Arterial Thrombosis: An interesting case

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Arterial ThrombosisAn interesting case

• Dr. Darren Yuen PGY-3
• Rheumatology Case Rounds
• May 17, 2005

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Case

• 59F
• SLE (Dx 1981)
• Diabetes mellitus (1990) - ? Type 1
• Hypercholesterolemia
• CAD (acute inferior MI 2001)
• Acalculous cholecystitis
• TAH-single salpingo-oophorectomy (for ovarian
  fibroid - benign)

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Case SLE History

• Arthritis (1981)
• MCP/PIPs initially ? diffuse distribution
• Skin/scalp (1981)
• Erythematous rash ? pale atrophic areas
• Alopecia
• Intermittent abdo pain (1980s)
• Partial SBO
• Diffuse transmural SB inflammation (1986)

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Case SLE History

• Pleuritis/pericarditis (1987)
• Episcleritis (1987)
• Membranous SLE nephritis with advanced sclerosis
  (1993)
• Re-biopsied for new nephrotic syndrome (Feb
  2005)
• membranous SLE nephritis but also.
• fingerprint pattern suggestive of
  cryoglobulin-mediated disease
• Serum cryocrit 3

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Case SLE serology

• ANA 1320 homogenous
• Persistent
• ? anti-dsDNA (152)
• ? complements
• discordant

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Case SLE Vascular Phenomena

• Tender, thrombosed R temporal art (1992)
• Intravascular papillary endothelial hyperplasia
• Cyanotic L hand (1992) angio
• ? flow L subclavian artery
• Occluded distal L brachial radial art
• Aortic arch, celiac, SMA, renal arts normal
• Raynauds R hand (1992, 1994)

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Case SLE Vascular Phenomena

• Mesenteric ischemia (1998)
• angio
• occluded celiac artery
• Severe SMA stenosis at origin ? angioplasty
• IMA patent
• Repeat angio (Feb 2005)
• Occluded celiac artery
• Severe SMA re-stenosis at origin

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Case Hypercoag W/U
No FHx
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Case Treatment

• Immunosuppression
• Initially treated with prednisone
• pt would often treat flares herself with ? dose
• Plaquenil recommended repeatedly ? pt refused or
  discontinued
• Anticoagulation
• 1998 - heparin/coumadin (post-SMA stenosis)
• 1999 - pt discontinued coumadin

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In Summary.

• 59F SLE
• serology-discordant
• poorly controlled d/t non-compliance
• multiple separate arterial ischemic events
• not on appropriate anticoagulation
• no clear etiology for arterial ischemic events as
  pt did not comply with investigations
• embolic?
• thrombotic? APLS?

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Case SLE Vascular Phenomena

• Multiple arterial thromboses (April 2005)
• R MCA M1 M2 segments occluded (L
  hemiplegia/homonymous hemianopsia)
• Mesenteric ischemia (acute abdo/lactic acidosis)
• CTA occluded celiac, SMA IMA not seen, L
  common iliac (to level of CFA)
• Ischemic L foot (clinical Dx)
• ARF

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Investigations?
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Case Investigations

• BC, 2D echo negative
• PTT normal
• Serology
• Anti-dsDNA 1640
• Complements C3 0.66, C4 0.08
• Cyrocrit negative

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Diagnosis?
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Management?
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Case Management

• PLEX
• Solumedrol 1 g iv daily
• Cyclophosphamide iv
• IV heparin (low-dose nomogram)

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What happened?

• Massive GI bleed (Hgb 98 ? 44)
• Code blue
• Failed resuscitation

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Arterial Thrombosis

• Non-Rheum related
• HIT
• hyperhomocysteinemia
• DIC (rarely)
• hyperviscosity states
• Waldenstroms
• myeloproliferative disorders
• blast crisis

• Rheumatology-related
• APLS
• Hyperviscosity states
• cryoglobulinemia (rarely)

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APLS Definition

• Syndrome characterized by
• persistent circulating antiphospholipid
  antibodies
• prothrombotic state

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APLS
Secondary
Primary

• NOT associated with any other syndrome

• AI diseases
• Drugs
• Infections
• Malignancies

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2 APLS not just SLE!

• AI diseases all seropos diseases, vasculitis,
  psoriatic arthritis
• Drugs hydralazine, procainamide, phenytoin,
  phenothiazines, quinine, quinidine, OCP
• Infections bacterial (sepsis, IE, syphilis,
  Lyme), viral (HIV, hep A/B), parasites (malaria)
• Malignancies solid tumours, lymphomas

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Antiphospholipid - a misnomer?

• Antiphospholipid Abs large family of Abs
  directed against
• plasma proteins bound to phospholipids (eg
  ?2-glycoprotein I) OR
• phospholipids
• actually unclear what the exact antigenic sites
  are! - but NOT just phospholipids themselves

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Pathophysiology

• 3 major isotypes (IgG, IgM, IgA)
• MANY APLAs exist
• often can occur TRANSIENTLY
• NOT all cause disease
• UNCLEAR which population is athogenic

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Incidental APLAs

• Often can occur following
• infections
• new drug initiation
• incidental APLAs
• usually LOW titres (lt 20 GPL or MPL)
• usually TRANSIENT
• usually directed against phospholipids directly
  NOT plasma proteins

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Pathophysiology
Actual mechanisms are poorly understood!
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APLS
Bleeding
Thrombosis

