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1. Rheum RC > APS > Flashcards

APS Flashcards

1
Q

** APL Abs **

A

-LAC
-ACL
-B2GP
-Anti-phosphatidylserine-dependent PT (Anti-PS/PT)

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2
Q

** How LAC measured **

A

-Phospholipid dep screening test (activated partial thromboplastin time [aPTT], Kaolin clotting time, dilute Russell viper venom time [dRVVT], hexagonal phase phospholipid neutralization assay [STACLOT-LA test])

-If prolonged, do mixing study: add normal plasma 1:1
-Corrects if factor deficiency NOT if LAC present
-Can correct if add phospholipid to overwhelm LAC

**false positive w/ warfarin, heparin, DOAC, coag inhibitors (eg factor 7)

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3
Q

How aCL, B2GP, and PS/PT measured

A

ELISA for IgG, IgM, and IgA

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4
Q

Use of VDRL in APL

A

APL ab bind cardiolipin in lipid particles causing agglutination (measured by VDRL) - not recommended

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5
Q

When to suspect APS

A

-Arterial or unprovoked venous thrombosis before 50
-Arterial AND venous event in same pt
-Unusual clot site (renal, hepatic, cerebral sinus, mesenteric, vena cava, retinal, and subclavian)
-Recurrent thrombosis

-Fetal loss or recurrent miscarriage
-Early/severe preeclampsia
-Unexplained IUGR
-HELLP

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6
Q

2023 ACR/EULAR APS classification criteria
-How to meet criteria

A

Entry: 1 clinical criterion + 1 positive APL test (LAC, or mod/high titer ACL or B2GP IgM/G) within 3 years of clinical criterion

-APS if at least 3 pts from clinical domains AND at least 3 points from lab domains

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7
Q

2023 ACR/EULAR APS classification criteria - Clinical domains

A

Venous thrombosis - if risk factor (1), without (3)

-Arterial thrombosis - if risk factor (2), without (4)

Microvascular - suspected (2), established (5)
- Livedo racemosa/vasculopathy (exam vs path),
- Acute/chronic aPL nephropathy (exam/labs vs path),
- Pulm hemorrhage (sx/imaging vs BAL/path),
- MINOCA (MI w/ normal coronary angio AND cMRI or path)
- Adrenal hemorrhage (established: imaging/path)

Obstetric:
->=3 consecutive loss <10-16wks (1),
- Fetal death 16-34w w/ PEC or PI (1),
- Severe PEC (severe HTN, CNS, visual, pulm edema, impaired liver or renal fcn, thrombocytopenia) (3)
- Placental insufficiency (4) - abN fetal surveillance test, Doppler flow, severe IUGR, oligohydramnios,

-Cardiac valve - thickening (2), vegetation (4)
-Thrombocytopenia 20-130 (2)

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8
Q

2023 ACR/EULAR classification criteria - lab domains

A

-Positive LAC single (1), persistent (5)
-Mod/high IgM aCL or B2GP (1),
-Mod IgG ACL or B2GP (4),
-High positive IgG ACL OR/AND B2GP (5/7)

-**persistent = 2 positive tests at least 12 weeks apart

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9
Q

Medium high aPL titer

A

> 40IgG or IgM or >99th percentile

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10
Q

High risk aPL profile

A

-Persistent (12wks) +LAC or double of any combo LAC, aCL, aB2GP
-Triple positive
-Persistently high aPL titers

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11
Q

Clinical manifestations APS

A

-Neuro: chorea, seizure, cognitive dysfcn

-Derm: livedo reticularis/racemosa/vasculopathy, splinter hemorrhage, cutaneous necrosis/infarction, gangrene, ulcers, vasculitis

-Cardiac: valvular

-Pulm: DAH, fibrosing alveolitis, pHTN

-Renal: acute thrombotic, chronic vasoocclusive

-MSK: AVN

-Heme: Thrombocytopenia or hemolytic anemia (immune or TMA)

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12
Q

Lab manifestations

A

IgA aCL
-IgA antiB2GP
-Anti-domain I-B2GP
-AB against: annexin, PS/PT, prot C/S, vimentin/cardiolipin complex

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13
Q

Primary vs 2ndary APS

A

Primary (Hughes): no associated disease
-Thrombocytoepnia, recurrent misciarraige and/or livedo reticularis
-⅔ venous (DVT, PE), ⅓ arterial (TIA, stroke, MI)

-Secondary: 50% hv rheum dz (MC: SLE)

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14
Q

** Diseases assoc’d w/ increased aPL ab production**

A

-Meds: hydralazine, TNFi, procainamide, quinidine, phenytoin, alpha interferon, chlorpromazine

