11 - Understanding Coagulation Disorders Through Case Vignettes - Bérangère Joly - Paris, France

Monday, January 6th 2020
Blood diseases in the ICU (BDI) training course
Understanding coagulation disorders

through case vignettes
Dr Bérangère JOLY
Laboratory of hematology, national Laboratory for ADAMTS13, Lariboisière hospital
EA3518, Institut de Recherche Saint-Louis, Saint-Louis hospital
AP-HP.Nord, Université de Paris
French Reference Center for Thrombotic Microangiopathies
INTRODUCTION
Physiological hemostasis
Vascular injury
Constriction of blood vessel
bleeding thrombosis
Primary hemostasis Coagulation
Platelet plug Fibrin clot
HEMOSTASIS
Mechanism that leads to cessation of bleeding
Platelet- and fibrin-rich clot
from a blood vessel
Process that involves several interlinked steps
- formation of a plug that closes up the Fibrinolysis
damage site of the blood vessel
- control of the bleeding Vessel repermeabilization
CASE 1
Case 1
• A 20-year-old female • Biological investigations
 ER: epistaxis, gingival bleeding, unexplained
fatigue, shortness of breath Parameters Values
WBC 8.5 x109 /L
• Past history: easy and spontaneous bruising, RBC 4.5 x1012 /L
severe epistaxis, heavy menstrual bleedings Hemoglobin 8.0 g/dL
Hematocrit 30.0%
• Past surgical history: excessive bleeding with
tooth extraction MCV 66 fL
Platelets 250 x109 /L
• Familial history: none
PT 90% [70-100]
• Medication: none APTT (P/Ctl) 32/31 sec (r: 1.03) [r <1.20]
• Physical exam: Fibrinogen 3.60 g/L [2-4]
• BP: 106/55 mmHg Ferritin <10 μg/L
• Pulse: 100/min
• Temp: 37.2°C
• Hemorrhagic syndrome: epistaxis, gingival
bleeding
Case 1
• Interpretation of clinical / biological investigations

• Additional investigations?
• Diagnosis suspected?
• Pathophysiology of the disease?
• Treatments?
Case 1

• Treatments?
 Bleeding diathesis
 Iron-deficiency anemia
 Normal platelet count
 Normal coagulation global assays
Coagulation
Procoagulant coagulation factors
Factor XII Contact

Tissue
Tissue factor Factor XI factor
factor
pathway Factor VII Factor IX pathway
Factor VIII
Factor V
Factor X
Prothrombin (Factor II)
Thrombin (FIIa)
Fibrinogen (Factor I)
Fibrin (FIa)
Limits of global assays
Prothrombin time (PT), activated partial thromboplastin time (aPTT)
Citrated plasma
PT Activator aPTT
Reagents: Thromboplastin & Ca++
TF - FVII
FXII - FXI Citrated plasma
Reagents: Cephalin & Ca++
FVIII - FIX
FII - FX - FV FII - FX - FV
Thrombin Thrombin
Fibrin Fibrin
• In case of bleeding diathesis, normal coagulation global assays (PT, aPTT, platelet count …) do not exclude the
diagnosis of a bleeding disorder.
 Minor deficiencies of FVIII and IX, VWF, thrombopathies: specific laboratory investigations are needed.
Primary hemostasis
Platelet
Platelet
GPIIb/IIIa Platelet
aggregation fibrinogen
VWF
Platelet
Vascular injury
GPIb
Platelet
VWF
adhesion
Endothelial cells
Subendothelial matrix
Primary hemostasis
Main steps - platelets
Platelet adhesion
Platelet activation bleeding thrombosis
Platelet secretion ± sufficient

(vessel diameter)
Platelet aggregation Platelet plug Vessel, platelets, fibrinogen,

VWF-ADAMTS13
Primary hemostasis
VWF
- Circulating multimeric glycoprotein, produced by platelets and endothelial cells