• Most clinical manifestations of APLS relate to
  prothrombotic state created by APLAs
• medium/large vessel
• small vessel

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Classic Manifestations

• Venous thrombosis
• Arterial thrombosis
• Pregnancy-associated morbidity mortality

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Thrombosis

• General rules of thumb
• HIGH risk of recurrent thrombosis
• actual risk is UNCLEAR (most data based on
  retrospective studies, selection bias)
• without Rx up to 50 over 5 yrs
• ? risk with ? ACA titres
• recurrent events tend be in same system
• venous ? venous
• arterial ? arterial

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Pregnancy-associated disorders

• Maternal
• severe preeclampsia
• Fetal
• fetal loss (50 T1, 50 post-T1)
• ? risk with ? ACA titre
• placental insufficiency
• IUGR
• prematurity

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Other Manifestations

• Hematologic
• thrombocytopenia (either as part of TTP-like
  syndrome or otherwise)
• usually moderate (50,000 - 100,000) unless TTP
• hemolytic anemia
• AIHA
• MAHA
• bleeding

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Other Manifestations

• Cardiac
• valvulitis
• MV most commonly (AoV can be affected)
• pericardial effusions
• intracardiac thrombi
• CAD (weak association)

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Other Manifestations

• Pulmonary
• ARDS
• intra-alveolar hemorrhage
• GI
• mesenteric ischemia/infarction
• splenic or pancreatic ischemia/infarction

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Other Manifestations

• Renal
• renal artery thrombosis
• renal vein thrombosis
• TTP (small vessel disease)
• (glomerulonephritis rarely)

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Other Manifestations

• Skin
• livedo reticularis
• digital infarctions, skin ulcers/necrosis
• splinter hemorrhages
• subcutaneous nodules
• purpura
• Endocrine
• adrenal insufficiency (d/t bilat adrenal
  hemorrhagic infarction)

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Catastrophic APLS

• RARE variant (0.8)
• Widespread thrombosis leading to MOF
• ? 3 organs/tissues
• multiple organ involvt within 1 wk
• most common kidney! (TMA, malig HTN)
• CNS (microinfarcts)
• lungs (ARDS)
• heme (DIC)
• cardiac (microinfarcts)
• Can lead to DIC

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Catastrophic APLS

• Pathophysiology
• diffuse small vessel occlusion (DIFFERENT from
  other APLS manifestations)
• Triggers (unclear)
• infection, surgery, oral anticoag w/d, OCP
• FREQUENTLY FATAL (50 mortality rate despite Rx!)

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Diagnostic Tests

• 2 major tests available
• lupus anticoagulant
• anticardiolipin antibodies

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Lupus Anticoagulant

• FUNCTIONAL assay
• NOT measuring a quantity
• Based on ability of APLAs to inhibit
  phospholipid-dependent clotting tests (e.g., PTT,
  kaolin clotting time)
• prolongation of PTT in vitro
• seems to correlate with thrombosis risk in vivo

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Anticardiolipin Abs

• Quantitative ELISA
• can measure IgG (GPL units) IgM (MPL units)
• as aCL titres ?
• thrombosis risk ? (both initial recurrent)

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APLS Diagnostic Criteria

• Clinical criteria
• Vascular thrombosis
• venous, arterial, small vessel
• Pregnancy morbidity
• ? 3 consecutive miscarriages (lt 10 wks)
• ? 1 fetal death (gt 10 wks)
• ? 1 premature birth d/t preeclampsia, placental
  insuff

• Lab criteria
• med/high ACA titre (IgG/IgM)
• lupus anticoag
• 2 occasions, ? 6 wks apart

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Management

• Very few treatment options that are based on
  solid evidence
• pathophysiology poorly understood!
• General principles
• rule out Rx secondary causes
• presentation-specific Rx

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1st venous thrombosis

• Anticoagulation (heparin then warfarin)
• target INR?

• No significant difference
• between INR 2-3 3-4
• recurrent thrombosis
• major bleeding

N Engl J Med 2003 349 1133 - 1138.
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1st Venous Thrombosis

• Optimal duration of anticoagulation
• UNCLEAR
• probably lifelong as recurrence rates
  post-warfarin cessation are HIGH (? 50)
• Other options LMWH? (not studied)

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1st Venous Thrombosis

• Antiplatelet
• VERY little evidence
• NOT as monotherapy
• Immunosuppressives
• NO good evidence supporting use
• Abs quite resistant, sig S/E

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1st Arterial Thrombosis

• POOR evidence
• several options
• warfarin (target INR 2 - 3)
• ASA 325 mg/d warfarin (target INR 2 - 3)
• warfarin (target INR 3 - 4)
• optimal duration unclear

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Recurrent thrombosis(on anticoag)

• Anticoagulation
• NO evidence
• several options
• warfarin (target INR 3 - 4)
• LMWH
• ? adjuvant ASA

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Catastrophic APLS

• Management based on case series only
• anticoagulation (heparin ? warfarin)
• steroids (solumedrol 1 g daily x 3, oral pred 1 -
  2 mg/kg/d)
• PLEX (if evidence of TMA)
• IVIG

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Incidental APLA pts(Not APLS)

• No good evidence supporting prophylaxis
• likely NOT sig hypercoagulability
  (underreporting)
• Suggestions
• ECASA 81 mg po daily
• avoid OCP

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THANK YOU