-Autoimmune: SLE, RA, SS, SSc, DM

-Infection: bacterial, viral, herpes, hep c, HIV

-Neoplasm: lymphoma

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15
Q

Lupus anticoagulant effect on PT / PTT

A

PT: no effect
-PTT: 50% prolonged (normal does not exclude LAC)

-**Prolonged PT may mean prothrombin deficiency (hereditary, SLE AB, liver dz, vit k def, warfarin) → hemorrhage w anticoag

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16
Q

dRVVT
-What does it do
-How to interpret test

A

Russel viper venom activates factor X (bypasses intrinsic pathway ie not affected by factor deficiency)

-If test prolonged, add phospholipid and retest. If LAC present, dRVVT test normalizes

-dRVVT/dRVVT + phospholipid >1.2 diagnostic of LA

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17
Q

How to interpret STACLOT-LA

A

Test plasma incubated with and without phospholipid
If difference between test >8sec, LAC present

**False positive if CRP elevated

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18
Q

Reasons for false negative aPL abs despite thrombosis from aPL

A

-Large clot consumed aPL abs

-aPL abs directed against targets not detected by assays (eg prothrombin, phosphatidylserine, vimentin-cardiolipin, annexin 5, thrombomodulin, prot c/s)

-AB against domain I-B2GP

-Thrombosis due to inherited hypercoagulable states

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19
Q

** APS pathogenesis**

A

B2GP AB binds B2GP on phospholipid surfaces of endothelium → prothrombotic and proinflammatory state

Prothrombotic state:
-Decreased NO, Annexin, Prot C, fibrinolysis
-Tissue factor activates coag cascade
-Plt activation releases procoagulant factors
-Upregulate adhesion molecules

Proinflammatory
- Increased complement activation (C5a)
- Increased E selectin, VEGF, tissue factor
- Monocytes/neutrophils activated → NETs

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20
Q

Describe 2 hit hypothesis for APS

A

aPL AB necessary but not enough to cause clot
-2nd hit tips clotting cascade toward thrombosis

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21
Q

** Thrombosis risk factors**

A

Abnormal endothelium
– Infxn or Surgery
– Active vasculitis/inflamm dz (SLE)
– Atherosclerosis and risk factors (DM, DLPD, HTN)
– Catheter for IV access

Prothrombotic risk factors
– Deficiency: Prot C/S, antithrombin III
– Factor V leiden, Homocysteinemia
– Triple +, LAC, High titer APL AB, IgG B2GP
– Genetics: hereditary hypercoag disorder, prothrombin gene mutation
– Smoking
– OCP, Preg, previous fetal loss or clot
– Use of COX2i (controversial)

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22
Q

** CNS manifestations in aPL abs + **

A

-Stroke → dementia, migraine
-Ischemic optic neuropathy
-Retinal artery/vein occlusion
-Sensorineural hearing loss
-Chorea, Seizure
-Transverse myelitis, myelopathy
-Pseudotumor cerebri

23
Q

Other clots in pt w/ aPL abs

A

-Adrenal/pituitary infarct
-Retinal artery/vein thrombosis → blindness
-Digital gangrene / ulceration
-PE → pHTN
-Budd chiaria
-Renal artery/vein thrombosis → ARF
-Vena cava syndrome
-Subclavian vein thrombosis
-AVN

24
Q

Non-clot related manifestations of aPL abs

A

-Migraines
-Seizures (can hv normal MRI)
-Livedo reticularis
-Valvulopathy (MV>AoV)
-Atherosclerosis
-Thrombocytopenia
-Hemolytic anemia (DAT+)

