, ↓plts
    5) PT, PTT, and plts all decreased
    6) PT, PTT, plts all nml
    • 1) DIC, liver dz, degraded specimen, amyloidosis, severe coumadin, heparin, Vit K def, Dysfibrinogenemia, primary fibrinolysis
    • 2) Coumadin, Vit K def, FVII def/inhib, liver dz, dysfibrinogenemia
    • 3) Factor 8,9,11 deficiencies/inhibitors, lupus anticoagulant (PT may be elevated), heparin, nephrotic syndrome, prekallikrein def, kallikrein def, vWD, HMWK def (cofactor of prekallikrein and FXI)
    • 4) TTP/HUS, other plt issues (sequestration, decreased production, Bernard Soulier)
    • 5) Liver dz, DIC, HIT
    • 6) Mild factor def, FXIII def, dysfibrinogenemia, vascular d/o, mild vWD, uremia, surgery, inherited plt d/o
  15. What are the symptoms of TTP/HUS?
    • Mnemonic: Brain FARTS
    • Brain = neurologic sxs
    • Fever
    • Anemia
    • Renal insufficiency
    • Thrombocytopenia (<20k/μL)
    • Schistocytes
  16. What factor has the shortest t1/2?
    FVII, 4-6 hrs
  17. What is the lab test for FV Leiden?
    Activated Protein C resistance
  18. How does F7a activate the clotting cascade? When is F7a given under the chest/trauma protocol?
    • Directly activates both extrin & intrinsic paths via F10 & F9, and catalyzes formation of add'l F7a → activation of clotting cascade
    • Coagulopathy by labs (INR >2 or PT >23 or aPTT >53 or fibrinogen <100mg/dL) or there is ongoing life threatening coagulopathic bleeding
  19. What is monitored for LMW heparin?
    Factor 10a
  20. What does FXII deficiency cause?
  21. What do the following anticoagulants act on:
    1) Protein C & S ("back brake")
    2) Antithrombin ("front brake")
    3) tPA
    4) TF pathway inhibitor ("hand brake")
    • 1) F5 and F8
    • 2) Thrombin, F12a, F11a, F10a, F9a
    • 3) Plasminogen
    • 4) Extrinsic pathway: TF/10a/7a complex
  22. There are two coagulation "brakes" that induce fibrinolysis: tPA and Plasmin. What are their inhibitors?
    • tPA inhibitor: PAI (Plasminogen activator inhibitor)
    • Plasmin inhibitor: α2 anti-Plasmin
    • TAFI (thrombin activatable fibrinolysis inhibitor): inhibits plasminogen or tPA binding to fibrin
  23. What does thrombin activate?
    Fibrinogen (F1), F5,8,11,13; also promotes plt aggregation
  24. When is activated clotting time (ACT) used? What sample type is tested? What ACT level is desired?
    When high dose heparin is used (ex. bypass surgery) and aPTT immeasurable b/c too high (>150 secs); whole blood in tube w/intrinsic path activator like glass or kaolin; >400 secs
  25. Name four causes of increased thrombin time?
    ↑paraproteins, amyloid, heparin, dysfibrinogenemia
  26. What materials are required to test aPTT? PT? Thrombin time?
    • PTT (intrinsic + common pathway): activator (kaolin, silica), phospholipid, excess calcium, citrated plasma
    • PT (extrinsic + common): TF, phospholipid, excess calcium, citrated plasma
    • Thrombin time (common path): thrombin + pt plasma (measures fibrinogen to fibrin, doesn't need calcium, phospolipid)
  27. Why are D-dimers specific for clot formation?
    D-dimers is a form of fibrin degradation product, which is only formed by plasmin-mediated degradation of fibrin, NOT fibrinogen, so this means a clot had formed and been degraded
  28. Why are fibrin degradation products not as specific as D-dimers for clot formation?
    Detects fibrinogen degradation products as well as D-dimers and fibrin degrad prods
  29. How is protein C activated?
    Thrombomodulin binding to thrombin to activate protein C, and Prot C (w/Prot S as carrier) inhibits F5 and F8
