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AP/CP Boards > Heme/Coag > Flashcards

Heme/Coag Flashcards

1
Q

Platelet granules

  • Alpha
  • Delta (dense)
A

Platelet granules

  • Alpha granule
    • thromboglobulin
    • P-selectin
    • PDGF
    • PF4
    • platelet fibrinogen
    • thrombospondin
    • VWF
  • Delta (dense) granule [Delta’s CASA]
    • Ca++
    • ATP
    • Serotonin
    • ADP dense granule -> vasoconstriction
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2
Q

Fibrinolysis

  • TPA cleaves __ to __
  • Plasmin cleaves __into __

Three inhibitors:

  1. _
  2. _
  3. _
A

Fibrinolysis

  • TPA cleaves plasminogen to plasmin
  • Plasmin cleaves fibrin into fibrin split products

Three inhibitors

  1. Alpha two antiplasmin inhibits plasmin
  2. PAI inhibits plasminogen
  3. TAFI (thrombin activatable fibrinolysis inhibitor) inhibits binding of plasminogen and TPA to fibrin
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3
Q

Anticoagulation

  • Thrombomodulin
  • Activated protein C + protein S (its carrier)
  • AT
A

Anticoagulation

  • Thrombomodulin
    • binds to thrombin to activate protein C
  • Activated protein C + protein S (its carrier)
    • inhibit FV and FVIII
  • AT
    • binds to heparin and inhibits conversion of II to IIa
    • also inhibits Xa action
    • Liver-produced
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4
Q

Platelets cell-surface antigens

  • The GP (glycoprotein) Ib/V/IX complex:
    • receptor for __
    • CD__
  • The GP IIb/IIIa complex:
    • receptor for __
    • platelet antigen __ a/w GP IIIa
      • __ alleles, __
    • Platelet antigens __ a/w GP IIb
    • CD41 = __
    • CD61 = __
  • GP Ia/IIa complex:
    • __receptor __
  • GP Ic/IIa complex:
    • __receptor
  • Red cell antigens:
    • __
  • Class __ MHC antigens
  • Passively adsorbed __
A

Platelets cell-surface antigens

  • The GP (glycoprotein) Ib/V/IX complex:
    • receptor for vWF
    • CD42
  • The GP IIb/IIIa complex:
    • receptor for fibrinogen
    • platelet antigen PLA a/w GP IIIa
      • 2 alleles, PLA1 and PLA2
    • Platelet antigens baka and bakb a/w GP IIb
    • CD41 = GP IIb/IIIa
    • CD61 = GP IIIa
  • GP Ia/IIa complex:
    • collagen receptor Bra/Brb
  • GP Ic/IIa complex:
    • fibronectin receptor
  • Red cell antigens:
    • ABO, I, i, P, Le (no Rh antigens)
  • Class I MHC antigens
  • Passively adsorbed IgG and coagulation factors
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5
Q

Extrensic Pathway

Intrinsic Pathway

The Common Pathway

A

Extrensic Pathway

  • FVII
  • tissue injury leads to the release of tissue factor (III)
  • FVIIa cleaves factor X to factor Xa
  • Xa is capable of activating VII to VIIa
  • VIIa capable of activating IX to IXa, so in vivo activation of VII can propel the intrinsic pathway
    • major mechanism by which the administration of FVIIa exerts its therapeutic effect

Intrinsic Pathway

  • FXII, FXI, FIX, FVIII, prekallikrein, and HMWK (plus calcium and phospholipids)
  • endpoint is conversion of factor X to factor Xa
  • initiated by the proximity of prekallikrein, HMWK, FXII and FXI to one another and to a negatively charged surface (contact phase)
    • early evolutionion (ocean/sand)
  • results in conversion of prekallikrein to kallikrein, which activates FXII to FXIIa
  • XIIa activates more prekallikrein to kallikrein, establishing a cycle
  • activation of FX carried out by the tenase complex (Calcium, FVIIIa, FIXa) on plt surface
  • Platelets
    • when activated, express an abundance of phosphatidylserine (PS) and phosphatidylinositol (PI) on surface
    • facilitate attachment of the tenase complex
  • Xa is capable of activating VII to VIIa, thus providing a link with the intrinsic pathway