- Several ligands: binding sites for both platelet glycoprotein receptors and collagen
- VWF supports platelet adhesion and aggregation at sites of vascular injury.
- The adhesive activity of VWF depends on the size of its multimers (from 500 to
>10 000 kDa)
- HMWM (5000–10 000 kDa) are the most effective in supporting interaction with
collagen and platelet receptors and in facilitating wound healing under conditions
of shear stress
- Key role in both platelet adhesion and aggregation, and coagulation
Furine ADAMTS13
S
D1 D2 D’ D3 A1 A2 A3 D4 C1 C2 C3 C4 C5 C6 CK
P
FVIII GPIb Collagen I IIb3

Collagen IV Collagen III
Sulfatides
Heparin
Zhou et al, Blood. 2012;120(2):449–58

Primary hemostasis
Diseases of primary hemostasis
• Clinical symptoms: mainly skin and mucosal bleeding (ecchymosis, purpura, epistaxis, gum bruising,
menorrhagia, delivery and post-partum hemorrhage, post-surgery or post-traumatism hemorrhage, cerebral
bleeding, digestive bleeding)
• Platelet disorders:
• thrombocytopenia
• thrombopathy (inherited/acquired)
• membrane glycoproteins: Bernard-Soulier syndrome (GpIb), Glanzmann thrombasthenia (GPIIbIIIa)
• granules: grey platelet syndrome (defect of alpha granules), storage pool disease (defect of dense
granules)
• secretion pathways
• Defect of VWF
• von Willebrand disease (different types / subtypes): abnormality of VWF (concentration, structure, function)
• acquired von Willebrand syndrome (AVWS): mainly autoantibodies to VWF
• Hypo- / dysfibrinogenemia
Case 1
 ER: epistaxis, gingival bleeding, unexplained
fatigue, shortness of breath Parameters Values
WBC 8.5 x109 /L
• Past history: easy and spontaneous bruising, RBC 4.5 x1012 /L
severe epistaxis, heavy menstrual bleedings Hemoglobin 8.0 g/dL
Hematocrit 30.0%
• Past surgical history: excessive bleeding with
tooth extraction MCV 66 fL
PT 90% [70-100]
• Medication: none APTT (P/Ctl) 32/31 sec (r: 1.03) [r <1.20]
• Physical exam: Fibrinogen 3.60 g/L [2-4]
• BP: 106/55 mmHg Factor VIII 75% [50-150]
• Pulse: 100/min VWF:Ag 70% [50-150]
VWF/RCo 68% [50-150]
• Temp: 37.2°C
(activity)
• Hemorrhagic syndrome: epistaxis, gingival
bleeding Ferritin <10 μg/L
Case 1

• Treatments?
 mucocutaneous hemorrhage  primary hemostasis: platelets, VWF, fibrinogen
 Normal platelet count
 Normal coagulation global assays do not exclude the diagnosis of a bleeding disorder
 Normal VWF investigations
Case 1

• Treatments?
 Specific laboratory investigations needed

 Platelet morphology
 Platelet aggregation in the presence of ristocetin, epinephrin, collagen, arachidonic
acid, ADP
 Flow cytometry
 Thrombopathy (Glanzmann’s thrombasthenia)

Case 1

• Treatments?
 Thrombopathy: deficiency of platelet function (platelet count may be normal), bleeding

