DIC – Epatopatia – HIT

Lorenzo ALBERIO

Médecin chef

Hématologie générale et Hémostase

Service et Laboratoire centrale d‘Hématologie

CHUV, Lausanne

Disseminated Intravascular Coagulation

Coagulation studies

PT (Quick) 23 %

Fibrinogen 0.20 g/l

aPTT 57.8 sec

TT 59.8 sec

Reptilase no clot

Pediatr Emerg Care 2010;26:932 Legend: PT, prothrombin time; TT, thrombin time

FII:C 92 % FV:C 59 % FVII:C 47 % FX:C 111 %

D-dimers >10‘000 ng/ml

DIC : Plasmin degrades FV and FVII

FII:C 92 % FV:C 59 % FVII:C 47 % FX:C 111 %

(D-dimers)

ISTH DIC score

Clinical Underlying disorder Indispensable points + Laboratory Platelets ≤ 100 G/L 1 ≤ 50 G/l 2 Prothrombin time ≥ 3 sec prolonged 1 ≥ 6 sec prolonged 2 Fibrinogen ≤ 1 g/l 1 Fibrinolysis marker moderate increase 2 (D-dimers) strong increase 3

Thromb Haemost 2001;81:1327

< 60% < 45%

Overt DIC ≥ 5

> 1’000 ng/ml > 4’000 ng/ml

Conditions associated with DIC

Sepsis and severe infection - e.g. meningococcemia Trauma - e.g. severe head injury Organ destruction - e.g. pancreatitis, brain injury, burns Malignancy - solid tumors, promyelocytic leukaemia Obstetric complications - amniotic fluid embolism, placental abruption, pre-eclampsia Vascular abnormalities - large haemangiomata, vascular aneurysm Severe liver failure Toxic insults - snake bite, recreational drugs Immunological insults - ABO transfusion incompatibility, transplant rejection Purpura fulminans

Br J Haematol 2009;145:24

Purpura fulminans

... is characterized by hemorrhagic skin necrosis

It is usually seen in association with: 1) homozygous protein C or S deficiency (neonatal) 2) acquired protein C deficiency (meningococcemia)

What about varicella zoster virus?

Protein S deficiency in VZV

Acquired, transient (1-3 months)

auto-antibodies increasing PS clearance

How frequent? Antibodies 60% PS deficiency 20%

Purpura … rare

… develops 7-10 days after the onset of VZV-infection

J Pediatr 1995;127:355

DOAC in DIC ?

Ann Intern Med 2014;161:158

A 75-year-old man aortic dissection and thoracic aortic aneurysm, treated conservatively with a stent Chronic DIC: Platelet count 20 G/l (130-350 G/l) Fibrinogen level 0.8 g/l (1.8-3.8 g/l) D-dimers 9750 ng/ml (<500 ng/ml) Purpura Rivaroxaban 10 mg/d p.os

DOAC in DIC ?

Ann Intern Med 2014;161:158

DIC

Diagnosis ISTH score, FV&FVII << FII&FX Aetiology DIC is a symptom, not a disease Treatment Aetiologic + supportive DOAC Chronic DIC (e.g., vascular)

Monitor [drug] & efficacy !

Liver disease

Hemostasis

Circulation 2011;124:e365

von Willebrand factor (VWF) & Platelets Coagulation factors Endogenous antifibrinolytics

ADAMTS13 NO and PGI2

Endogenous anticoagulants Fibrinolysis

Cirrhosis and Coagulation

Digestion 2016;93:149

Cirrhosis and Coagulation

JTH 2011;9:1713

Coagulation factors & Platelets (Quick, aPTT, fibrinogen)

VWF & FVIII

Endogenous Thrombin Potential

JTH 2011;9:1713

Legend:

ETP, Endogenous Thrombion Potential TM, Thrombomodulin (activates protein C)

Cirrhosis and ETP

Gastroenterology 2009;137:2105

Cirrhosis and Risk of VTE

Thromb Haemost 2017;117:139

Cirrhosis with PVT : Anticoagulation D

igestion 2

016;9

3:1

49

Cirrhotic patients with

portal vein thrombosis

Cirrhosis & Anticoagulation

VKA - Baseline INR ? - Monitor factors (e.g. II and VII) - D-dimers LMWH - Acquired antithrombin (AT) deficiency ! - Monitor anti-Xa (test based on patient AT) - D-dimers DOAC - ?

