Hysterical Drama Leading to Hysterectomy

Dr. Amir Bieber

Ha’Emek Medical Center, Afula, Israel

Rheumatology Unit

Case Presentation

• 37 y/o female, Teacher,

• 4 children, s/p current CS (caesarean section) at 33 weeks, IUGR

• In Hospital – (June 2019) – Anemia d/t vaginal bleeding.

• Relevant Medical History• 2009 – SLE? = Arthralgia, Rash, ANA positive SSA positive, low complement

• 2012 –APLA triple positive, DVT – treated with Coumadin -> Rivaroxaban 2015 recurrence + PE -> Coumadin

Case Presentation

• Maternal and Gestational history

• 4 Live Births:• G1 - normal vaginal birth, 2400gr• G3 - IUGR 28th week, 900gr, placental microthrombi and fibrin clots, APLA

positive• G4 – Caesarean Section at 40th week, 2900gr, IUGR, Clexane Aspirin from

23rd week• G6 – 33week, urgent Caesarean Section, IUGR, Clexane Aspirin

• 2 Abortions• G2 – 12th week, • G5 – 5th week

Past Laboratory tests

• Serology• ANA + (homogenous + Dense speckled)• Complement (past low values)• SSA (positive bioplex)• B2GP – POS – IgG high titers (>160) X2 2012 and 2015• Anti Cardiolipin IgG high titers (>160) X2 2012 and 2015• LAC SCT ratio 2.21 – 2013

• Baselines –• Creatinine 0.7 mg /dl, Normal Liver Function Tests• Hemoglobin – 12 g/dl, PLT 120-150, WBC – 4K (lymphopenia 900)• Protein/Create – 400 mg/g (24 weeks), No HTN

1st Admission

• June- (9 day post Casesarean section)

• Gynaecology dept –

• Vaginal bleeding and Curettage– in utero bleeding and gestational debris.

• 1st Rheumatology Consultation –• Weakness, fatigue and headache

• Physical exam – Tachycardia – 110, RR – 22, normal BP and no fever

• Abdominal tenderness w/o peritoneal irritation,

• Leg edema and Livedo Reticularis

30/5 7/6

1st ad 1st dis

Hb 10 6.6 8

Plt 81 90

WBC 7.8 3.7

ANC 6.3 2.5

INR 1.2 1.3

Creat 0.95 1.1

AST 45 60

ALT 37 43

Bil Tot 0.4 0.5

ALKP 279 730

LDH 541

Alb

HIT neg

Hapto 225

`` 30/5 7/6

1st ad 1st dis

C3 99

C4 13

ANA 1:160

Pattern Nu+Ho

DSDNA 13

SSA-60 3.6

CRP mg/dl

9.2

RF <10

Coombs neg

Schisto Neg

2nd Admission (+ 3 days)

• Recurrent bleeding (vaginal) (Hg – 10 → 6.8) -> blood transfusions. • Subjective-

• Abdominal pain

• Shortness of breath and cough

• Bloody Vaginal discharge• Objective

• Fever (39 degr, chills), Tachycardia, Tachypnea, Pallor

• Lung – Bilt Crackles,

• Abdominal tenderness

30/5 7/6 10/6 13/6 19/6

1st ad 1st dis 2dn adm +3 days

Hb 6.6 8 6.8 6.1

Ret:2.8% Fib:713

Plt 81 90 136 86

WBC 7.8 3.7 4.6 4.4

ANC 6.3 2.5 3.6 3.2

INR 1.2 1.3 1.4 1.3

Creat 0.95 1.1 1.2 1.3

AST 45 60 149 149

ALT 37 43 79 79

Bil Tot 0.4 0.5 0.7 0.7

ALKP 279 730 834 1091

LDH 541 1291

Alb 3 2.6

HIT neg

Hapto 225 <10

30/5 7/6 10/6 13/6

1st ad 1st dis 2dn adm +3 days

C3 99

C4 13

ANA 1:160

Pattern Nu+Ho

DSDNA 13

SSA-60 3.6

CRPmg/dl 9.2 14.5

RF <10

Coombs neg

Schisto Neg positive

Blood cuture

Ecoli +

Cervix GBS and Ecoli

Hospitalization workup

• Abdominal US + Hepatic vein Doppler – Splenomegaly (16cm), normal liver, normal cystic duct and gallbladder• No abnormalities with hepatic vein and cava (Doppler)

• Gynecological US –• Remanences of blood clots in utero (less than 100ml) – curettage ->

• Total of 3 curettage – halted d/t of risk of perforation

• Minimal Douglas pouch fluid

Hospitalization workup

• DVT ruled out

• CT – (Indication – ongoing sepsis)