disorder (mucocutaneous hemorrhage of varying severity)
Glanzmann thrombasthenia (rare):
- deficiency or abnormality of the platelet glycoprotein IIb and/or IIIa (fibrinogen receptor)
- normal platelet count
- defect of aggregation
Others: drug-induced (antiplatelet therapy, NSAIDs…), cardiopulmonary bypass, renal insufficiency,
(accumulation of uremic toxins), malignant paraproteinemia (multiple myeloma, Waldenstrom), alcohol, other
inherited thrombopathy.
 Treatments: platelet transfusion, preventive care, other
CASE 2
Case 2
• A 75-year-old male • Biological investigations
ICU: after colon resection in emergency
Complications: septic shock (E.coli) Parameters Values
Undergoing mechanical ventilation WBC 10.5 x109 /L
Bleedings from the surgical site, skin- Hemoglobin 8.5 g/dL
punctures sites Platelets 55 x109/L
Treatments: PT 64% [70-100]
- IV antibiotics APTT (P/Ctl) 65/35 sec (r: 1.86) [r <1.20]
- subcutaneous UFH 5000U x2/d Fibrinogen 1.20 g/L [2-4]
- continuous morphine infusion Liver-function tests Normal
• Past history: hypertension, hypercholesterolemia

• Past surgical history: none
Case 2
• A 75-year-old male • Biological investigations (H+8)
ICU: after colon resection in emergency
Complications: septic shock (E.coli) Parameters Values
Undergoing mechanical ventilation WBC 10.5 x109 /L
Bleedings from the surgical site, skin- Hemoglobin 8.5 g/dL
punctures sites Platelets 35 x109/L
Treatments: PT 50% [70-100]
- IV antibiotics APTT (P/Ctl) 72/35 sec (r: 2.06) [r <1.20]
- subcutaneous UFH 5000U x2/d Fibrinogen 0.80 g/L [2-4]
- continuous morphine infusion Liver-function tests Normal
• Past history: hypertension, hypercholesterolemia

Case 2

• Management?
Case 2

• Management?
 Thrombocytopenia, coagulation disorders*, bleedings

* very common in critically ill patients, >=1 cause(s) may be present
Causes of bleeding among patients in the ICU
1. History: rule out inherited defect or use of antithrombotic drugs.
2. Examination: Is bleeding general or local? General bleeding Local bleeding
Hunt BJ. N Engl J Med 2014;370:847-859

Case 2

• Management?
 Thrombocytopenia, coagulation disorders*, bleedings

 Blood smear (confirm thrombocytopenia, schistocytes)
 D-dimers (fibrin degradation), factors II-V (VII+X)
 4T-score +/- screening tests for HIT
Case 2

• Management?
• Septic shock: the most common cause of disseminated intravascular coagulation (early
or low-grade DIC, reduced platelet count, prolonged PT)
• Heparin induced thrombocytopenia (HIT)

Thrombocytopenia
Differential diagnosis of thrombocytopenia in the ICU?
• Is the patient taking drugs that could induce thrombocytopenia?

• Heparin (heparin-induced thrombocytopenia - HIT - with thrombosis), GpIIbIIIa inhibitors, ADP-receptor
antagonists, acute alcohol toxicity
• Does the patient have a hematinic deficiency (acute folate deficiency)
• Does the patient have any of the following:

• Disseminated intravascular coagulation
• Sepsis (HIV, DIC)
• Major blood loss and hemodilution
• Mechanical fragmentation (post-cardiopulmonary bypass, intraaortic balloon pump, renal dialysis,
extracorporeal membrane oxygenation)
• Immune-mediated disorder (ITP, APL syndrome, post-transfusion purpura)
• TMA (DIC, TTP, HUS)
• Hypersplenism
• Pregnancy-related (HELLP, AFLP)
• Other (myelodysplasic syndrome, cancer, inherited thrombocytopenia)

Laboratory findings in various platelet and
coagulation disorders in the ICU

Disseminated intravascular coagulation (DIC)
Diagnostic Scoring System for DIC

Pathophysiology
Aminophospholipids Expression of tissue factor Proteases

(hemolysis, traumatisms) on the cell surface (snake venoms, solid tumors,
(monocytes, endothelial cells, tumoral cells) promyelocytes PML)
Prothrombinase
TF FVIIa
FX FXa
↑ thrombin generation
Pathophysiology: activation and regulation of coagulation
Activation of coagulation Regulation of coagulation
 Consumption process:  Consumption process:
- ↓ fibrinogen, FII, FV, FVII and others - ↓ inhibitors: AT, PC, PS
- ↓ platelets - ↑ TAT complexes
 Activation of fibrinolysis
• Virchow’s triad
• Vessel wall  Endothelial lesion ++
• Blood  Coagulation activation +++
• Hemodynamic  Vascular shock +
• Thrombus rich in fibrin and platelets