25
APS microangiopathy and microvascular manifestations
Small vessel involvement → ischemia and microinfarct:  --Microangiopathy w/ hemolytic anemia (schistocytes), severe thrombocytopenia <20, and thrombosis of small vessels  -- CAPS -- Livedoid vasculopathy w/ necrosis -- Cerebral microinfarct → MCI, hearing loss, Autonomic dysfcn -- Alveolar hemorrhage, fibrosing alveolitis -- pHTN w/o major emboli -- Ischemic CM -- GI/pancreatitic/hepatic/splenic microinfacrts -- Chronic vaso occlusive lesions w/ renal insuff -- Bone marrow infarction 
26
** CAPS definition **
1. 3+ organs involved simult  2. Within 1wk  3. Histology shows small vessel thrombosis 4. aPL abs  Definite: all 4 Probable:  -All 4 except only 2 organs -All 4 except lab confirmation at least 6 wks apart bc early death of patient -1, 2, 4 -1, 3, 4 and 3rd event >1wk but <1 mo despite anticoag
27
** CAPS manifestations **
-CNS -Cardiopulm w/ hemorrhage -Abdo pain -Renal insuff -Cutaneous -Thrombocytopenia -Hemolytic anemia (must differentiate from TTP, HUS, malignant HTN, and DIC)
28
** Primary prevention - aPL+ w/o hx clot or obstetrical complication** -Low risk -High risk -If General Surgery -If Orthopedic surgery -If pregnant
Low risk: NOTHING **High risk (ie triple positive, SLE, LA+, high titer B2GP, 10y CVD risk >10%) -ASA 81mg daily ** -LMWH x1 if going on flight >4-8h -Gen Surg: heparin 5k SC q8-12h starting 1-2h before surgery, Fragmin 30mg SC q12h 12-24 after surg, or 40mg SC daily 1-2h before surgery -Ortho: same as Gen surg except heparin starts 1-2 after surgery Preg:  -ASA 81-325mg daily and ppx LMWH postpartum  **for all: - Treat smoking, lipids, HTN, DM, imobilization, OCP 
29
DDx CAPS
HIT, TTP, HUS, DIC, HELLP, Malignant hypertension, SLE flare Table 23.1
30
** Tx options for APS **
Heparin (HIT and OP risk) -PPX: 500 BID SC -Tx: 80U/kg bolus → 18U/kg/h maintenance LMWH (caution AKI) -PPX: enox 40mg SC q24 -Tx: 1mg/kg SC q12h DOAC only if fail to reach INR despite VKA adherence or contraindication VKA **NO DOAC in triple positive aPL or arterial**
31
Tx options for APS with HIT
Argatroban (Direct thrombin inhib) - 2ug/kg/min Fonda (inhib factor Xa via antithrombin) -Tx: 7.5mg (>50kg) or 10mg (>100kg) -not if CrCl<30
32
How to monitor heparinization if LA → prolonged aPTT
Measure antifactor Xa level or thrombin time (measures system distal to aPL AB)  -On warfarin: PT/INR unaffected by LA
33
** 2ndary prevention in pt w/ aPL and previous VENOUS clot**
Heparin → Warfarin (INR 2-3) -Provoked: DC after 6mo if clot resolved w/ normal D dimer (controversial) -Unprovoked or high risk clot: lifelongterm anticoag
34
2ndary prevention in pt w/ aPL and previous CNS arterial clot
1st 48h stroke: Low dose ASA 81mg and ppx LMWH  -If cardioembolic: warfarin (INR 2-3) -If not cardioembolic and no risk factor and/or high risk bleed → ASA + Plavix 75 or Ticag 90 -If not cardioembolic but HIGH risk clot: warfarin (INR2-3) plus antiplatelet or high dose warfarin (INR 3-4) -Control smoking, HTN, DLPD, DM
35
Bleeding risk factors
HASBLED Hypertension (sBP >160) Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly ( >65-70) Drugs/alcohol concomitantly (NSAIDs, Ticag>Plavix, >1EtOH/d)
36
** Tx noncerebral arterial thrombosis and aPL+**
Medium clot risk or high bleeding risk: ASA + Plavix/Ticag High risk clot:  -Warfarin INR 2-3 + antiplatelet OR Warfarin INR 3-4 -If high risk + stent = warfarin 2-3INR and DAPT  -As per guideline: VKA > ASA for 1st arterial clot
37
** Pathogenesis of fetal loss w/ aPL **
B2GP AB binds B2GP on **trophoblasts** →  -complement fixation and C5a release → inflamm cells influx → prothrombotic state - alters adhesion molecules and downreg prolactin, insulin like growth factor binding prot secretion → insuff trophoblastic invasion & defective implantation
38
**aPL obstetric complications and mech **
Thrombosis → placental insuff and infarcts→ Preeclampsia, Fetal death after 10th wk, IUGR, Preterm labor 
39
**Tx aPL+ w/ fetal loss hx  - NO CLOT hx**
NO Clot hx -ASA 81-100mg daily before conception -Enox 40mg SC daily until 34wks GA, stopped, then restarted 1wk post delivery at ppx dose (up to 6wks pp if clotting RF) -NO WARFARIN (fetal malformation)
40