The Common Pathway

  • FX, FII, and fibrinogen
  • Xa converts FII (prothrombin) to FIIa (thrombin)
  • thrombin converts fibrinogen (I) to fibrin (Ia)
  • prothrombinase complex forms on the surfaces of platelets
    • anchored by PS and PI
    • consists of Va and Xa
  • Fibrinogen is composed of pairs of three polypeptides:
    • A-α, B-β, γ
    • A and B are referred to as fibrinopeptides (FpA and FpB)
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6
Q

Control of Coagulation

  • Thrombin concentration controlled by:
    • __degradation
    • __
  • Thrombin activation controlled by:
    • __
      • inactivates thrombin and __
      • can be stimulated by __
    • __
    • __
    • __
    • thrombin combines with __ on endothelial cell surfaces forming __ complex that converts __ to __
      • __ inactivates__, with __as its cofactor
  • Plasmin
    • primary agent of __degradation
    • formed from __which is structurally incorporated into the fibrin clot
  • Tissue plasminogen activator (tPA)
    • converts __to __
    • released from __ following injury
    • exposure to __activates tPA
  • Plasmin is controlled by:
A

Control of Coagulation

  • Thrombin concentration controlled by:
    • fibrin degradation
    • tissue factor pathway inhibitor (TFPI)
      • inhibition of the tissue factor-FVIIa-FXa complex
  • Thrombin activation controlled by:
    • Antithrombin
      • inactivates thrombin and FIXa, FXa, FXIa and FXIIa
      • can be stimulated by heparin (basis for therapy)
    • α2-macroglobulin
    • heparin cofactor II
    • α1-antitrypsin
    • thrombin combines with thrombomodulin on endothelial cell surfaces forming thrombin-TM complex that converts protein C to activated protein C (APC)
      • APC inactivates FVa and FVIIIa, with protein S as its cofactor
  • Plasmin
    • primary agent of fibrin degradation
    • formed from plasminogen which is structurally incorporated into the fibrin clot
  • Tissue plasminogen activator (tPA)
    • converts plasminogen to plasmin
    • released from vascular endothelial cells following injury
      • mechanisms for fibrin degradation and formation set into motion simultaneously
    • exposure to fibrin activates tPA
  • Plasmin is controlled by:
    • rapid degradation by α2-antiplasmin
    • inhibition by plasminogen activator inhibitors (PAI-1 and PAI-2)
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7
Q

PLATELET AGGREGATION STUDIES

  • Optical density (%)
    • w/ aggregation __
    • __and __are weak agonists and biphasic
A

PLATELET AGGREGATION STUDIES

  • Optical density (%)
    • w/ aggregation, less light scattering, lower optical density
    • ADP and epinephrine are weak agonists and biphasic
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8
Q

Platelet aggregometry

  • Pre-analytical
    • no aspirin or NSAIDs for __ days
    • tubes kept at __ temp (__causes platelet activation)
    • test performed within __ hours
  • sample of__ (prepared by?)
  • sample stirred continuously within a cuvette while being exposed to various agonists
  • light transmission through the sample __as aggregation takes place
    • optical density __
  • Is there spontaneous aggregation?
  • adult __% platelet aggregation (__in newborns) in response to platelet agonists:
    • __
  • biphasic curve (primary and secondary wave of aggregation)
    • __
  • monophasic curve (primary aggregation only)
    • __
  • ___
    • response with concentration >1.2 mg/mL
    • little to no response <0.8 mg/mL
  • __
    • response follows a short lag
  • Monitor release of platelet dense granules (secondary wave) during aggregation
    • assay __ using __ assay
A

Platelet aggregometry

  • Pre-analytical
    • no aspirin or NSAIDs for >7 days
    • tubes kept at room temp (cold causes platelet activation)
    • test performed within 2 hours
  • sample of platelet-rich plasma (slow-centrifugation of whole blood)
  • sample stirred continuously within a cuvette while being exposed to various agonists
  • light transmission through the sample increases as aggregation takes place
    • optical density decreases
  • no spontaneous aggregation
  • adult >60% platelet aggregation (less in newborns) in response to platelet agonists:
    • (AACRE)
    • ADP, Arachidonate, Collagen, Ristocetin, Epinephrine
  • biphasic curve (primary and secondary wave of aggregation)
    • low-dose ADP and epinephrine
  • monophasic curve (primary aggregation only)
    • high-dose ADP, collagen, ristocetin
  • ristocetin
    • response with concentration >1.2 mg/mL
    • little to no response <0.8 mg/mL
  • collagen
    • response follows a short lag
  • Monitor release of platelet dense granules (secondary wave) during aggregation
    • assay secreted ATP using firefly luminescence assay
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9
Q