  30. What does heparin act on to inhibit clotting?
    Antithrombin, which acts on thrombin/FII and FXa
  31. What method is used for plt count?
    electrical impedance with <13 fL (range 2-20 fL) = one plt
  32. How is INR calculated? Why is INR used?
    INR = [PTmeasured/PTmean]ISI where ISI is provided by manufacturer; thromboplastin (used as TF for PT measurement) sensitivity differed among labs so PTs differed for same level of anticoagulation
  33. In factor deficiencies, what factor level is required for the following scenarios:
    1)severe with spontaneous bleeding
    2) bleeding w/minor trauma
    3) excessive bleeding following surgery or significant trauma
    • 1) <1% or <1U/dL
    • 2) 1-5%
    • 3) >5%
  34. What factor levels cause prolonged PTT?
    below 30%
  35. What factors are missing in the following blood products:
    1) aged plasma
    2) adsorbed plasma
    3) serum
    • 1) F2,5,8,13 (*F5 and F8 degrade fastest in vitro)
    • 2) Vit K dependent factors: X, IX, VII, II
    • 3) F2,5,8,13 (same as aged plasma) + fibrinogen
  36. What happens to plts in Fe deficiency anemia?
    Plts increase
  37. How is reptilase time performed? What does it measure? When is it used? When is it elevated?
    bothrox atrox venom + pt plasma; fibrinogen to fibrin conversion (like thrombin time); tests coag in presence of heparin (unaffected by it); non-heparin causes of ↑TT like dysfibrinogenemia, amyloid, ↑paraproteins
  38. What can neutralize heparin?
    protamine + reptilase
  39. How does plt aggregometry test plt aggregation?
    • Plt-rich plasma @ RT is stirred while exposed to agonists (ADP, epi, arachidonate, collagen, ristocetin), look for change in light transmission (↓optical density = ↓ turbidity = ↓light scatter =
    • ↑transmission means plts aggregated at bottom of cuvette)
  40. What curves are generated in plt aggregometry studies with agonists? Which agonist shows an initial lag phase?
    • 1) low-dose ADP & Epi - biphasic curve from primary aggregation and plt degranulation of dense granules causing secondary wave of aggregation
    • 2) high-dose ADP, collagen, ristocetin - monophasic curve; collagen
  41. What can cause an absent 2nd wave in plt aggregation with low-dose ADP or epi? What test can help determine the cause of defect?
    ASA (TXA2 stimulates dense granule release) and storage pool defects; high-dose thrombin can complete aggregation w/out TXA2 and overcome ASA effects while inherited defects can't be overcome by thrombin
  42. What is the defect in Bernard Soulier? What is seen with plt aggregation? Peripheral smear findings?
    GPIb/V/IX (CD42) defect → can't bind vWF → aggregation with everything except Ristocetin (promotes plt binding to vWF); giant plts w/ pseudonucleolus & thrombocytopenia
  43. What is the defect in Glanzmann's thrombasthenia? What is seen with plt aggregation? What does the peripheral smear show? What additional test is diagnostic?
    GPIIb/IIIa in plt binding to fibrinogen; no aggregation except for ristocetin (b/c you can still bind plts to vWF); normal sized dispersed plts; clot retraction test show poor/absent retraction