Pathophysiology: action of plasmin
Plasmin is the key enzyme of fibrinolysis
Fibrinolysis is a physiological process to dissolve fibrin-clots, by a proteolytic enzyme, plasmin
This process allows repermeabilisation of the vessel after repairing of the vascular injury
ACTIVATORS
(t-PA, pro-UK)
ANTIPLASMIN
PLASMINOGEN PLASMIN
(alpha-2-antiplasmin)
FIBRIN FDP/D-dimers
FIBRINOGEN FDP/soluble complexes
Heparin-induced thrombocytopenia (HIT)
HIT type 2
• Mechanism: antibodies to complex of PF4 and heparin

• Timing: 5-10 days, but within one day if prior heparine exposure within 3 months
• Platelet nadir: <50% baseline
• Clinical significance +++
• Greatest risk: THROMBOSIS
• Diagnosis: 4Ts score +/- immunoassays, functional assays
• Treatment: stop heparine, start argatroban or danaparoid

Heparin-induced thrombocytopenia (HIT)
The 4Ts scoring system

4Ts category 2 points 1 point 0 points
Thrombocytopenia Platelet count fall > 50% Platelet count 30%-50% Platelet count fall < 30% or
and platelet nadir ≥ 20 or platelet nadir 10-19 platelet nadir < 10
Timing of platelet Clear onset days 5-10 Consistent with days 5-10 fall, but Platelet count ≤ 4 days
count fall or platelet fall ≤ 1 day (prior heparin not clear (eg, missing platelet without recent exposure
exposure within 30 days) counts);
onset after day 10;
or fall ≤ 1 day (prior heparin
exposure 30-100 days ago)
Thrombosis or other New thrombosis (confirmed); skin Progressive or recurrent None
sequelae necrosis; thrombosis;
acute systemic reaction non-necrotizing (erythematous)
postintravenous unfractionated skin lesions; suspected
heparin bolus thrombosis (not proven)
Other causes of None apparent Possible Definite
thrombocytopenia
The 4Ts score is the sum of the values for each of the 4 categories.
Scores of 1-3, 4-5, and 6-8 are considered to correspond to a low, intermediate, and high probability of HIT, respectively.
Case 2

• Management?
• DIC associated with minor bleeding

• HIT excluded
 Repeat the laboratory tests in 8 to 12 hours
or sooner if there is evidence of increased bleeding
 Treat the underlying disorder (infection) and provide hemodynamic support (hypovolemic
shock)
CASE 3
Case 3
• A 58-year-old male • Biological investigations
ICU: hemorrhagic syndrome Parameters Values
Jaundice, bruising, epistaxis, confused and WBC 4.5 x109 /L
lethargic RBC 3.5 x1012 /L
Hepatosplenomegaly Hemoglobin 9.6 g/dL
Alcohol Hematocrit 27.9%
Neutrophils 1.38 x109 /L
• Past history: former IV drug user, grade 2 Reticulocytes 39 x109 /L
inflammation with stage 1 fibrosis at liver biopsy PT 45% [70-100]
in 2016 APTT (P/Ctl) 47/31 sec (r: 1.52) [r <1.20]
• Past surgical history: none Fibrinogen 1.60 g/L [2-4]
• Familial history: none Clotting factors: [70-100%]
Factor II 40%
Factor V 42%
Factor VII 41%
Factor X 45%
Case 3

• Management?
Coagulation cascade
Intrinsic pathway Extrinsic pathway
XI XIa
IX IXa VIIIa VIIa-TF
X Xa Va
Ca2+
II IIa PL
I fibrin
Vitamin K-dependent factors: FII, VII, IX, X, protein C, protein S

