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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
Q

APS microangiopathy and microvascular manifestations

A

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
Q

** CAPS definition **

A
  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
Q

** CAPS manifestations **

A

-CNS
-Cardiopulm w/ hemorrhage
-Abdo pain
-Renal insuff
-Cutaneous

-Thrombocytopenia
-Hemolytic anemia (must differentiate from TTP, HUS, malignant HTN, and DIC)

28
Q

** Primary prevention - aPL+ w/o hx clot or obstetrical complication**
-Low risk
-High risk
-If General Surgery
-If Orthopedic surgery
-If pregnant

A

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
Q

DDx CAPS

A

HIT,
TTP,
HUS,
DIC,
HELLP,
Malignant hypertension,
SLE flare

Table 23.1

30
Q

** Tx options for APS**

A

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
Q

Tx options for APS with HIT

A

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
Q

How to monitor heparinization if LA → prolonged aPTT

A

Measure antifactor Xa level or thrombin time (measures system distal to aPL AB)

-On warfarin: PT/INR unaffected by LA

33
Q

** 2ndary prevention in pt w/ aPL and previous VENOUS clot**

A

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
Q

2ndary prevention in pt w/ aPL and previous CNS arterial clot

A

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
Q

Bleeding risk factors

A

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
Q

** Tx noncerebral arterial thrombosis and aPL+**

A

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
Q

** Pathogenesis of fetal loss w/ aPL **

A

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
Q

**aPL obstetric complications and mech **

A

Thrombosis → placental insuff and infarcts→

Preeclampsia,
Fetal death after 10th wk,
IUGR,
Preterm labor

39
Q

Tx aPL+ w/ fetal loss hx - NO CLOT hx

A

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
Q

Tx aPL+ w/ fetal loss hx - WITH CLOT hx

A

Clot hx:
- Change warfarin to therapeutic dose LMWH and low dose ASA
-Warfarin ok in breastfeeding

41
Q

How to treat obstetric APS w/ recurrent pregnancy complication despite low dose ASA and ppx LMWH

A

-Change ppx dose LMWH to therapeutic dose
-Add HCQ
-Low dose prednisolone in T1
-IVIG

42
Q

Tx APS pt w/ clot while on warfarin

A

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
Q

Tx APS pt w/ clot while on LMWH

A

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
Q

HCQ and statin mech of action in APS

A

HCQ:
- Inhib PLT
- Preventing B2GP1-APL complexes from binding phospholipids
-Protect annexin V anticoag shield from disruption

Statins:
-Suppress B2GP1 mediated endothelial activation

45
Q

How to test APS in DOAC patients

A

Hold DOAC for 24-48 h

46
Q

**CAPS Tx **

A

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
Q

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

A
  • 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
Q

How to test aPL if already anticoag

A

-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
Q

AbN INR Tx

A
  • High (>5 = bleed risk):
  • Hold warfarin or Vit K (cause warfarin resistance for days)

-If bleeding: FFP acutely (increase clot risk)

50
Q

** What skin finding would confirm suspicion of APS?**

A

Livedo racemosa - net pattern more persistent, generalized, widespread, with IRREGULAR broken circles
- Seen in livedoid vasculopathy, APS, SLE, TO, PV, PAN

51
Q

** Which psych drug causes drug induced APS?**

A

Chlorpromazine

52
Q

** What’s the main clinical difference between primary and drug-induced APS?**

A

aPL antibodies are typically transient and rarely associated with thrombosis

53
Q

** Mixing study vs dRVVT vs STACLOT-LA **

A

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
Q

aPL nephropathy labs and path

A

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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