  44. What plt antigen is missing in Glanzmann's thrombasthenia? What transfusion reactions are associated with this Ag?
    HPA-1a/PLA1; Neonatal alloimmune thrombocytopenia and post-transfusion purpura
  45. How does Glanzmann differ from afibrinogenemia based on coag studies?
    • Glanzmann: nl PT, PTT
    • Afib: ↑PT & PTT
  46. All of the following diseases have giant platelets except:
    A) Bernard Soulier
    B) May Hegglin
    C) ITP
    D) Grey platelet syndrome
    E) Glanzmann thrombasthenia
    F) Alport syndrome
  47. All of the following diseases have giant platelets except:
    A) Montreal plt syndrome
    B) vWD
    C) Sebastian syndrome
    D) Mediterranean macrothrombocytosis
    E) Fechner syndrome
    F) Epstein syndrome
  48. Name five major platelet storage pool disorders and give the type of abnml granules.
    • 1) Grey plt syndrome (α granules)
    • 2) Chediak-Higashi (dense granules)
    • 3) Hermansky-Pudlak (dense granules)
    • 4) Wiskott-Aldrich (dense granules)
    • 5) Quebec plt disorder (α granules)
  49. How are plt storage pool diseases identified on plt aggregation? What does EM show? What ratio is altered (test Q!)?
    low-dose ADP & epi - no 2nd wave, collagen, high-dose ADP, collagen - decreased, ristocetin nml; absence of granules; ↑ATP:ADP
  50. Puerto Rican patient comes in complaining of nosebleeds. He has a hx of multiple nevi, pulmonary fibrosis, and a congenitally absent radius. Labs show nml plts but prolonged bleeding time and peripheral smears show "swiss cheese" appearing plts. Dx? What gene is likely related to his dz?
    Hermansky-Pudlak; single duplication of HPS1 gene on chrom 10q23
  51. Patient presents with thrombocytopenia, eczema, and numerous infections involving encapsulated bacteria, PCP, and herpes. Peripheral smears show really, really small plts. Dx? Mutation? What else is in the DDx?
    Wiscott-Aldrich with no dense granules; X-linked WAS gene mutation (Xp11.22) involved in cytoskeletal malleability;T- and B-cell immunodeficiency with ↓IgM, ↑IgE and IgA, ↓T-cells; Fe def anemia
  52. How does ASA affect plt aggregation studies?
    • Absent 2nd wave with low-dose ADP and epi (no degranulation)
    • No aggregation w/ arachidonic acid
    • Prolonged lag phase w/ collagen
    • Nml ristocetin
    • Nml w/high-dose collagen and high-dose thrombin
  53. How does ASA produce plt impairment? What is the role of COX-2 in plt inhib?
    Inhibits COX1 → ↓TXA2 → ↓dense granule release; ASA doesn't have much effect on COX2, which produces prostacyclin, a plt inhibitor, in nucleated endothelial cells and prostacyclin inhibits plts so given the lack of COX2 inhibition by ASA, overall there is plt inhibition
  54. What other disease(s) does vWD look like on plt aggregation studies? What disease(s) look like ASA toxicity?
    • vWD looks like Bernard Soulier (all nml except ristocetin)
    • ASA toxicity kinda looks like plt storage pool dz, dysfibrinogenemia and Glanzmann (all abnml except ristocetin) with some minor differences
  55. What disease causes thromboses, oral telangiectasias, Fe def anemia with bleeding that can mimic a plt d/o?
  56. What factor is decreased in amyloidosis?
    F10 - plts don't stick b/c vessels coated with λ light chains
  57. What is the deficiency in TTP? How do you tx?
    ADAMTS-13, which cleaves large vWF multimers; plasmapharesis vs. steroids/IVIG OR cryo-poor plasma vs. splenectomy if it's refractory
  58. What blood type has decreased vWF?
    Type O
  59. What is the difference btw Ristocetin Cofactor assay and ristocetin-induced plt aggregation?
    • RCof:pt plasma + nml plts + ristocetin, if pt def in vWF → ↓ aggregation
    • RIPA: pt plasma + nml plt + low-dose ristocetin, if pt Type 2B or plt-type vWD → ↑aggregation
  60. Give the multimeric analysis result for the weird vWD types: IIM and IIN
    IIM: Nml but defective vWF binding to GPIb → nml [vWF Ag] but RCof ↓

    IIN: Nml with (nml RCof, RIPA) but ↓vWF binding to FVIII (low FVIII levels look like Hemophilia A but in women too)
  61. Give the multimeric analysis result for the following vWD types:
    1) Type I
    2) IIa
    3) IIb
    4) III
    • 1) I: Normal distrib but ↓ amounts
    • 2) IIa: ↓medium & large HMW multimers (low vWF:RCoF (quality) relative to vWFAg (quantity)
    • 3) IIb: ↓large HMW multimers with ↑affinity for GPIb
    • 4) III: None
  62. What is plt-type vWD?
    Looks like IIb with abnml ↑plt binding to GPIb but due to plt abnormality (GPIb) rather than vWF defect