• Bilateral small amount of pleural effusion

• Utero – enlarged with HU40 fluid

• Spleen – infarcts (new hypodense lesions 2X3cm), total size of spleen 17cm,

• Kidney – Rt – multiple hypodense lesions (infarcts?), Lt- perinephric fat infiltration

• Normal SMV, HV, IVC

• Normal Echo (EF=60, EPAP = 32, no diastolic, no valvular mass)

2nd adm

2016

Decisions

• Problem List:

• Sepsis – possible sources:

• Obstetric- Utero

• Pyelonephritis (nephronia + Ecoli) – unresponsiveness to ABx

• Acute Kidney Injury

• Elevated Liver Enzymes

• Anemia (+\- vaginal bleeding, low hapto, neg coombs)

• Thrombocytopenia

• Spleen and kidney Infarcts

Hysterectomy

• 18/6 – Operating Room• Free abdominal fluid – small amount, non bloody

• Hysterectomy– Inflamed, partial necrosis with blood clots.

• Pathology – Severe inflammation, microabscses no evidence of placental or vascular thrombi

ICU and post operative care

• 2nd-- 5th day Post Operation

• Sepsis Source Control - lower fevers, no chills, improvement in SIRS parameters.

• Thrombocytopenia (50)

• Urine – Leu +, Erythrocytes +++, Sediment – Hyaline, Granular, some WBC casts, Epithelial casts.

• Advanced AKI –• Labs: Cr 2.17,

• Urine Pro/Creat ratio – 3Grams

• Elevated Liver Enzymes

30/5 7/6 10/6 13/6 19/6

1st ad 1st dis 2dn adm POD 1

Hb 6.6 8 6.8 6.1 10.7

Ret:2.8% Fib:713

Plt 81 90 136 86 51

WBC 7.8 3.7 4.6 4.4 8.3

ANC 6.3 2.5 3.6 3.2 7.5

INR 1.2 1.3 1.4 1.3 1.22

Creat 0.95 1.1 1.2 1.3 2.17

AST 45 60 149 149 41

ALT 37 43 79 79 62

Bil Tot 0.4 0.5 0.7 0.7 0.6

ALKP 279 730 834 1091 153

LDH 541 1291 1165

Alb 3 2.6 2.9

HIT neg Xa = 0.95

Hapto 225 <10 <10

Pr/Cr 400* 3266

30/5 7/6 10/6 13/6 19/6

1st ad 1st dis 2dn adm POD 1

C3 99 68

C4 13 9.6

ANA 1:160 1:160

Pattern Nu+Ho

DSDNA 13 +confirm

SSA-60 3.6 +

CRPmg/dl 9.2 14.5 4

RF <10

Coombs neg neg

Schisto Neg positive

Blood cuture

Ecoli +

Cervix GBS and Ecoli

Differential Diagnosis

• Catastrophic APLA – (Kidney, Spleen, Utero, MAHA), induced by infection, Caesarean Section

• HELLP – (Elevated LF, low platelets, Hemolysis)

• SLE • Renal – GN? New onset? (Proteinuria)• Haemolysis

• APLA • Renal – Vascular thrombi, Membranous GN associated with APLA• Hemolysis and low platelets (hematologic APLA)?

• TTP / HUS (d -)

Agenda

• Catastrophic APLA in pregnancy.

• HELLP and APLA

• Kidney and APLA

• Treatment Issues

Cervera R, Rodr´ıguez-Pint´o I, Colafrancesco S,et al. 14th International Congress onAntiphospholipid Antibodies Task Force Reporton Catastrophic Antiphospholipid Syndrome.Autoimmun Rev. 2014;13(7):699-707

APLA and Obstetrics

• Late pregnancy loss (aCL and anti-β2GPI poor predictors)• Pre-eclampsia (aCL) • IUGR and Placental insufficiency

• angiogenic biomarkers of placental insufficiency, s-FLTt-1/PlGF ratio

• Thromboembolic events:• DVT• PE• Stroke• Renal Vein Thrombosis

• Catastrophic APLA Syndrome ?