Cirrhosis & DOAC

De Gottardi A et al. Liver Int 2016; Oct 25. doi: 10.1111/liv.13285.

Cirrhosis

Coagulopathy Procoagulant ! Correlates w/ Child stage FVIII & Protein C

Anticoagulation Indicated Tc >50G/l Exclude esophageal varices DOAC Possible Clinical study

Monitor [drug] & efficacy !

DD : DIC versus Liver disease

FVIII D-dimers

N/ N/

Heparin-induced thrombocytopenia

HIT : definitions and clinical presentations

HIT type I = non immune-mediated, heparin-associated HIT □ trombocytopenia develops within 4 days from start heparin □ and is transient (disappears while on heparin) □ NO thrombotic risk

HIT type II = heparin-induced, immune-mediated HIT □ HIGH thrombotic risk Typical onset: 5-14 days after start heparin Mechanism: de novo anti-PF4/heparin antibodies Rapid-onset: first 24 hours of heparin-treatment Mechanism: circulating anti-PF4/heparin antibodies Requirement: heparin exposure in the preceding 1(-3) months Delayed: 5-40 days after stop heparin Mechanism: de novo and high titre anti-PF4/heparin antibodies

HIT pathogenesis

6. Coagulation activation

1. Heparin/PF4

2. Heparin/PF4 ← IgG

3. Tc’Activation

4. - Degranulation

- Aggregation

- Procoagulant

5. Endothel

- Procoagulant

N Engl J Med 1995;332:1374

HIT is a clinico-pathologic syndrome

are both necessary for the diagnosis of HIT

Clinical clues Laboratory evidence and

4+1 T

HIT-Abs

Thrombin

Think of (h)it ! D-dimers

Clinical clues : 4T score

Thrombocytopenia >50% drop of platelet count

Time 5–10 days after start heparin

Thrombosis while on heparin

oTher causes for Tc‘penia excluded

0 – 2

0 – 2

0 – 2

0 – 2

Score 0-3 low Score 4-5 intermediate Score 6-8 high

Br J Haematol 2003;121:535

Can the 4T score predict HIT ?

Haematologica 2012;97:89

A low 4T score almost excludes HIT

A high 4T score cannot diagnose HIT

Blood 2012;120:4160

Immunoassays ELISA PaGIA-H/PF4 Chemiluminescence (AcuStar) Functional assays Platelet activation

Laboratory evidence

Can rapid immunoassays for anti-PF4/heparin antibodies predict

the results of the gold standard functional assays ?

Assessing the the ability to predict a disease

False-positive Rate (1-Specificity)

Tru

e-p

ositiv

e R

ate

(Sensitiv

ity)

A B

C

A : Test result with a 100% NPV (i.e. excludes the disease) B: Best cut-off C: Test result with a 100% PPV (i.e. predicts the disease)

Legend:

NPV, Negative Predictive Value PPV, Positive Predictive Value

Can the PaGIA predict HiPAT result ?

Haematologica 2012;97:89

A: Titer of 1 B: Titer of 4 C: Titer of 32

Legend:

A: Test result with a NPV of 100% C: Test result with a PPV of 100%

Comparison : ELISA vs. AcuStar vs. PaGIA

Work in progress

PaGIA A: Titer of 1 B: Titer of 4 C: Titer of 16 AcuStar A: 0.12 B: 0.6 C: 3.0

Legend:

A: Test result with a NPV of 100% C: Test result with a PPV of 100%

•

Rapid diagnosis of HIT:

combine clinical pre-test probability

with the magnitude of a rapid HIT-immunoassay

(AcuStar or PaGIA)

HIT treatment principles

Stop in vivo thrombin generation

A. Remove all sources of heparin

B. Avoid platelet transfusion

C. Postpone Vit. K-Antagonists nn(CAVE: coumarin necrosis)

D. Alternative anticoagulants nn(e.g. Direct IIa Inhibitors)

HIT : Alternative anticoagulants

Danaparoid(Orgaran®)