  63. What is type Vicenza vWD?
    ↑clearance of vWF from blood →↓ vWF in plasma, normal vWF in plts, and large multimers
  64. What vWD type is treated with DDAVP? What is the tx in the other vWD types?
    Type I; vWF admin
  65. What do RCof and RIPA tests show in Type IIb or plt-type vWD?
    RCof ↓ b/c overall ↓HMW multimers but RIPA ↑ b/c hyperaggregation
  66. What are expected coag parameters for the following vWD types:
    A) Type I
    B) Type IIa
    C) Type IIb
    D) Type III
    • I:  Normal PT, normal plt count, prolonged PTT, prolonged bleeding time
    • IIa:  PT normal, TT normal, PTT slightly prolonged
    • IIb:  Low plt count           
    • III:  Low FVIII, low vWF antigen
  67. How can vWD IIb be distinguished from plt-type vWD?
    • 1) Use pt plasma + nml plts + cryoppt + ristocetin - they aggregate with plt-type but not IIb (b/c all abnml vWF binds up all nml plts?)
    • 2) ↑ristocetin dose required in plt-type but not IIb
  68. How does Hemophilia B differ from A?
    • 1) Hem B is more rare (1:25,000 vs. 1:5,000 births)
    • 2) Factor replacement therapy for B has only 30% dose recovery (t1/2 = 8hrs) while A has 100% dose recovery w/IV admin (t1/2 = 12 hrs)
    • 3) Factor inhibitors more common in Hem A
  69. How are female carriers of Hem A ID'd?
    Ratio of F8:vWF = 1:2 (nml is 1:1)
  70. What is the unit of measurement for factor inhibitors?
    • 1 Bethesda = 50% activity
    • 2 Bethesda = 25% activity
  71. What is the tx for Hem B?
    • Give F9 concentrate, whole blood or FFP
    • *NO cryoppt (lacks F9)
  72. A patient complains of frequent miscarriages, says her wounds heal slowly and she gets these weird hypertrophic scars. Labs show normal PT, PTT, TT. A clot stability test shows clot dissolving in <24hrs w/5M urea and a positive 1% monochloroacetic acid test. What is her likely factor def and what is the mutation?
    Factor XIII def, most commonly chrom 6p (catalytic A subunits) but also chrom 1q (non-catalytic b subunits) - can't crosslink fibrin
  73. What FXIII polymorphism plays a role in DVT prevention?
    50% have Val34Leu
  74. What is the mechanism of bleeding in FXI def? Mode of inheritance?
    Can't activate TAFI so no inhibition of plasmin or tPA binding to fibrin; AR in Ashkenazi
  75. What are the clinical sxs of FXII def? What does mixing study show?
    ↑PTT, ↓contact factor(s) (FXII, prekallikrein and ↓HMWK (intrinsic pathway so causes ↑aPTT w/out clinical bleeding), thrombosis but no bleeding; prolonged
  76. What is the chromosome involved in factor V deficiency? What do labs show? What combined deficiency involving FV is more common than FV deficiency alone?
    Chrom 1q21-25; PT & PTT prolonged but TT normal; combined FV and FVIII def
  77. What is the cluster of genes for fibrinogen and what chromosome are they located on? What is the structure of fibrinogen and polypeptide chain is most often mutated in disease?
    Fibrinogen α, β,γ on chrom 4q; Dimer with each composed of Aα, Bβ, and γ; Aα
  78. What is the mode of inheritance for afibrinogenemia, hypofibrinogenemia and inherited dysfibrinogenemia?
    • Afib and hypofib - AR (protein truncations)
    • Inherited dysfib - AD (missense muts)
  79. How does congenital afibrinogenemia present?  At what fibrinogen level does bleeding occur? What is the first manifestation of the inherited dz?