Antovic A, et al. Lupus Science & Medicine 2018;5:e000197. doi:10.1136/lupus-2016-000197

Highlights from CAPS in pregnancy

• CAPS • 1 during pregnancy • 12 postpartum or post-abortum (in labour in 3 patients)

• The most frequent manifestations of CAPS • Cutaneous (n = 11): skin necrosis , purpura ,splinter hemorrhage • Hepatic (n = 11) • Renal (n = 10) → dialysis in five cases, 3 Biopsies. • Cardiac (n = 8) • Neurological (n = 5)• Hematologic -Thrombocytopenia occurred in 11 cases and haemolytic anaemia in 9

• Obstetrics - 12 HELLP, 6 Pre-eclampsia, 3 Eclampsia• No predictive factor of HELLP or CAPS was found • HELLP – mean 26 weeks

Highlights from CAPS in pregnancy

• Due to the absence of histological proof in eight cases and to a course longer than 1 week in one case • definite CAPS = 4

• probable CAPS = 9

• Triggers • Pregnancy

• Changing anticoagulants prior to C-section

• Surgical procedures – C-section performed in 6 (!) because of HELLP (!)

• Concomitant lupus flare

• Triple Positive APLA – 10/13

Highlights from CAPS in pregnancy

• Outcomes• 7 out of 16 fetal death, 1 developmental problems all other healthy but

most IUGR

• No maternal mortality – but – Adrenal insufficiency and CKD in 5, Stroke in 3

• Treatment• Anticoagulation – mostly (15/16) Heparin

• Corticosteroids – in 12 patients

• IVIG -5 , Plasmapheresis – 5, CYC – 3 (1 LN)

Gomez et al. Ann Rheum Dis 2007;66:740–746.

• In all, 7 (46%) mothers died due to the catastrophic APS.

• Only 6 (46%) babies survived (3 of them were premature new-borns), whereas 7 (54%) babies died.

• 8\15 HELLP • The real incidence of HELLP syndrome in APS is difficult to estimate. Around

50 well-documented cases are reported with both conditions

• 3\15 - Schistocytes

Gomez et al. Ann Rheum Dis 2007;66:740–746.

HELLP

HELLP

Clinical Liver Disease, Vol 4, No 3, September 2014

The HELLP syndrome in the antiphospholipid syndrome: retrospective study of 16 cases in 15 women

• None were treated with cyclophosphamide

• Most patients were treated with Steroids, Aspirin and LMWH

D Le Thi Thuoang et al. Ann Rheum Dis 2005;64:273–278

The HELLP syndrome in the antiphospholipid syndrome: retrospective study of 16 cases in 15 women

D Le Thi Thuoang et alAnn Rheum Dis 2005;64:273–278

Corticosteroids for HELLP syndrome in pregnancy. Cochrane Systematic Review (Woudstra M, et al.)

• Main results—• Eleven trials (550 women) compared corticosteroids with placebo or no

treatment.

• There was no difference in the risk of maternal death

• There was no difference in the risk of maternal death or severe maternal morbidity or perinatal/infant death.

• The only clear effect of treatment on individual outcomes was improved platelet count.

Cochrane Database Syst Rev. 2014; (9): CD008148.

doi:10.1002/14651858.CD008148.pub2

Renal involvement in Antiphospholipid Turrent-Carriles A, et al Renal Involvement in Antiphospholipid Syndrome. Front Immunol. 2018;9:1008. Published 2018 May 17.

• Arteriosclerosis :

• Fibrous intimal thickening with luminal reduction of arcuate and interlobular arteries

• Fibrocellular and arteriolar occlusion in small diameter interstitial arteries.

• TMA : Thrombotic Micro Angiopathy

• Preglomerular and glomerular capillaries.• Non- Vasculitis - with occlusion of vessel lumen.

• Immunoglobulins are absent

(Vascular) Renal involvement in Antiphospholipid Syndrome

Nochy D, et al. The intrarenal vascular lesions associated with primary antiphospholipid syndrome. J Am Soc Nephrol (1999) 10:507–18

Glomerular involvement in APS• Membranous glomerulonephritis is the most frequently reported glomerular disease in

APS in different series and case reports .

• Dorel M, et al.

• Idiopathic membranous glomerulonephritis associated with primary

antiphospholipid syndrome. Nephron (2000) 86:366–7.

• Case report of primary APLA 69 year old man with new onset proteinuria and

Membranous GN in biopsy.

• Quereda C et al.

• Prevalence of antiphospholipid antibodies in non SLE - nephropathies 20%. Am J

Kidney Dis (1994) 23:555–61.

• Fakhouri et al. (2003) - 29 renal biopsies of patients with primary APS – 3

cases. Am J Kidney Dis (2003) 41:1205–11 Renal involvement in Antiphospholipid Turrent-Carriles A, et al Renal Involvement in Antiphospholipid Syndrome. Front Immunol. 2018;9:1008. Published 2018 May 17.

Tektonidou MG, et al. Ann Rheum Dis 2019;0:1–9.