Cofactors: FV + FVIII
Coagulation
Factor XII Contact

Tissue
factor
Factor VIII
Factor V
Factor X
Thrombin (FIIa)
Fibrinogen (Factor I)
Fibrin (FIa)
Limits of global assays
Prothrombin time (PT), activated partial thromboplastin time (aPTT)
Citrated plasma
PT Activator aPTT
Reagents: Thromboplastin & Ca++
FT - FVII
FXII - FXI Citrated plasma
Reagents: Cephalin & Ca++
FVIII - FIX
FII - FX - FV FII - FX - FV
Thrombin Thrombin
Fibrin Fibrin
• In case of bleeding diathesis, normal coagulation global assays (PT, aPTT, platelet count …) do not exclude the
diagnosis of a bleeding disorder.
 Minor deficiencies of FVIII and IX, VWF, thrombopathies: specific laboratory investigations are needed.

Laboratory findings in various platelet and
coagulation disorders in the ICU

Hemostasis in hepatic failure

Case 3

• Management?
 Pancytopenia: hemolytic anemia, thrombocytopenia, neutropenia

 Chronic liver failure
 Bleedings
 An important function of the liver: synthesis and secretion of blood coagulation factors:
- hepatocytes are involved in the synthesis of most blood coagulation factors (fibrinogen, FII,
V, VII, IX, X, XI, XII, PC, PS, AT)
- liver sinusoidal endothelial cells produce FVIII and VWF
CASE 4
Case 4
ICU: hemorrhagic syndrome
• spontaneous bruising Parameters Values
• spontaneous hematoma of the left hand WBC 6.20 x109 /L
• extensive subcutaneous ecchymoses of RBC 3.60 x1012 /L
the abdomen Hemoglobin 10.8 g/dL
Hematocrit 32.1%
• Past history: systemic sclerosis
PT 90% [70-100]
• No prior history of trauma or mucosal bleeding,
no history of smoking /alcohol /drug use APTT (P/Ctl) 89.3/35.4 sec (r: 2.52) [r <1.20]
Fibrinogen 3.60 g/L [2-4]
Case 4

• Management?
Case 4

• Management?
• Coagulation defect
• Normal platelet count
• Normal PT and thrombin time  normal common pathway
• Prolonged APTT  intrinsic pathway defect
Case 4

• Management?
• Mixing test (37°C at H0 and H2)  correction? Parameters Values

• FVIII:C, FIX:C, FXI:C, FXII:C +/- VWF FVIII:C <1%
• +/- autoantibody titer if anti-factor Ab (no APTT correction) FIX:C 82%
FXI:C 97%
FXII:C 81%
• Diagnosis suspected: acquired hemophilia A VWF:Ag 102%
• Acquired deficiency in FVIII:C (<1%) + inhibitor VWF:RCo 98%
• Normal VWF:Ag and VWF:RCo Inhibitor anti-FVIII 50 UB/mL
Case 4

• Management?

Acquired hemophilia A (AHA)
Pathophysiology and epidemiology
• Acquired hemophilia A is a rare autoimmune disorder caused by autoantibody to FVIII (IgG mainly)
• Incidence: 0.2-4 cases /million /year
• Incidence increases with age: peak incidence  30 yo (post-partum), 70-80 yo (older)
• High mortality rate (8-22%)
• The clinical phenotype does not correlate with the FVIII level or inhibitor titer
• Patients remain at risk of life-threatening bleeding
• Idiopathic (50% of cases)