**Tx aPL+ w/ fetal loss hx  - WITH CLOT hx**
Clot hx: - Change warfarin to therapeutic dose LMWH and low dose ASA  -Warfarin ok in breastfeeding
41
How to treat obstetric APS w/ recurrent pregnancy complication despite low dose ASA and ppx LMWH
-Change ppx dose LMWH to therapeutic dose -Add HCQ -Low dose prednisolone in T1 -IVIG 
42
**Tx APS pt w/ clot while on warfarin**
Check if adequately anticoag (INR 2-3 and confirmed chromogenic factor X lvl <20%) OR antifactor Xa level If yes to above and venous clot:  -Increase warfarin to INR 3-4 or switch to LMWH  - If arterial clot: INR to 3-4 + either ASA or Plavix Can add HCQ and statin
43
Tx APS pt w/ clot while on LMWH
Check if adequately anticoag with antifactor Xa level If yes to above and venous clot:  -Change to BID LMWH  If arterial: add low dose ASA (or switch/add Plavix if alrdy on ASA)   Can add HCQ and statin
44
HCQ and statin mech of action in APS
HCQ: - Inhib PLT - Preventing B2GP1-APL complexes from binding phospholipids -Protect annexin V anticoag shield from disruption Statins: -Suppress B2GP1 mediated endothelial activation 
45
How to test APS in DOAC patients
Hold DOAC for 24-48 h
46
** CAPS Tx ** 
TREAT triggers: infxn, gangrene, cancer 1st line:  -UNFRACTIONATED Heparin (NOT LMWH) - only delay if life threatening hemorrhage -GC pulse → high dose PO pred 2nd line: **-PLEX x3d (replacement fluid w/ albumin NOT FFP unless TTP/HUS) --IVIG after PLEX ** *Add on antiplatelet or use antiplatelet as alternative if contraindication for reasons OTHER than bleeding 3rd line:  -CYC and/or Ritux if active SLE 4th line: Eculizumab (complement inhib) 
47
Tx for nonthrombotic APS manifestations -Immune mediated thrombocytopenia / hemolytic anemia -ARF from thrombotic microangiopathy -Chronic ischemic nephropathy - Heart valve lesion -Neuro sx -Migraines -Livedoid vasculopathy
- Immune mediated thrombocytopenia / hemolytic anemia → GC +/- IVIG ; otherwise DMARDs, Ritux (AVOID splenectomy for clot risk) -ARF from thrombotic microangiopathy  → PLEX -Chronic ischemic nephropathy from vasoocclusive lesions→ sirolimus post renal tx -Heart valve lesion: NOTHING effective, anticoag to PREVENT emboli -Neuro sx: AED for sz, antiDA/GC for chorea, GC/DMARDs for transverse myelitis -Migraines: 2 wk trial of LMWH (continue if effective) - Livedoid vasculopathy: antiplatelet, sildenafil, IVIG, hyperbaric O2, anticoag
48
How to test aPL if already anticoag
-Heparinase to remove heparin before LA -Warfarin only prolongs PT (so abN PTT can suggest LA or vit K def - do 1:1 mix, if doesnt correct = suggests LA)  -Anticardiolipin and B2GP unaffected by heparin or warfarin
49
AbN INR Tx
- High (>5 = bleed risk): - Hold warfarin or Vit K (cause warfarin resistance for days) -If bleeding: FFP acutely (increase clot risk)
50
** What skin finding would confirm suspicion of APS?**
Livedo racemosa - net pattern more persistent, generalized, widespread, with IRREGULAR broken circles - Seen in livedoid vasculopathy, APS, SLE, TO, PV, PAN
51
** Which psych drug causes drug induced APS?**
Chlorpromazine
52
** What’s the main clinical difference between primary and drug-induced APS?**
aPL antibodies are typically transient and rarely associated with thrombosis
53
** Mixing study vs dRVVT vs STACLOT-LA **
Mixing study: - LAC = PTT stays prolonged - Factor deficiency = corrects w/ mixing *Can add phospholipid to overwhelm LAC and correct PTT dRVVT (diluted Russel’s Viper Venom time): - Uses less phospholipid - Not affected by factor deficiencies (more sensitive for LAC) -A ratio of dRVVT/dRVVT plus phospholipid of >1.2 is diagnostic of LA. STACLOT-LA: - Hexagonal phase phospholipid neutralization assay - 2 part aPTT assay - Plasma is incubated with and without phospholipid and aPTT measured - aPTT difference>8 seconds = LAC is present *Elevated CRP can cause false-positive
54
aPL nephropathy labs and path
Labs - Proteinuria ≥0.5 g/24h or PCR ratio ≥0.5 mg/mg - ARF -Glomerular microscopic hematuria. Path: - Acute: fibrin thrombi in arterioles/glomeruli w/o inflamm cells or immune complexes - Chronic: arterial/arteriolar microthrombi +/- fibrous/fibrocellular occlusions, focal cortical atrophy +/- thyroidization, fibrous intimal hyperplasia, or chronic/organized glomerular thrombi.

1. Rheum RC (23 decks)

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