APS Flashcards
** APL Abs **
-LAC
-ACL
-B2GP
-Anti-phosphatidylserine-dependent PT (Anti-PS/PT)
** How LAC measured **
-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)
How aCL, B2GP, and PS/PT measured
ELISA for IgG, IgM, and IgA
Use of VDRL in APL
APL ab bind cardiolipin in lipid particles causing agglutination (measured by VDRL) - not recommended
When to suspect APS
-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
2023 ACR/EULAR APS classification criteria
-How to meet criteria
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
2023 ACR/EULAR APS classification criteria - Clinical domains
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)
2023 ACR/EULAR classification criteria - lab domains
-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
Medium high aPL titer
> 40IgG or IgM or >99th percentile
High risk aPL profile
-Persistent (12wks) +LAC or double of any combo LAC, aCL, aB2GP
-Triple positive
-Persistently high aPL titers
Clinical manifestations APS
-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)
Lab manifestations
IgA aCL
-IgA antiB2GP
-Anti-domain I-B2GP
-AB against: annexin, PS/PT, prot C/S, vimentin/cardiolipin complex
Primary vs 2ndary APS
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)
** Diseases assoc’d w/ increased aPL ab production**
-Meds: hydralazine, TNFi, procainamide, quinidine, phenytoin, alpha interferon, chlorpromazine
-Autoimmune: SLE, RA, SS, SSc, DM
-Infection: bacterial, viral, herpes, hep c, HIV
-Neoplasm: lymphoma
Lupus anticoagulant effect on PT / PTT
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
dRVVT
-What does it do
-How to interpret test
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
How to interpret STACLOT-LA
Test plasma incubated with and without phospholipid
If difference between test >8sec, LAC present
**False positive if CRP elevated
Reasons for false negative aPL abs despite thrombosis from aPL
-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
** APS pathogenesis**
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
Describe 2 hit hypothesis for APS
aPL AB necessary but not enough to cause clot
-2nd hit tips clotting cascade toward thrombosis
** Thrombosis risk factors**
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)
** CNS manifestations in aPL abs + **
-Stroke → dementia, migraine
-Ischemic optic neuropathy
-Retinal artery/vein occlusion
-Sensorineural hearing loss
-Chorea, Seizure
-Transverse myelitis, myelopathy
-Pseudotumor cerebri
Other clots in pt w/ aPL abs
-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
Non-clot related manifestations of aPL abs
-Migraines
-Seizures (can hv normal MRI)
-Livedo reticularis
-Valvulopathy (MV>AoV)
-Atherosclerosis
-Thrombocytopenia
-Hemolytic anemia (DAT+)
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
** CAPS definition **
- 3+ organs involved simult
- Within 1wk
- Histology shows small vessel thrombosis
- 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
** CAPS manifestations **
-CNS
-Cardiopulm w/ hemorrhage
-Abdo pain
-Renal insuff
-Cutaneous
-Thrombocytopenia
-Hemolytic anemia (must differentiate from TTP, HUS, malignant HTN, and DIC)
** 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
DDx CAPS
HIT,
TTP,
HUS,
DIC,
HELLP,
Malignant hypertension,
SLE flare
Table 23.1
** 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
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
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
** 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
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
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)
** 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
** 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
**aPL obstetric complications and mech **
Thrombosis → placental insuff and infarcts→
Preeclampsia,
Fetal death after 10th wk,
IUGR,
Preterm labor
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)
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
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
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
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
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
How to test APS in DOAC patients
Hold DOAC for 24-48 h
**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)
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
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
AbN INR Tx
- High (>5 = bleed risk):
- Hold warfarin or Vit K (cause warfarin resistance for days)
-If bleeding: FFP acutely (increase clot risk)
** 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
** Which psych drug causes drug induced APS?**
Chlorpromazine
** What’s the main clinical difference between primary and drug-induced APS?**
aPL antibodies are typically transient and rarely associated with thrombosis
** 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
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.
