“Controversies in Hematology: Case-Based Discussion · Catastrophic antiphospholipid syndrome Pichika Chantrathammachart MD ... Evidence of involvement of > 3 organs, systems

“Controversies in Hematology: Case-Based Discussion”

Catastrophic antiphospholipid syndrome

Pichika Chantrathammachart MD Division of Hematology, Department of Medicine

Ramathibodi Hospital

Introduction • Clinical syndrome

– Rapid onset of multifocal thrombosis associated with multi-organ failure

– Serological criteria for APS

• Rare – Prevalence of less than 1 in 2000 (app. 600

reported cases) – Mortality estimated at 50%.

• <1% of patients with the APS

David Garcia, and Doruk Erkan, n engl j med 378;21 nejm.org May 24, 2018

Summary of the Proposed Pathogenesis of Antiphospholipid-Antibody–Mediated Clinical Problems.

Presenter

Presentation Notes

Summary of the Proposed Pathogenesis of Antiphospholipid-Antibody–Mediated Clinical Problems.�In Panel A, antiphospholipid antibodies are produced by B cells; binding to anionic surfaces converts the closed, nonimmunogenic β2-glycoprotein I (β2GPI) to the open, immunogenic β2GPI. In Panel B (left), antiphospholipid antibodies bind to the immunogenic β2GPI, resulting in endothelial-cell, complement, platelet, neutrophil, and monocyte activation (including the release of neutrophil extracellular traps [NETosis]). In Panel B (middle), antiphospholipid antibodies promote clot formation, and in Panel B (right), antiphospholipid antibodies interfere with trophoblasts and decidual cells. Panels C and D show that, on the basis of multiple mecha- nisms that are not mutually exclusive, antiphospholipid antibodies result in inflammation, vasculopathy, thrombosis, and pregnancy complications. n engl j med 378;21 nejm.org May 24, 2018

Catastrophic antiphospholipid syndrome (CAPS) spectrum

• Definite or probable APS • CAPS-like disease • Microangiopathic APS • Thrombotic storm

Presentations

CAPS : thrombotic microangiopathic condition, characterized by a diffuse thrombotic microvasculopathy (a) Clinical evidence of multiple organ involvement

developing over a very short period of time

(b) Histopathological evidence of multiple small-vessel occlusions

(c) Laboratory confirmation of antiphospholipid (aPL) antibodies, usually in high titer

Preliminary Criteria for Classification of CAPS

1. Evidence of involvement of > 3 organs, systems and/or tissues 2. Development of manifestations simultaneously or in < 1 week 3. Confirmation by histopathology of small vessel occlusion in at least one organ or tissue 4. Laboratory confirmation of the presence of antiphospholipid antibodies (lupus anticoagulant and/or anticardiolipin antibodies)

Definite catastrophic APS : all 4 criteria Probable catastrophic APS : - All 4 criteria, except for only 2 organs, systems and/or tissues involved - All four criteria, except for the absence of laboratory confirmation at least 6 weeks apart - 1, 2 and 4 - 1, 3 and 4 and the development of a third event in more than a week but less than a month, despite anticoagulation

Asherson et al. 2003

Case 1 ชายไทยค 69 ป

CC : ปลายมอ-เทา เยน ปวด เปลยนส 1 วน

PI : 2 wk PTA ขาบวม ปสสาวะลดลง เหนอยงายขน

5 days PTA ปวดทอง ปวดบดๆตลอดทงวน ถายเหลว วนละ 1-2 ครง เหนอยมากขน อาการเปนมากขนเรอยๆ

1 day PTA ปวดเทามาก เทาเยนและสคลาขน จงมาโรงพยาบาล

PH : - CAD S/P CAG (2007)

- Smoking 50 pack-year

Physical examinations V/S T 36.8 C, BP 105/48 mmHg, PR 91 BPM, RR 20 /min RS : fine crepitation BLL, decreased BS RLL

Investigations

CBC Hb/Hct 8/25.1 WBC 6700 N86 L4 M9 Plt 174,000 Coag PTT 30.1 sec (22-33) PT 17.6 sec (10.5-13.5) TT 10.6 sec (10-13) D-dimer 21530 BUN/CR 120/7.71 K 5.7 UA prot 3+, blood marked+ WBC 0-1, RBC 0

Investigations & management - I

• Anti-GBM , • p-ANCA , c-ANCA • ANA homogeneous > 1:1280 nucleolar > 1:1280 • Antithrombin 45% • Protein S 63% • Protein C 43% • Cryoglobulin

DDx • RPGN vs RPGN mimics • Raynuad’s phenomenon

Treatment • Dexamethasone 5 mg IV q 6 hr • Nifedipine • Hemodialysis

MDCT Angiography of Aorta and Peripheral Run Off

- Severe stenosis at bilateral ATA, proximal right peroneal artery and proximal right PTA.