Bivalirudin (Angiox®)

Argatroban (Argatra®)

Chemistry

Action

Half-life

Excretion

Monitoring

Dose

Glycosaminoglycan Hirudin analogue Synthetic

Anti-Xa AT

Direct anti-IIa (free + bound)

Direct anti-IIa (free + bound)

24 hours ~ 20-30 min ~ 40-60 min

Renal Proteolysis/Renal Hepatic

Anti-Xa (spec.) TT/Anti-IIa (spec.) TT/Anti-IIa (spec.)

bolus 2250 U 400 U/h for 4h 300 U/h for 4h 150-200 U/h

0.06 mg/kg/h 1.0 μg/kg/min

Argatroban : starting dose

Patients with normal hepatic function

- Stable, “non-critically ill” 1.0 μg/kg/min

- Unstable, “critically-ill” (heart failure, multiple organ dysfunctions)

0.5 μg/kg/min

Patients with impaired hepatic function - bilirubin >25.5 μmol/l - ALAT >3x upper norm

- “Slightly impaired” 0.25 μg/kg/min

- “Severely impaired” contraindicated

Patients with anasarca contraindicated (accumulation in “3rd space”)

J Transl Sci 2015;1:37 Critical Care 2015;19:396

La storia di Igea

A 77-year-old woman ER: dyspnea and cough, hypoxia CT-scan: pulmonary embolism & bilateral DVT Lab: Hb 137 g/, Hct 0.40 l/l, Lc 13.1 G/l, Tc 77 G/l Treatment: ICU, LMWH Follow-up: Tc 35 G/l History: 3 weeks earlier: pain left lower leg Therapeutic nadroparine for 5 days Duplex & MRI : Backer cysts, no DVT New Dg: 4T score 7/8 (high) Anti-PF4/heparin abs: AcuStar 128 U/ml Delayed-onset HIT

La storia di Igea

Argatroban 1.0 μg/kg/min target : [argatroban] 0.4-1.0 (<1.5) μg/ml

Despite therapeutic argatroban: multiple arterial thromboembolism with critical ischemia both lower limbs and left upper limb How to proceed ?

HIT treatment principles (2)

Remove the HIT antibodies

A. Intravenous immunoglobulins

B. Plasma-exchange

Plasma-exchange

Anesth Analg 2010;110:30

A single plasmapheresis treatment only removes about two-thirds of the HIT antibodies (IgG antibodies are distributed between the extravascular and intra- vascular spaces)

J Cardiothoracic Vasc Anesth 2016;doi.org/10.1053/j.jvca.2016.07.009

La storia di Igea

Argatroban 1.0 μg/kg/min target : [argatroban] 0.4-1.0 (<1.5) μg/ml

Despite therapeutic argatroban: multiple arterial thromboembolism with critical ischemia lower limbs bilateral and left upper limb New ttt: Plasma exchange daily for 3 days “disappearance” of anti-PF4/heparin antibodies normalisation of platelet count

Embolectomy

Follow-up: Rivaroxaban increasing D-dimer, low [rivaroxaban]

Apixaban decraesing D-dimer, therapeutic [apixaban]

HIT

Pathophysiology Increased in vivo thrombin generation Diagnosis Combine clinical probability (4T) with the quantitative result of a rapid IA for anti-PF4/H abs (100% NPV/PPV) Treatment Alternative anticoagulant drugs Remove HIT-abs (PEX, IvIg) DOAC Possible Sub-acute HIT

Monitor [drug] & efficacy !

My HIT MD-students Sabine KIMMERLE (MD 2003)

Hyunju KIM (MD 2005)

Vanessa NELLEN (MD 2011)

Martina TSCHUDI (MD 2009)

Sabine SCHNEITER (MD 2008)

Lara CHILVER-STAINER (MD 2004)

Thomas HOFER (MD 2014)

Niels RITECO (MD 2015)

Matteo MARCHETTI (work in progress)

DIC – Epatopatia – HIT

Grazia! Grazie! Merci! Danke! Thank you!