Abnormal aggregometry

  • most common cause of abnormal aggregometry is __
  • decreased aggregation with arachidonate
  • no secondary phase with epinephrine and ADP
  • poor response to epinephrine
  • response to everything but risotocetin
  • poor response to all agents except ristocetin
A

Abnormal aggregometry

  • most common cause of abnormal aggregometry is a medication
  • decreased aggregation with arachidonate
    • aspirin/aspirin-like agents
  • no secondary phase with epinephrine and ADP
    • storage pool defects and aspirin
  • poor response to epinephrine
    • myeloproliferative diseases
  • response to everything but risotocetin
    • von Willebrand disease and Bernard-Soullier syndrome
  • poor response to all agents except ristocetin
    • Glanzmann thombasthenia
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10
Q
A

Response to everything but risotocetin

  • von Willebrand disease and Bernard-Soullier syndrome
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11
Q
A

Poor response to all agents except ristocetin

  • Glanzmann thombasthenia
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12
Q

Congenital Platelet Disorders

A

Congenital Platelet Disorders

  • Bernard-Soulier Disorder
  • Glanzmann thrombasthenia
  • May Hegglin
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13
Q

___

  • What type of problem?
  • Defect __ (CD__)
  • Can’t bind __
  • Thrombocytopenia?
  • __PT, PTT, ___bleeding time
  • Impaired __ aggregation
  • Platelet flow cytometry shows ↓ __
A

Bernard-Soulier

  • Adhesion problem
  • Defect GPIb/V/IX (CD42)
  • Can’t bind vWF
  • Large giant platelet w pseudonucleolus
  • Thrombocytopenia
  • Normal PT, PTT, increased bleeding time
  • Impaired ristocetin aggregation
  • If you add normal ptls + ristocetin, aggregation will be nl b/c the abnormality is on the patients plt.
  • Platelet flow cytometry shows ↓ CD42a, b and d (GPIba, V and IX)
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14
Q

___

  • __problem
  • Plts can’t bind __
  • Abnormal __
  • Thrombocytopenia?
  • Plt aggregation studies?
  • Dx: Flow cytometry shows ↓ __
  • Differential diagnosis
    • _& _
      • both defect in__ interactions
    • __normal PT/PTT
    • __↑PT/PTT
A

Glanzmann thrombasthenia

  • Aggregation problem
  • Plts can’t bind fibrinogen
  • Abnormal GP IIb-IIIa
  • Normal plt count
  • Poor response to all agents except ristocetin
  • Dx: Flow cytometry shows ↓ CD41 (GPIIb) and CD61 (GPIIIa)
  • Differential diagnosis
    • Glanzmanns & Afibrinogenima
      • both defect in fibrin:fibrin interactions
    • Glanzmann’s normal PT/PTT
    • Afibrinogenemia ↑PT/PTT
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15
Q

May Hegglin Anomaly

  • Mutation
  • Inheritance
  • Thrombocytopenia?
  • PMN function?
A

May Hegglin Anomaly

  • Mutation in myosin heavy chain 9 gene
  • Autosomal dominant
  • WBC inclusion (Dohle-like) + Giant plt
  • Thrombocytopenia, but little bleeding
  • PMN function is normal
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16
Q

Giant Platelets

A

Giant Platelets

Lying about how big your plts are: FIB GAMMMES

  • Fechner syndrome
  • ITP
  • Bernard Soulier
  • Gray platelet syndrome
  • Alport syndrome
  • May Hegglin
  • Montreal plt syndrome
  • Mediterranean macrothromocytosis
  • Epstein syndrome
  • Sebastian syndrome
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17
Q

Storage Pool Deficiency

  • Decreased plt __due to deficiencies in __
  • __morphology, __ on EM
  • Plt agg studies:
    • __
    • __ collagen & AA
    • __ristocetin
    • __ATP:ADP ratio
  • 5 Examples of Storage Pool Deficiency
A

Storage Pool Deficiency

  • Decreased plt aggregation due to deficiencies in dense/alpha granules
  • Normal morphology, no granules on EM
  • Plt agg studies:
    • No 2nd wave ADP, EPI
    • Decreased collagen & AA
    • Normal ristocetin
    • ↑ ATP:ADP ratio
  • 5 Examples of Storage Pool Deficiency (Quebec is Gray, Cold & Wet, never Hot)
    • Quebec plt disorder
    • Gray platelet syndrome
    • Chediak Higashi
    • Wiscott Aldrich syndrome
    • Hermansky-Pudlak Syndrome
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18
Q