Presenter

Presentation Notes

IMPRESSION: �CTA�- Severe stenosis at bilateral ATA, proximal right peroneal artery and proximal right PTA. �- Moderate stenosis at proximal left PTA and left peroneal artery. �- Mild to moderate stenosis at bilateral mid superficial femoral arteries. �- Segmental severe stenosis at left internal iliac arteries from its origin, about 3.5 cm in length with reconstitution at distal part. �- Mild focal stenosis at celiac origin. �- Atherosclerotic change of aorta and its branches with calcified plaques and soft plaques as described. ��Others: �- Diffuse irregular dilatation of the pancreatic duct (measuring up to 2.9 cm) with small cystic lesion at the pancreatic tail; possible main duct type IPMN (Intraductal papillary mucinous neoplasm). Further ERCP is recommended. �- Evidence of portosystemic collateral vessels. �- A wedge-shaped non-enhancing hypodense lesion at posterosuperior aspect of spleen, likely splenic infarction. �- Impaired parenchymal enhancement and poor perfusion of both kidneys, probably due to parenchymatous disease of both kidneys. �- A small cortical cyst at left kidney and a 2.9-cm right parapelvic cyst. �- Cardiomegaly with 1.3-mm pericardial effusion. �- Moderate amount of ascites and bilateral pleural effusions. �- Old comminuted fracture at right greater trochanter.

Investigations & management - II

• Pleural fluid ANA

homogeneous > 1:1280

nucleolar > 1:1280

speckle > 1:1280

• B2-GPI Ab 4 (0-20)

• aCL 24.0

(neg <12)

• Lupus anticoagulant

• Anti-Scl-70 3

DDx • SLE with CAPS * (SNAPS) • Scleroderma renal crisis • Other TMAs • Cancer-associated thrombosis

Treatment • Dexamethasone 5 mg IV q 6 hr • Enoxaparin 0.4 ml SC OD • ASA (81) 1x1

Planned renal biopsy >> cancelled

Thrombotic microangipathy (TMA)

STEC-HUS and STEC-

like aHUS

(associated with complement

Secondary TMA

TTP

Shiga toxin-producing E. coli - Strain O157:H7 and other strains - Shigella disenteriae type I - Streptococcus pneumoniae (neuraminidase)

Complement abnormalities - Mutations in FH, MCP, FI, THBD, FB and C3 - Polymorphism risk in FH and MCP - Anti-FH antibodies

TTP (ADAMTS13 acitvity <5-10%) - Genetic cause - Antibodies

Causes of secondary TMA

Pregnancy • Pre-eclampsia, eclampsia • HELLP syndrome • Postpartum TMA Systemic disease • SLE • Scleroderma • Vasculitis • APS/CAPS

Glomerulonephritis • C3 glomerulopathies • Glomerulopathies ass with

MGUS • IgA nephropathy Malignant arterial hypertension Infections • HIV, HCV, H1N1, others Neoplasms

Differential diagnosis of catastrophic APS

History & condition CAPS TTP-HUS HELLP

syndrome Sepsis DIC HIT SRC

History APS/SLE/malignancy/pregnancy

None Pregnancy Infection Infection Heparin exposure

Scleroderma

Thrombosis

Small/large vessels

Small vessels

Small vessels

Large/small vessels

Small vessels

Large/small vessels

Small vessels

Hemolysis -/+ ++ + -/+ -/+ - +

Schistocytes -/+ ++ -/+ -/+ -/+ - +

Fibrinogen Normal/high

Normal/high

Normal/high

Normal/low

Normal/low

Normal/high

Normal/high

Typical Abs aPL ADAMTS

13 None None None Anti-PF4 None

EXPERT REVIEW OF HEMATOLOGY, 2017, VOL. 10, NO. 4, 365–374

Clinical manifestations

• Thrombosis-related manifestations

– Intra-abdominal thrombotic complications

: kidneys, adrenal glands, splenic, intestinal, and mesenteric or pancreatic vasculature

• SIRS-related manifestations

– ARDS : cytokine storm

Severity of thrombosis Organ dysfunction

Clinical manifestations

CAPS: Descriptive analysis of 500 patients from the International CAPS Registry I. Rodríguez-Pinto et al. Autoimmunity Reviews 15 (2016) 1120–1124

Lab and serology features


Triggers

• Infection : common • Anticoagulant withdraw, subtherpeutic INR • Other medications : OCPs • Obstetric complications • Malignancy • SLE flares • Others : trauma, surgery ~ 1/3 of cases - no obvious precipitating factors

Demographic characteristics and precipitating factors of patients with CAPS

(CAPS registry; 1992-2014)