    ↑PT, ↑PTT, mixing study that corrects and bleeding d/o; <50mg/dL; umbilical cord hemorrhage followed by lifelong bleeding diathesis
  80. How does dysfibrinogenemia present clinically? What do labs show?
    Can be asx (50-60%) or cause bleeding (30-40%) or thrombosis (10-20%); ↑reptilase time and ↑TT, plt aggregation shows ↓ ADP, Epi, and AA (GPIIb/IIIa binds fibrinogen)
  81. All of the following are possible causes of acquired Factor XIII deficiency except:
    A) Liver disease
    B) Warfarin treatment
    C) DIC
    D) Inflammatory conditions
    E) Drugs (phenytoin, isoniazid, valproate)
  82. What chrom is assoc w/FX deficiency? What are typical lab findings? What is not a good tx for amyloid-acquired FX deficiency? What are FX activators?
    Chrom 13q; ↑PT and PTT, nml TT and bleeding time; should NOT use factor X transfusions b/c doesn't effectively raise levels; VIIa, VIIIa-IXa complex, Russell Viper Venom
  83. What is the role of Vitamin K in coagulation? What is a potential cause of skin necrosis with warfarin tx?
    γ carboxylation of Gla domains of Factors X, IX, VII, II, protein C, protein S; Congenitally def protein C (t1/2 6-8hrs)
  84. Name 3 causes of acquired hypofibrinogenemia.
    • 1) Liver failure
    • 2) DIC
    • 3) L-asparaginase therapy
  85. All of the following cause arterial thrombosis except:
    A) Prothrombin mutation 20210
    B) HIT
    C) High PAI-1 activity or tPA deficiency
    D) ATIII deficiency
    E) Vasculitis
  86. All of the following cause venous thrombosis except:
    A) Vasculitis
    B) Protein C or S def
    C) APC + prothrombin 20210 mutation
    D) Heparin cofactor II
    E) Trauma
  87. Which two diseases cause arterial and venous thrombosis?
    Hyperhomocysteinemia & anti-phospholipid Ab syndrome (ACA type)
  88. What are lab findings in α2-antiplasmin def?
    • Nl PT, PTT but euglobulin lysis <2hrs to dissolve clot
    • Low fibrinogen, ↑tPA, and have DIC
  89. Name 2 causes of pseudo ↓plts?
    • 1) Plt clumping in EDTA tube containing Abs against GPIIb/IIIa - redraw with Na Citrate corrects
    • 2) Satellitism - plts adhere to leuks in EDTA
  90. All of the following can cause acquired plt disorders except:
    A) Acetaminophen
    B) Uremia
    C) Cardiopulm bypass
    D) Paraproteinemia
    E) MPD
    • A - ASA and NSAIDs cause plt defects, not acetaminophen
    • *Cardiopulm bypass causes depletion of granules, paraproteinemia causes Ig coating of plts
  91. All of the following are direct thrombin inhibitors except:
    A) r-Hirudin (lepirudin or desirudin)
    B) Bivalirudin
    C) Fondaparinux
    D) Argatroban
    E) Melgatroban
  92. How is unfractionated heparin monitored?  LMWH?
    aPTT; anti-Xa activity
  93. How does heparin and LMWH work?
    Heparin binds to ATIII/IIa/Xa complex, brings the them together to inactivate IIa & Xa; LMWH binds only to ATIII to bring the factors together for inactivation
  94. What is the mechanism of action for these drugs:
    1) Clopidogrel (Plavix) and Ticlopidine (Ticlid)
    2) Abciximab (ReoPro)
    3) Fondaparinux
    4) Argatroban
    5) Amicar (ε aminocaproic acid)
    • 1) ADP inhibition
    • 2) GPIIb/IIIa inhibitor (fibrinogen and vWF receptor on plts)
    • 3) Factor Xa inhibitor via ATIII
    • 4) Direct thrombin inhibitor
    • 5) Lysine derivative that treats post-op bleeding by inhibiting factors w/ lysine-binding cmpts like plasmin (fibrinolysis enzyme)
  95. All of the following are advantages regarding factor Xa inhibitors such as fondaparinux except:
    A) No antidote
    B) Rapid onset reduces bridging with parenteral anticoagulant
    C) Don't require frequent monitoring
    D) Don't require frequent re-dosing
    E) No food interactions
  96. How do factor Xa inhibitors work?
    Inactivates factor Xa by binding to AT to inactivate it - so it can't bind with thrombin to form a clot