Storage Pool Deficiency

A

Storage Pool Deficiencies

5 Examples of Storage Pool Deficiency (Quebec is Gray, Cold & Wet, never Hot)

  • Quebec plt disorder
    • No α granules
  • Gray platelet syndrome
    • No α granules
    • Large gray plts, no granules
    • From cardio pulmonary bypass
    • Plt agg blunted with all agents except ADP/EPI
  • Chediak Higashi
    • No δ granules EM
  • Wiscott Aldrich syndrome
    • x-linked
    • No δ granules EM
    • Small granulated plts, like FeDa
    • Thrombocytopenia, infection, eczema
    • Increased malignancy
  • Hermansky-Pudlak Syndrome
    • No δ granules EM
    • pigment reticuloendothelial cell
    • Swiss cheese platelets
    • ↑AK, nevi, tumors, pulmonary fibrosis
    • Puerto Rican/Swiss, ↑vWF
    • Thrombocytopenia w absent radii
19
Q

Aspirin/NSAIDS

  • Decrease platelet function by:
    • acetylation of platelet __ -> decreased __formation
  • Platelet aggregation studies
A

Aspirin/NSAIDS

  • Decrease platelet function by:
    • acetylation of platelet cyclooxygenase -> decreased thromboxane formation
  • Platelet aggregation studies
    • No 2nd wave ADP and epi
    • Absent response to collagen and arachidonic acid
20
Q

Other platelet type bleeding disorders

  • Hereditary Telangectasia
  • Ehlers Danlos, Type 4
  • Henoch-schonlein
  • Arteriovenous malformation
  • Scurvy
  • Marfans, osteogenesis imperfecta, fabry syndrome
  • Amyloidosis
A

Other plt type bleeding disorders

  • Hereditary Telangiectasia
    • Osler-Weber-Rendu
    • Oral Telangiectasia FeDA
  • Ehlers Danlos, Type 4
    • Connect tissue disorder plts cant stick, bruising and prupura, loose skin
  • Henoch-schonlein
    • Vasculitis, prupura, thrombocytopenia
  • Arteriovenous malformation
    • ↓plts
  • Scurvy
    • decreased Vit C, bad teeth, perifollicular petechiae
  • Marfans, osteogenesis imperfecta, fabry syndrome
  • Amyloidosis
    • decreased factor X
    • platelets don’t stick, endothelium coated, lambda light chains
21
Q

Von Willebrand factor and disease

  • vWF binds to:
    • __
    • __
  • Large multimers cleaved by __
    • deficiency of __ a/w __
  • Made in __(α granules) and endothelial cells (__)
  • vWD most common__
  • ↓vWF-blood type__
  • Quant/qual deficiencies?
  • Secondary vWF deficiency?
A

Von Willebrand factor and disease

  • vWF binds to:
    • F8 and stabilizes it
    • subendothelial collagen and GPIba
  • Large multimers cleaved by ADAMTS-13
    • deficiency of ADAMTS-13 a/w TTP
  • Made in megakaryocytes (α granules) and endothelial cells (Weibel-Palade bodies)
  • vWD most common genetic Plt type bleeding disorder
  • ↓vWF-blood type O, old blood sit
  • Quant or qual deficiencies
  • Secondary vWF deficiency
    • Wilms tumor
    • congenital heart disease
    • hypothyroid
22
Q

VWD diagnostic tests

  1. Platelet count
    • __
  2. FVIIICo
    • __
  3. vWF Ag
    • __
  4. vWF:Rcof
    • __
  5. RIPA (Ristocetin induced platelet aggregation)
    • _
  6. __
  7. __
  8. __
A

VWD diagnostic tests

  1. Platelet count
    • Plts ↓sometimes, screening test
  2. FVIIICo
    • measure F8 activity
  3. vWF Ag
    • measures vWF quantity
    • blood add F8 -> measure vWF
  4. vWF:Rcof
    • measures vWF activity
    • Pt plasma + nl plts + ristocetin, then measure time to aggregation
    • very specific & most sensitive test
    • Quantitate pt vWF activity (%) using ristocetin, standard curve with quantitative endpoint
  5. RIPA (Ristocetin induced platelet aggregation)
    • pts plasma + pt plts + low dose ristocetin = time to aggregation
    • all or none, does pt aggregate with ristocetin
  6. Platelet agg studies
  7. VWF multimers
  8. Mixing study
23
Q

vWD Type I

  • multimers?
  • frequency?
  • tests?
  • treated w DDAVP?

vWD type 2a and 2b

  • Type 2a
    • multimers?
    • tests?
    • treated w DDAVP?
  • Type 2b
    • multimers?
    • tests?
    • treated w DDAVP?
    • mutation?