• Underlying conditions (50% of cases): pregnancy, autoimmune disorders, (rheumatoid arthritis,
Sjögren syndrome, SLE), malignancy (solid tumors, leukemia, lymphoma), medications, dermatologic
conditions, infections
• Bleedings: mucosal bleedings (epistaxis, GI, genitourinary), ecchymosis, soft tissue hemorrhage
(retroperitoneal). Hemarthrosis is rare.
Baudo F et al, Blood 2012;120(1):39-46)
Borg JY et al, Haemophilia 2013;19:564-570
Acquired hemophilia A (AHA)
Treatment
Bypassing agents
1 Management of bleeding Stop the bleeding
(rFVIIa or aPCC)
Immunosuppressive therapy
2 Autoantibody removal Autoantibody removed
(cyclophosphamide, rituximab)
CASE 5
Case 5
ICU: dyspnea, sudden onset chest pains and
loss of consciousness
Parameters Values
Altered general health status, pallor,
tachycardia, BMI 22 PT 90% [70-100]
APTT (P/Ctl) 29/35.4 sec (r: 0.82 <1.20)
• Past history: one miscarriage in 2017
• No history of smoking /alcohol /drug use
• Past surgical history: one orthopedic surgical
interventions during childhood
• Treatment: combined oral contraceptives
(introduction 3 weeks ago)
• Angio-CT: pulmonary embolism

Case 5
• A 23-year-old female • Biological investigations - thrombophilia
ICU: dyspnea, sudden onset chest pains and
loss of consciousness
Parameters Values
Altered general health status, pallor,
tachycardia, BMI 22 PT 90% [70-100]
APTT (P/Ctl) 29/35.4 sec (r: 0.82 <1.20)
• Past history: one miscarriage in 2017 Antithrombin activity 30% [>80]
• No history of smoking /alcohol /drug use Protein C activity 80% [>70]
Protein S activity 70% [>55]
• Past surgical history: one orthopedic surgical
interventions during childhood
• Treatment: combined oral contraceptives
(introduction 3 weeks ago)
• Angio-CT: pulmonary embolism

Case 5

• Management?
Case 5

• Management?
• Antithrombin deficiency  characterization of AT deficiency (heparin cofactor AT assay,

progressive AT assay, AT antigen assay; SERPINC1 sequencing)
• Additional investigations:
• Genetic testing: factor V Leiden (A506G), factor II (G20210A)
• Lupus anticoagulant, anticardiolipin Ab and anti-beta2-GPI IgM and IgG
• Inherited AT deficiency
Case 5

• Management?
Case 5

• Management?
• Venous thrombosis: Virchow’s triad

• vessel wall  hypotonicity +
• blood  hypercoagulability +++
• hemodynamic  stasis +++
• Thrombus rich in erythrocytes and fibrin
• Risk factors
• acquired: elderly, pregnancy, prolonged immobilization, surgery, hormonotherapy, APLS, myeloproliferative
syndromes
• inherited: FVL Arg506Gln, FII G20210A, HTZ defect of coagulation inhibitors (AT, PC, PS)
Coagulation
Factor XII Contact

Tissue
factor
-
TFPI Factor VIII
-
Protein C
Factor V Protein S
- Factor X
Thrombin (FIIa) -
Fibrinogen (Factor I) Antithrombin

Protein C
Fibrin (FIa)
Protein S
Coagulation inhibitors
Inhibitors Target enzyme In vivo ½-life of

the inhibitor
Antithrombin (AT) Thrombin (IIa) 48 hours
Serine-protease inhibitors form complexes Factor Xa
with coagulation enzymes (stable equimolar Factor IXa
complex including the inactive enzyme) Factors XIa and XIIa
Heparin induces a 2000-3000 increase of the kinetic
reaction between thrombin and AT Heparin Cofactor II Thrombin (IIa)
Protein C system induces a proteolytic Activated Protein C FVa and FVIIIa 4-6 hours
degradation of coagulation factors Protein S (cofactor of 50 hours
PC and PS are vitamine K-dependent glycoproteins. aPC)
PS: free-form* (40%) and C4bBP (60%)
Tissue Factor Pathway Inhibitor TFPI Factor VIIa

inactivates the complex FVIIa/Tissue Factor Factor Xa
within the quaternary complex FVIIa/Fxa/TFPI
Case 5