  97. What is the mechanism of action of drugs like Dabigatran, Rivaroxaban, Otamixaban, etc.?
    Direct thrombin inhibitors (Factor IIa inhibitors) without having to use ATIII
  98. All of the following can be seen in DIC except:
    A) High PT, PTT, TT
    B) Low plts, fibrinogen
    C) High plasminogen and ATIII
    D) High D-dimers and FDPs
    E) Low protein C, protein S, α2 anti-thrombin
    C - both are LOW
  99. What are the most sensitive tests for DIC?
    1) D-dimers and PT1+2 (prothrombin fragments) (95% sensitive) and 2) AT and fibrinopeptide A (85% sensitive)
  100. How does TTP differ from HUS?
    • 1) Cause TTP is ADAMTS-13 def, HUS is infection from Shigella or E. coli O157LH7, and rarely d/t factor H deficiency in complement pathway
    • 2) Tx TTP is FFP (replace ADAMTS-13) and plasmapharesis while HUS tx is supportive and antibx
  101. All of the following are risk factors for HIT except:
    A) Male gender
    B) unfractionated heparin
    C) Surgery
    D) Extended heparin use
    E) LMW heparin
    • A - females have 2x greater risk
    • *LMW heparin still has risk of HIT!
  102. What is the gold std test for type II HIT? What other tests are more widely available?
    Serotonin release assay - high dose heparin breaks up immune complexes → no serotonin release from plt granules; 1) HIT aggregation assay - plt aggregation with heparin as agonist → enhanced aggregation is abnormal (95% specific); 2) anti-PF4 Ab by ELISA (90% sensitive and 95% specific)
  103. Answer the following questions regarding Types I and II of HIT: Time of onset? Plt level? What types of thromboses occur? Tx?
    • I: up to first day, <100k, no thromboses, no tx
    • II: 5-10d, <50k, arterial thromboses, discontinue heparin or Coumadin, no plts, don't give LMWH b/c it can still cross-rx with anti-PF4 Abs, thrombin inhibitors
  104. What are the antibodies causing HIT type II?
    Anti-PF4 (remember: produced in α granules!)
  105. What are non-coag related lab findings in TTP and HUS?
    Same as DIC but fibrinogen nml
  106. What is the mutation in Factor V Leiden? What is the mode of inheritance? How is it dx?
    Chrom 1q mutation - Arginine to Glutamine point mutation on nucleotide 1691 at position 506 (FV R506Q) → Factor V resistance to cleavage by APC → thrombosis; AD; 1) ↓PTT ratio of APC:no APC (nml >2), 2) RFLP
  107. What thrombophilic mutation is also present in up to 10% of pts with Factor V Leiden? Mode inheritance? Mutation? Lab findings/dx?
    Prothrombin variant G20210A (guanine to adenine); point mutation at 3' untranslated region → enhanced prothrombin gene transcription and translation; Elevated prothrombin + PCR detection of mutation
  108. Mutation in Factor V Cambridge?
    • Arginine to threonine at position 306
    • (FV R306T)
  109. What is the incidence of prot C and S def? Mode inheritance? How do homozygous newborns present clinically? Tx?
    1:200; both AD; purpura fulminas (DIC form); Coumadin + LMW heparin to start (or else they get skin necrosis from venous thrombosis!)
  110. What are Protein C deficiency types I & II?
    • I - qualitative and quantitatively low (MC)
    • II - nml Ag level, ↓activity
  111. What are Protein S deficiency types I-III?
    • I - quantitative defect (MC)
    • II - qualitative defect
    • III - ↓free Prot S (nml total Prot S)
  112. What syndrome causes increased Prot S and C but no increase in ATIII? What viral infection causes reduced Prot S?
    Nephrotic syndrome; HIV
  113. What is Prot S bound to in circulation?
    60% bound C4d so decreased during stress when C4d levels ↑; 40% bound Prot C (fxnal protein)
  114. What is the action of antithrombin? How does ATIII def present clinically? What level of AT activity is deficient and indicative of def?