Histological characterization of APS-associated nephropathy

Sciascia, S. et al. Nat. Rev. Nephrol. (2014) 10, 279–289

Presenter

Presentation Notes

Histological characterization of APS-associated nephropathy.�a | Haematoxylin and eosin stain showing two glomeruli, one of which contains intracapillary thrombi (white arrows). The afferent arteriole of the glomerulus on the left is entirely occluded by a fibrin thrombus (black arrow). b | Haematoxylin and eosin stain showing fibrinoid necrosis and mucoid intimal oedema in the intima of an arteriole (arrow) with fragmented red blood cells. The interstitium around the arteriole is oedematous. c | Haematoxylin and eosin stain showing thrombi occluding peritubular capillaries (arrow). Interstitial oedema, haemorrhage and acute tubular injury might be present dependent on the severity of acute ischaemic injury. d | A large intravascular thrombus at the vascular pole of a glomerulus stained red with trichrome staining (arrow). e | Direct immunofluorescence also shows positive staining for fibrinogen in glomerular capillary lumina and at the vascular pole (arrows). f | On ultrastructural analysis fibrin can be seen occluding the capillary lumen. Endothelial cells have lost fenestration and podocytes reveal extensive foot process effacement. g | In chronic disease, double contours without interposition of electron dense immune-complexes can be seen (arrows). Platelets are seen in capillary lumina in both acute and chronic phases (black circle). Podocytes are often injured and reveal foot process effacement (black arrows).

Scleroderma renal crisis

Thrombotic microangiopathy changes in SRC

• Small vessel thrombi : 11/17 (65%) • Glomerular thrombi : 3/17 (18%), (P = 0.01)

Thrombotic microangiopathy

changes in HUS • Glomeruli : 11/12 (92%) • Small vessels : 4/12 (33%) (P = 0.009)

Prominent arterial onion skin lesion

Arterial thrombosis associated with prominent glomerular ischemic collapse

Seronegative CAPS

• First introduced to describe patients with clinical manifestations highly suggestive of APS but with persistently negative LA, aCL and anti-b2 glycoprotein I (anti-b2GPI)

Hughes GR, Khamashta MA. Ann Rheum Dis 2003;62:1127.

• Antiphospholipid antibodies

– Lupus anticoagulant

– aCL (IgG and/or IgM)

– Anti-b2GPI antibody (IgG and/or IgM)

Non-criteria aPLs • Antibodies to vimentin/cardiolipin complex

– Persistently positive in almost all APS patients and a large number of SNAPS patients.

• Anti-PT: aPT-A and aPS/PT

– Good specific tests to confirm APS; but standardization needed to be included in the diagnostic criteria.

– Anti-PT-A + other tests: good risk marker for thrombosis.

• The annexin A5 resistance assay

• IgA aCL and IgA anti-b2GPI antibodies

• Antibodies to negatively charged phospholipids : PE, PA, PS and PI

Treatments of CAPS

• Anticoagulant • Glucocorticoids • Plasmapheresis • IVIg • Cyclophosphamide • Rituximab • Eclulizumab • Others : Defibrotide, Prostacyclin

Summary of recommendations

Legault K, et al Thromb Haemost 2018; 16: 1–9

Treatment algorithm for CAPS

EXPERT REVIEW OF HEMATOLOGY, 2017, VOL. 10, NO. 4, 365–374

Treatments


Treatment outcome

Recovery rate

Anticoagulants + corticosteroids 63.8 %

AC+ CS+ therapeutic plasma exchange 77.8 %

AC + CS + TPE and/or IVIG 69 %

CAPS registry

AC+ CS+ therapeutic plasma exchange

16/21 full response

3/21 partial response

Uthman I, Transfus Apher Sci 2005;33(1):11–7

Therapeutic apheresis in the treatment of CAPS

• Response rate in combine with other treatments (AC+CS) ~ 76-78%

• FFP vs albumin – FFP provide natural anticoagulant, complement activation

products and cytokines.

• Volume – 2-5 L

• Start within first 12 hours and daily session in first 3 days,

• Duration of treatment 3-5 days

Final diagnosis • Disseminated CMV infection • HAP

– Acinetobacter baumannii - XDR

• IPA – Lung C/S : Aspergillus fumigatus

• Scleroderma : SRC

Treatment • Dexamethasone 5 mg IV q 6 hr • Enoxaparin 0.4 ml SC OD • ASA (81) 1x1 • Plasmapheresis, IVIg • ATB

Management of SRC

Autoimmunity Reviews 17 (2018) 882–889

Presenter

Presentation Notes

ERAs Endothelin receptor antagonists

Conclusions Catastrophic antiphospholipid syndrome (CAPS) • Disseminated thrombosis, mainly in small vessels • Leads to multi-organ failure • Many.. many mimic syndromes

1. Exclude condition that need specific treatment : TTP : HIT : SRC 2. Treatments should be started ASAP : Anticoagulant : Immunosuppressions e.g CS, PE, IVIg : Supportive care : RRT, infection etc.

THANK YOU FOR YOUR ATTENTION

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“Controversies in Hematology: Case-Based Discussion · Catastrophic antiphospholipid syndrome Pichika Chantrathammachart MD ... Evidence of involvement of > 3 organs, systems