• Management?
• Bolus UFH 5000 UI

• UFH 20000 UI IV, with close monitoring of anti-Xa activity
• UFH 50000 UI IV for 5 days
• Acenocoumarol (3 mg/day, oral VKA, life-long) + close monitoring of INR
• Medical consultation  additional investigations + family

Common antithrombotic agents
Mechanisms of action and reversibility
Agent DOAC Mechanism of
• Treatment: Site of clearance Half-life Procedure for
action immediate
reversal
Unfractionated Indirect anti-Xa and Cellular and renal 45-90 min Protamine (1mg)
heparin (UFH) anti-IIa effect, (at high doses) neutralizes 80-100 U
increase the action of UFH
AT x10,000
Low-molecular- Same as UFH but Renal 4h (variability among Protamine reverses
weight heparin mainly anti-Xa effect products) 60% of effect
(LMWH)
Vitamin K Reduction in Hepatic Varies according to IV vitamin K (1-5 mg)
antagonists functional levels of drug and prothrombin
vitamin K-dependant complex concentrate
clotting factors (25-50 U/kg)
Dabigatran Direct thrombin 80% renal 13h (11-22h) Idarucizumab
inhibiton If creatinine clearance
<30 mL/min: 22-35h
Rivaroxaban, Direct anti-Xa Hepatic and renal Rivaroxaban: 7-9h Andexanet
apixaban inhibition Apixaban: 9-14h
CASE 6
Case 6
 ER: headaches, fatigue , confusion,
ecchymoses, multiple bruises on both legs Parameters Values
 ICU WBC 12.5 x109 /L
• Past history: none RBC 2.75 x1012 /L
Hemoglobin 7.8 g/dL
Hematocrit 30.0%
• Familial history: none MCV 93 fL
• Medication: none Platelets 16 x109 /L
Schistocytes 4%
• Physical exam: Reticulocytes 7.6% (210 x109 /L)
• BP: 106/55 mmHg
PT 90% [70-100]
• Pulse: 100/min
APTT (P/Ctl) 32/31 sec (r: 1.03) [r <1.20]
• Temp: 37.2°C Fibrinogen 2.60 g/L [2-4]
• Pallor
Total bilirubin 19.2 µmol/L
• No hepatosplenomegaly LDH 1550 IU/L
• Skin midly jaundiced Haptoglobin <0.20 g/L
Case 6

• Treatments?
Case 6

• Treatments?
 TMA syndrome
 Microangiopathic hemolytic anemia
 Severe thrombocytopenia
 Organ ischemia (neurological features)
 PT, APTT, fibrinogen: N
Case 6

• Treatments?
 ADAMTS13 activity + Autoimmune investigations (direct Coombs, ANA, anti-dsDNA, …)

 Anti-ADAMTS13 IgG Renal function
Liver function
Troponin and echocardiogram
 Autoimmune TTP
Serology
β-hCG
TTP
Rare disease: annual prevalence ~10 cases/ million people

Adulthood-onset (30-40 year olds) in 90% of cases
Feminine predominance: ~2F/1M
Life-threatening thrombotic microangiopathy (TMA)
Severe functional deficiency of ADAMTS13 (activity < 10%)
Inherited (5% of all TTP cases) or acquired (95% of all TTP cases)
• Venous thrombosis: Virchow’s triad

• vessel wall  endothelial lesion +++
• blood  hyperadhesivity to platelets via UL VWF multimers +++
• hemodynamic  high shear stress enhancing the unfolding VWF +++
• Thrombus rich in VWF and platelets
• Risk and triggering factors
• Risk factors: female gender, black ethnicity, HLA-DRB1*11, obesity
• Triggering factors: conditions increasing VWF levels (inflammation, infections, pregnancy …)
TTP pathophysiology
Multimeric distribution of VWF

in a patient with acute TTP
Joly et al, Blood 2017;129(21):2836-2846

Case 6

• Treatments?
 PEX
 Steroids
 Rituximab
 Caplacizumab
Joly et al, ICM 2016

CONCLUSION
Biological investigation in hematology
3 levels of testing
• Level 1: Routine standard automated assays