Type 3

  • inheritance?
  • multimers?
  • tests?
  • treated w DDAVP?

vWF 2M and 2N

  • Type 2M
    • multimers?
    • tests?
    • treated w DDAVP?
  • Type 2N (Normandy)
    • genetics?
    • multimers?
    • tests?
    • treated w DDAVP?
  • Frequency
A

vWD Type I

  • Low quantity, normal multimers, functionally normal
  • Most common type
  • Sometimes all tests are normal
  • Only type treated w DDAVP

vWD type 2a and 2b

  • Type 2a
    • Decreased large and medium sized multimers
    • Disproportionately low vWF:RCo (quality) relative to vWFAg (quantity)
  • Type 2b
    • Mutation in exon 28 of VWF that causes increased affinity of VWF for GP1bα
    • Decreased high molecular weight (HMW) multimers
    • Leads to increase clearance of vWF
    • Increased RIPA
    • No DDAVP
    • Test: mutations in exon 28 of VWF gene

Type 3

  • Autosomal recessive, most AD
  • Severe marked deficiency
  • Absence of vWF, F8 also low
  • But may have nl coag parameters
  • vW multimer test, all multimers low
  • No DDAVP

vWF 2M and 2N

  • Type 2M
    • Defect in GP 1b binding, but no loss of HMW multimers
    • vWF made but doesn’t work
    • Decreased vWFRco
    • +/- normal RIPA, vWF Ag, F8
    • Suspect when vwf:RCo < vWF ag
  • Type 2N (Normandy)
    • Defective binding of vWF to F8
    • Hemophilia-like (but AR), women w low F8, think of this dz
    • Tests: decreased FVIII, decreased vWFAg:C levels
    • Normal RIPA, multimers, ristocetin
    • Normal sequence analysis of F8 gene to rule out hemophilia
  • Frequency
    • 2A>2N>2M>2B
25
Q

vWD Type I

  • multimers?
  • frequency?
  • tests?
  • treated w DDAVP?
A

vWD Type I

  • Low quantity, normal multimers, functionally normal
  • Most common type
  • Sometimes all tests are normal
  • Only type treated w DDAVP
26
Q

vWD type 2a and 2b

  • Type 2a
    • multimers?
    • tests?
    • treated w DDAVP?
  • Type 2b
    • multimers?
    • tests?
    • treated w DDAVP?
    • mutation?
A

vWD type 2a and 2b

  • Type 2a
    • Decreased large and medium sized multimers
    • Disproportionately low vWF:RCo (quality) relative to vWFAg (quantity)
  • Type 2b
    • Mutation in exon 28 of VWF that causes increased affinity of VWF for GP1bα
    • Decreased high molecular weight (HMW) multimers
    • Leads to increase clearance of vWF
    • Increased RIPA
    • No DDAVP
    • Test: mutations in exon 28 of VWF gene
27
Q

Type 3

  • inheritance?
  • multimers?
  • tests?
  • treated w DDAVP?
A

vWD Type 3

  • Autosomal recessive, most AD
  • Severe marked deficiency
  • Absence of vWF, F8 also low
  • But may have nl coag parameters
  • vW multimer test, all multimers low
  • No DDAVP
28
Q

vWF 2M and 2N

  • Type 2M
    • multimers?
    • tests?
    • treated w DDAVP?
  • Type 2N (Normandy)
    • genetics?
    • multimers?
    • tests?
    • treated w DDAVP?
  • Frequency
A

vWF 2M and 2N

  • Type 2M
    • Defect in GP 1b binding, but no loss of HMW multimers
    • vWF made but doesn’t work
    • Decreased vWFRco
    • +/- normal RIPA, vWF Ag, F8
    • Suspect when vwf:RCo
  • Type 2N (Normandy)
    • Defective binding of vWF to F8
    • Hemophilia-like (but AR), women w low F8, think of this dz
    • Tests: decreased FVIII, decreased vWFAg:C levels
    • Normal RIPA, multimers, ristocetin
    • Normal sequence analysis of F8 gene to rule out hemophilia
  • Frequency
    • 2A>2N>2M>2B
29
Q