    Inhibits F2a, F9a-12a; recurrent venous thrombosis or heparin tx unresponsiveness; <60% (heparin tx never <70% AT activity)
  115. All of the following can cause acquired antithrombin deficiency except:
    A) Nephrotic syndrome
    B) malignancy
    C) Pregnancy or estrogen tx
    D) Colitis
    E) DIC or acute thrombosis
    F) L-asparaginase tx
  116. What is this hyperhomocysteinemia thrombotic dz I've never heard of??? What is the mutation? Is this the same as homocystinuria?
    ↑homocysteine → ↑risk atherosclerosis and recurrent arteriovenous thromboemboli; 1) MTHFR/methyl tetrahydrofolate reductase mutation (Ala677Val/C677T) mutation → MTHFR protein thermolability & loss of activity → T allele for MTHFR gene at chrom 1p36.3 or 2) heterozygous cystathionine β synthase deficiency; homocystinuria is the manifestation of homozygous state of these two mutations with severe clinical sxs
  117. What are the 3 Abs in antiphospholipid Ab (APL) syndrome?
    • 1) Lupus anticoagulant
    • 2) anti-cardiolipin
    • 3) β2 glycoprotein
  118. How does APL syndrome present? What are the lab findings?
    APL: thrombotic event with ↓plts or ↑PTT but without bleeding; 1) ↑aPTT, 2) 1:1 mix doesn't correct but corrects with DRVVT (venom + FV + phospholipid + Ca activates FX) or partially corrects w/phospholipid, 3) plt neutralization procedure (PTT corrects w/hexagonal phase phosphatidyl ethanolamine), 4) kaolin clotting time, 5) VDL/RPR (false + in lupus anticoagulant)
  119. How is APL syndrome Abs detected?
    ELISA anti-cardiolipin and immunoassay for β2 glycoprotein I
  120. How are the clinical sxs of anticardiolipin and lupus anticoagulant syndromes of APL similar? Different?
    • Both: ↓plts, fetal wastage syndrome, associated with other dzs (SLE, HIV, malignancy, connective tissue dz), more common primary dz rather than secondary to SLE
    • ACA: ateriovenous thrombosis, premature coronary artery atherosclerosis, livedo reticularis, transient postpartum issues (fever, pleuritic chest pain, leural effusions), >60% fail Coumadin
    • LAC: mainly venous thromboses, Coumadin effective
  121. What % patients with APL syndrome have lupus?
    15-30% in both ACA and LAC types
  122. What are the antigenic targets of ITP? How is it dx? Tx?
    GPIIb, IIIa, Ib, or V; dx of exclusion; steroids or IVIG or splenectomy if other tx fails, and if splenectomy fails, anti-CD20 tx
  123. How can dysfibrinogenemia be distinguished from hypofibrinogenemia with a mixing study? What might a female patient experience with dysfibrinogenemia?
    Dysfib only partially corrects like an inhibitor while hypofib corrects completely; recurrent miscarriages
  124. What is DDAVP? What does it treat?
    synthetic vasopressin, hormone that stimulates release of VWF from endothelial cells by  acting on V2 receptors; diabetes insipidus, vWD (type I), mild Hemophilia A, bedwetting, thrombocytopenia
  125. Which inherited thrombocytopenias have small plts? Large plts?
    • Small plts: Wiscott-Aldrich, Congenital amegakaryocytic thrombocytopenia (CAMT), Thrombocytopenia with absent radii (TAR)
    • Large plts: May Hegglin, Bernard-Soulier, Grey plt syndrome
  126. In a patient with HIT and vitamin K depletion from coumadin tx, what should be done?
    Hold Coumadin, switch to direct thrombin inhibitor like argatroban
  127. What is the normal range for protein S in 1st, 2nd, and 3rd trimester of pregnancy?
    • 1st: 50-100%
    • 2nd: 25-75%
    • 3rd: 20-50%
  128. What is the euglobulin clot lysis time test? What causes decreased time? Increased time?
    Test of fibrinolytic activity in plasma; α2-antiplasmin def, factor XIII deficiency, tPA, streptokinase, etc.; DIC, liver dz, obesity, etc.
  129. T/F: HMWK deficiency leads to symptomatic bleeding.
  130. Which warfarin enantiomer (S or R) is metabolized by CYP2C9?
    S (4x more potent than R)