• Available in all biology labs (private and hospital)
• Available 24h/24h in hospital biology labs
• Basic medical competency
• Level 2: Routine specialized automated and manual assays

• Available in some biology labs (big private labs and all university hospital labs)
• Available 5 days/7 days and 8h/24h
• Specialized medical competency
• Level 3: Highly specialized manual (rarely automated) assays

• Available only in some university hospitals
• Available 5 days/7 days and 8h/24h
• Expert medical competency
• Specialized medical competency

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Monday, January 6th 2020

Blood diseases in the ICU (BDI) training course

Understanding coagulation disorders

Platelet plug Fibrin clot

• Interpretation of clinical / biological investigations

• Interpretation of clinical / biological investigations

Factor XII Contact

Prothrombin (Factor II)

Platelet activation bleeding thrombosis

Platelet secretion ± sufficient

Platelet aggregation Platelet plug Vessel, platelets, fibrinogen,

- Circulating multimeric glycoprotein, produced by platelets and endothelial cells

FVIII GPIb Collagen I IIb3

Zhou et al, Blood. 2012;120(2):449–58

• Interpretation of clinical / biological investigations

• Interpretation of clinical / biological investigations

 Specific laboratory investigations needed

 Thrombopathy (Glanzmann’s thrombasthenia)

• Interpretation of clinical / biological investigations

 Thrombopathy: deficiency of platelet function (platelet count may be normal), bleeding

• Past history: hypertension, hypercholesterolemia

• Past history: hypertension, hypercholesterolemia

• Interpretation of clinical / biological investigations

• Interpretation of clinical / biological investigations

 Thrombocytopenia, coagulation disorders*, bleedings

2. Examination: Is bleeding general or local? General bleeding Local bleeding

Hunt BJ. N Engl J Med 2014;370:847-859

• Interpretation of clinical / biological investigations

 Thrombocytopenia, coagulation disorders*, bleedings

• Interpretation of clinical / biological investigations

• Heparin induced thrombocytopenia (HIT)

• Is the patient taking drugs that could induce thrombocytopenia?

• Does the patient have a hematinic deficiency (acute folate deficiency)

• Does the patient have any of the following:

2. Examination: Is bleeding general or local? General bleeding Local bleeding

Hunt BJ. N Engl J Med 2014;370:847-859

Hunt BJ. N Engl J Med 2014;370:847-859

Hunt BJ. N Engl J Med 2014;370:847-859

Aminophospholipids Expression of tissue factor Proteases

• Thrombus rich in fibrin and platelets

• Mechanism: antibodies to complex of PF4 and heparin

• Diagnosis: 4Ts score +/- immunoassays, functional assays

• Treatment: stop heparine, start argatroban or danaparoid

The 4Ts scoring system

• Interpretation of clinical / biological investigations

• DIC associated with minor bleeding

• Interpretation of clinical / biological investigations

Intrinsic pathway Extrinsic pathway

IX IXa VIIIa VIIa-TF

Vitamin K-dependent factors: FII, VII, IX, X, protein C, protein S

Factor XII Contact

Prothrombin (Factor II)

2. Examination: Is bleeding general or local? General bleeding Local bleeding

Hunt BJ. N Engl J Med 2014;370:847-859

Hunt BJ. N Engl J Med 2014;370:847-859

Hunt BJ. N Engl J Med 2014;370:847-859

• Interpretation of clinical / biological investigations

 Pancytopenia: hemolytic anemia, thrombocytopenia, neutropenia

• Interpretation of clinical / biological investigations

• Interpretation of clinical / biological investigations

• Interpretation of clinical / biological investigations

• Mixing test (37°C at H0 and H2)  correction? Parameters Values

• Interpretation of clinical / biological investigations