Pseudo VWF—platelet type

  • Mutations in __ resulting in ↑ binding of __to __ multimers
  • The abnormality is on the patients __, not with __
  • VW multimer test shows __ vWF multimers
  • __RIPA studies
  • Platelet agg studies show __
  • Aggregation with __
  • Mutations in __gene, whereas __ has mutations in exon 28 of VWF gene
A

Pseudo VWF—platelet type

  • Mutations in GP1ba resulting in ↑ binding of GPIba to HMW VWF multimers
  • The abnormality is on the patients platelets (GP1b), not with vWF
  • Plts bind large VWF multimers
  • VW multimer test shows decreased large vWF multimers
  • Abn RIPA studies
  • Platelet agg studies show low dose ristocetin aggregation
  • Aggregation with cryoprecipitate
  • Mutations in GP1bα gene, whereas VWF 2B has mutations in exon 28 of VWF gene
30
Q

Factor deficiencies

  • Hemophilia A – decreased factor __
  • Hemophilia B – decreased factor __
  • Bleeding into __
  • __ PT/PTT
  • __ bleeding time
  • Symptoms rare if factor level > __%; severe disease if levels < __%
  • Chr __, 50% intron __inversion
A

Factor deficiencies

  • Hemophilia A – decreased factor VIII
  • Hemophilia B – decreased factor IX
  • Bleeding into joints
  • Increased PT/PTT
  • Often normal bleeding time
  • Symptoms rare if factor level > 15-20%; severe disease if levels < 1%
  • Chr (Xq28), 50% intron 22 inversion
31
Q

Thrombophilia

Inherited disorders of thrombosis

  • __
    • 6% Caucasians
  • __
    • 2% Caucasians
  • __
    • Less common
  • __ deficiency
  • __ deficiency
  • __

Acquired risk of thrombosis (4)

A

Thrombophilia

Inherited disorders of thrombosis

  • Resistance of activated protein C
    • 6% Caucasians
  • Prothrombin G20210A mutation
    • 2% Caucasians
  • Protein C deficiency
    • Less common
  • Protein S deficiency
  • Antithrombin III deficiency
  • Hyperhomocysteinemia

Acquired risk of thrombosis

  • Heparin Induced Thrombocytopenia
  • Oral contraceptives
  • Lupus anticoagulant
  • Estrogen replacement therapy
32
Q

Activated Protein C Resistance

  • Fequency?
  • Usually __ point mutation, which prevents inactivation by protein C, so __ production is unchecked, leading to thrombosis
  • __ gene Mutation:
    • Arg for gln at position 506 (__)
    • Arg for threonine at position 306 (__)
  • Mutation in __ and __

Dx

  • Functional assay:___
    • Screening test
    • If pt doesn’t have APCR and you add ProtC to their specimen, ↑ PTT __
    • If patient has APCR and you add ProtC to their specimen, ↑ PTT __
  • PCR for __
A

Activated Protein C Resistance

  • Most common cause of thrombophilia
  • Usually Factor V point mutation, which prevents inactivation by protein C, so prothrombin production is unchecked, leading to thrombosis
  • Factor V gene Mutation:
    • Arg for gln at position 506 (Factor V Leiden)
    • Arg for threonine at position 306 (Factor V Cambridge)
  • Mutation in factor II and methylene tetrahydrafolate reductase (MTHFR)

Dx

  • Functional assay: PTT:resistance ratio
    • Screening test
    • If pt doesn’t have APCR and you add ProtC to their specimen, ↑ PTT >2:1
    • If patient has APCR and you add ProtC to their specimen, ↑ PTT <2:1
  • PCR for Factor V Leiden mutations
33
Q

Protein C Deficiency

  • __heterozygous, homozygous __
  • Genetic cases have __risk of thrombosis
    • acquired __
  • __thromboembolism
  • Coumadin -> __
  • Laboratory diagnosis:
    • Patient must be off __
A

Protein C Deficiency

  • Usually heterozygous, homozygous die in infancy
  • Genetic cases have increased risk of thrombosis
    • acquired usually don’t
  • Venous thromboembolism
  • Coumadin -> skin necrosis
  • Laboratory diagnosis:
    • Patient must be off Coumadin
34
Q