K. Legault el at, HaemostasisJournal of

Thrombosis and Haemostasis, 2018; 16: 1656–

1664

CAPS management- EULAR

• Early diagnosis and management of infections and minimisationor discontinuation of low-intensity anticoagulation,

• Combination therapy with glucocorticoids, heparin and plasmaexchange or IVIG is recommended over single agents as first-line treatment of patients with CAPS

• For refractory CAPS, B cell depletion (eg, rituximab) or complement inhibition (eg, eculizumab) therapies may be considered based on data from case reports.

CAPS management- McMaster

• First-line treatment : combination therapy with glucocorticoid,

heparin and plasmapheresis or IVIG over single agents

• For first-line treatment of patients with CAPS, the panel suggests not

using rituximab

Decisions

• Kidney Biopsy – not performed

• Treatment –

• Antibiotics, supportive care • Methyl-Prednisolone – pulse 1gr X3 days -> 80 mg/day

• Plasmapheresis

• Cyclophosphamide - EUROLUPUS

30/5 7/6 10/6 13/6 19/6 23/6 9/2019

1st ad 1st dis 2dn adm Op day POD 1 Ward

Hb 6.6 8 6.8 6.1 10.7 9.8

Ret:2.8% Fib:713

Plt 81 90 136 86 51 55

WBC 7.8 3.7 4.6 4.4 8.3 10.4

ANC 6.3 2.5 3.6 3.2 7.5 8

INR 1.2 1.3 1.4 1.3 1.22

Creat 0.95 1.1 1.2 1.3 2.3 0.93 0.8

AST 45 60 149 149 41 24

ALT 37 43 79 79 62 21

Bil Tot 0.4 0.5 0.7 0.7 0.6 0.3

ALKP 279 730 834 1091 153 128

LDH 541 1291 1165 870 430

Alb 3 2.6 2.9 3.6

HIT neg Xa = 0.95 Xa = 1.03

Hapto 225 <10

Pr/Cr 400* 3266 250

30/5 7/6 10/6 13/6 19/6 23/6 30/6

1st ad 1st dis 2dn adm Op day POD 1 Ward

C3 99 75 68

C4 13 9.6 11

ANA 1:160 1:160

Pattern Nu+Ho

DSDNA 13 +confirm

SSA-60 3.6 +

CRPmg/dl 9.2 14.5 4 3.1 0.17

RF <10

Coombs neg neg

Schisto Neg positive

Blood cuture

Ecoli +

Cervix GBS and Ecoli

Take Home Message

• CAPS –• Prevent and treat trigger

• Can complicate pregnancy

• Obstetrics • Help ! (HELLP) – clinical mimic

• APLA and Obstetric complication

• SLE • IV Cyclophosphamide is a reasonable choice in a variety of clinical situations

THANK YOU

Pre-eclampsia: pathogenesis, novel diagnostics and therapies.

• Phipps, E.A., Thadhani, R., Benzing, T. et al. Pre-eclampsia: pathogenesis, novel diagnostics and therapies. Nat Rev Nephrol 15, 275–289 (2019) doi:10.1038/s41581-019-0119-6

New Biomarkers forAtherothrombosis inAntiphospholipid Syndrome:Genomics and EpigeneticsApproachesChary Lopez-PedreraFront. Immunol., 16 April 2019 |

HELLP management

Catastrophic antiphospholipid syndrome. Clinical and laboratory features of 50 patients. Asherson R A, et al.

Medicine [01 May 1998, 77(3):195-207]

Infections in APLAS,

• Antiphospholipid syndrome associated with infections:clinical and microbiological characteristics of 100 patients , R Cerveraet al. 2004

Ann Rheum Dis 2004;63:1312–1317. doi: 10.1136/ard.2003.014175

Infections in APLAS, SLE, and HELLP

• Antiphospholipid syndrome associated with infections:clinical and microbiological characteristics of 100 patients , R Cervera et al. 2004

Ann Rheum Dis 2004;63:1312–1317. doi: 10.1136/ard.2003.014175

What was the proteinuria?

• HELLP\Preeclampsia ? (clinical picture → postpartum?)

• APL\CAPS renal involvement ?

• SLE flare (low complement, dsDNA positivity)

• We decided to give first CYC (Eurolupus)

ICU and post operative care

Problem List -

Post - Source Controlled Sepsis

• Advanced AKI - Labs: Cr 2.3, Urine Pro/Crea ratio – 3Grams

• Spleen and Renal Infarcts

• Microangiopathic Hemolytic Anemia - Low hapto, Shcistocytes, LDH

• Elevated Liver Enzymes

• Thrombocytopenia