Protein S Deficiency

  • Prot S is a __to Prot C
  • 40% is __
  • 60% Protein S binds to ___
    • __is an acute phase reactant
      • increased __-> decreased Protein S
      • Thus __ during stress (pregnancy)
  • Labs:
    • __ (worst test)
    • __ (best test)
  • Inheritance?
  • Oral contraceptives, estrogen therapy and pregnancy
    • decrease protein S, but not ___
A

Protein S Deficiency

  • Prot S is a cofactor to Prot C
  • 40% is free, functional protein S
  • 60% Protein S binds to C4b binding protein
    • C4b is an acute phase reactant
    • increased C4b -> decreased Protein S
    • Thus ↓ Prot S during stress (pregnancy)
  • Labs:
    • total protein S (worst test)
    • protein S activity (best test)
  • Autosomal dominant
  • Oral contraceptives, estrogen therapy and pregnancy
    • decrease protein S, but not protein C or antithrombin
35
Q

Antithrombin III deficiency

  • Antithrombin binds to __to inhibit factors __
  • In ATIII deficiency, patient presents w ↓response to __
  • Acquired- __
  • If a patient has thrombosis that you treat with __and the PT does not rise sufficiently, the patient may have ATIII deficiency
A

Antithrombin III deficiency

  • Antithrombin binds to heparin to inhibit factors II and X.
  • In ATIII deficiency, patient presents w ↓response to heparin
  • Acquired- liver, nephrotic dz, DIC
  • If a patient has thrombosis that you treat with heparin and the PT does not rise sufficiently, the patient may have ATIII deficiency
36
Q

Prothrombin G20210A Mutation

  • __mutation leads to __prothrombin levels
  • __is the location of the mutation in the gene
  • Guanidine to adenine substitution in the 3’ untranslated portion of prothrombin gene on Chr _
A

Prothrombin G20210A Mutation

  • Point mutation leads to high prothrombin levels
  • 20210 is the location of the mutation in the gene
  • Guanidine to adenine substitution in the 3’ untranslated portion of prothrombin gene on Chr 11
37
Q

Anti-phospholipid syndrome

  • Heterogeneous group of autoantibodies associated with prolongation of__ clotting assays and __thrombosis
  • antibodies against phospholipids
    • __
      • Most common
    • __
    • __
  • __platelets, __thrombosis
  • Originally described in patients with __, but most cases develop in patients without __
A

Anti-phospholipid syndrome

  • Heterogeneous group of autoantibodies associated with prolongation of phospholipid dependent clotting assays and ↑thrombosis
  • antibodies against phospholipids
    • Beta2-glycoprotein
      • Most common
    • Anticardiolipin antibodies
    • Lupus anticoagulant
  • ↓platelets, increased thrombosis
  • Originally described in patients with SLE, but most cases develop in patients without SLE
38
Q

Antiphospholipid antibody tests

  • PTT __
  • Dilute Russell viper venom test
    • Russell Viper venom + __ activates Factor __
    • Plasma containing lupus Abs __PTT
  • Mixing study
    • Shows evidence __activity
    • __ fails to correct w mixing study, but partial correction w adding __
  • Anticardiolipin antibody
    • __NO ↑PTT
    • must be + on __ occasions __weeks apart to exclude __
  • β2 Glycoprotein I antibodies
    • must be + on __ occasions __weeks apart to exclude __
  • Platelet neutralization procedure
    • PTT fails to correct w mixing study, but corrects when you add __
  • Rule out other coagulopathies
    • Specifically __
  • ___
    • Falsely positive
A

Antiphospholipid antibody tests

  • PTT prolonged
  • Dilute Russell viper venom test
    • Russell Viper venom + Factor V, phospholipid and calcium activates Factor X.
    • Plasma containing lupus Abs prolongs PTT
  • Mixing study
    • Shows evidence inhibitor activity
    • ↑PTT fails to correct w mixing study, but partial correction w adding phospholipid
  • Anticardiolipin antibody
    • ELISA NO ↑PTT
    • must be + on 2 occasions 12 weeks apart to exclude transient Abs from another illness
  • β2 Glycoprotein I antibodies
    • must be + on 2 occasions 12 weeks apart to exclude transient Abs from another illness
  • Platelet neutralization procedure
    • PTT fails to correct w mixing study, but corrects when you add hexagonal phase phosphatidyl ethanolamine
  • Rule out other coagulopathies
    • Specifically other inhibitors
  • Nontreponemal VDRL/RPR
    • Falsely positive
39
Q

Heparin induced thrombocytopenia and thrombosis (HITT)

  • __Ab to __ in __ granules
  • __% unfractionated heparin
    • Less in __
  • __ plts usually after__
  • Thrombosis
  • Treatment
    • __ heparin/ __warfarin
    • Give plts?
    • __, monitored by PTT
  • Diagnosis
    • Numerous assays; patient blood add __look for __
    • Serotonin release assay
      • Measure plt __
      • Pt given low dose __, radioactive labeled __released
      • Pt given high dose __, __ if patient has HITT
    • PF4 ELISA
      • __ test, measures __
      • rapid turnaround, but often false __
A

Heparin induced thrombocytopenia and thrombosis (HITT)

  • IgG Ab to heparin PF4 complex in α granules
  • ~8% unfractionated heparin
    • Less in LMW or porcine heparin
  • ↓ plts usually after 5-8 days
  • Thrombosis
  • Treatment
    • Stop heparin/ no warfarin
    • Platelets release granules so don’t give plts
    • Thrombin inhibitors, monitored by PTT
  • Diagnosis
    • Numerous assays; patient blood add heparin look for coagulation
    • Serotonin release assay
      • Measure plt granule release
      • Pt given low dose heparin, radioactive labeled serotonin released
      • Pt given high dose, no serotonin released if patient has HITT
    • PF4 ELISA
      • best test, measures Abs
      • rapid turnaround, but often false +
40
Q

Homocysteinemia

  • Inheritance, __dislocate, __, peripheral __
  • sometimes __↓
  • Dx
    • __levels
    • __ mutation
    • Mutation in __
A

Homocysteinemia

  • AR, lens dislocate, MR, peripheral neuropathy
  • sometimes folate ↓
  • Dx
    • serum levels
    • Methyl tetrahydrofolate reductase mutation
    • Mutation in CBS cysathionine βsynthase
41
Q

Pregnancy

  • __coagulability
  • Increase in factors__
  • Decrease __
  • __remain constant
  • Resistance to __
  • __stasis
  • Risk of __
A

Pregnancy

  • Hypercoagulability
  • Increase in factorsVII, VIII, IX, X, PAI & fibrinogen
  • Decrease protein S
  • Protein C and ATIII remain constant
  • Resistance to activated Prot C
  • Venous stasis
  • Risk of PE and DVT
42
Q

Liver

  • Liver synthesizes all clotting factors except __
  • End stage liver disease results in __hemostasis
  • __clotting factors
  • Factor __ are sensitive indicators
    • Factor __falls first
  • __ may be increased due to increased vWF
  • __is an acute phase reactant so it may be normal or decreased
  • Vit __ deficiency
  • __
A

Liver

  • Liver synthesizes all clotting factors except VW factor
  • End stage liver disease results in failed hemostasis
  • Reduces clotting factors
  • Factor V and VII are sensitive indicators
    • Factor VII falls first
  • Factor VIII may be increased due to increased vWF
  • Fibrinogen is an acute phase reactant so it may be normal or decreased
  • Vit K deficiency
  • DIC
43
Q

Heparin

  • Unfractionated heparin is monitored by __
    • Adequate anticoagulation is when __ is __ x mean normal heparin
  • Heparin prolongs PTT, DRVVT and shows inhibitory effect with mixing studies
    • lab testing can look like __
  • LMWH is monitored by __
A

Heparin

  • Unfractionated heparin is monitored by PTT
    • Adequate anticoagulation is when PTT is 2x mean normal heparin
  • Heparin prolongs PTT, DRVVT and shows inhibitory effect with mixing studies
    • lab testing can look like antiphospholipid syndrome
  • LMWH is monitored by anti-factor Xa
44
Q
A

aPTT

  • Phospholipid (contact activator of FXII- (silica, kaolin, etc) + excess Ca + citrated plasma
  • time to clot formation = PTT
  • screen for factor deficiency
  • Prolongation of the PTT is caused by deficiencies of
  • XII, XI, IX, VIII (intrinsic pathway constituents)
  • X, V, II, fibrinogen (common pathway)
  • an inhibitor
  • Prolongation of PT and PTT - deficiencies of factors
  • X, V, II, fibrinogen (the common pathway)
  • inhibitor
  • to cause prolonged PTT
  • factor < 30%
  • higher if multiple factor deficiencies
  • PTT more sensitive to deficiencies in intrinsic than common pathway factors
  • elevated FVIII level
  • capable of shortening the PTT

AP/CP Boards (29 decks)

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