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Thyroid dysfunction :effects on coagulation and fibrinolysis
Cedric Hermans, MD, MRCP(UK), PhDCedric Hermans, MD, MRCP(UK), PhD
Haemostasis and Thrombosis UnitHaemostasis and Thrombosis UnitDivision of HaematologyDivision of Haematology
Cliniques universitaires SaintCliniques universitaires Saint--LucLuc1200 Brussels 1200 Brussels -- BELGIUMBELGIUM
EE--mail : [email protected] : [email protected] : 02Tel : 02--764764--17851785
Clinical case : 23Clinical case : 23--yearyear--old womanold woman
•• EpistaxisEpistaxis•• MenorrhagiaMenorrhagia•• Bleeding postBleeding post--dental extractiondental extraction
•• APTTAPTT : 4: 422 secsec (24(24--34 sec)34 sec)•• Prothrombin time, thrombin time and fibrinogen : normal valuesProthrombin time, thrombin time and fibrinogen : normal values
•• Bleeding time : prolongedBleeding time : prolonged•• PFAPFA--100 (Platelet function analyzer) : prolonged100 (Platelet function analyzer) : prolonged•• Von Willebrand Factor level : 35 % (50Von Willebrand Factor level : 35 % (50--150 %)150 %)•• FVIIIc : 45 % (50FVIIIc : 45 % (50--150 %)150 %)
Clinical case : 23Clinical case : 23--yearyear--old womanold woman
•• Full blood count : normalFull blood count : normal•• TSH : increasedTSH : increased•• T4 : reducedT4 : reduced•• Antithyroïd antibodies : +Antithyroïd antibodies : +
•• Initiation of replacement therapy with LInitiation of replacement therapy with L--T4T4
•• Correction of APTT, PFACorrection of APTT, PFA--100, FVIII and VWF100, FVIII and VWF•• Resolution of bleeding symptomsResolution of bleeding symptoms
Acquired von willebrand disease secondary to hypothyroïdism
Is there an association between hypothyroïdismand bleeding tendency ?
Basic principles of clot formationBasic principles of clot formation
Endothelium
AdhesionRelease
Aggregation
TXA2 ADP
Primary Haemostasis
Platelets aggregates
CLOT
X XaProthrombine
ThrombineFibrinogen
FibrinTF/FVIIa
Blood coagulation
Fibrin clot+
TF = Tissue Factor
Vascular injury
Primary Haemostasis
- Vasoconstriction (immediate)
- Platelet adhesion (seconds)
- Platelet agregation (minutes)
Secondary Haemostasis
- Activation of coagulation factors
- Fibrin formation(minutes)
Fibrinolysis
- Activation of fibrinolysis (minutes)
- Clot lysis (hours)
Physiology of Physiology of haemostasishaemostasis
Primary Primary haemostasishaemostasis
Inactive platelets
Aggregation
Active platelets
AdhesionActivationEndothelial cells
vWF Collagen
Platelets
Collagen
FVIIIc
2. Platelet adhesion
1. Factor VIII binding
Endothelium
Platelets
Platelets 3. Platelets aggregation
Von Von Willebrand Willebrand FactorFactor
A1A3
C2
A2A1
C1
FVIII
von Willebrand factor
FVIII FVIII –– von willebrand factor complexvon willebrand factor complex
Endothelium
FVIII = vWF
Thrombin
Fibrinogen Fibrin
Coagulation cascade
Fibrin Clot
XII Coagulation cascadeIntrinsic
ExtrinsicXI
IX
VIII VII
X
V
II
Fg
Tissue Factor
Revised model of the coagulation cascadeRevised model of the coagulation cascade
Tissue Factor (TF)
Factor VIIa
II
Thrombin (IIa)
(Co) FactorsX,IX,V,VIII,XI
TF ThrombinFVaFXaFVIIa
FibrinogenFibrinogen
Thrombus
Platelets
Fibrin, von Willebrand factor
Blood clotBlood clot
Fibrinolysis
Physiological clearance of fibrin clots
FibrinolysisFibrinolysis
Plasmin
t-PA
PG
PG
PL
t-PA
Plasmin
t-PA
PG
t-PAPG
PL
Plasminogen
Fibrin
FDPs
Plasminogen
FibrinFibrin
Coagulation versus FibrinolysisCoagulation versus Fibrinolysis
Coagulation Coagulation cascadecascade
ThrombinThrombin
Fibrinogen Fibrin
FibrinolysisFibrinolysis
PlasminPlasmin
Fibrin FDPs
Clot formation Clot dissolution
Vascular injury
Primary Haemostasis
- Platelet count
- Platelet function- Bleeding time- PFA-100- Platelet aggregation studies
- Von Willebrand factor levels
Secondary Haemostasis (coagulation cascade)
- APTT
- Prothrombin Time
- Fibrinogen level
- Thrombin Time
Fibrinolysis
- Euglobulin Lysis Time
- D-Dimers
- RoTEM
Evaluation of Evaluation of haemostasishaemostasis
Bleeding time in vivo
Normal value< 8 minutes
Before
ouverture∅ 150 µm
cupule
filtre+
Epinéphrineou ADP
membrane
800 µlde sang
capillaire∅ 200 µm
After
thrombusplaquettaire
Bleeding time in vitroClosure Time
PFA-100 (Platelet Function Analyzer 100)
Cedric Hermans - UCL
T-15 sec T- 45 sec
T-90 sec T- 110 sec
« Temps de saignement in vitro »
Closure time (PFA-100)
Cedric Hermans - UCL
Platelet aggregation studies
Light tranmission 0%
PRP
Addition of aggregation inducer :ADP, arachidonic acid….
Platelets aggregation
PRP = platelet rich plasma
Agreggometry37°C, agitation
% TL
Temps en minutes
0%
100%
Reversible aggregation
Irreversible aggregation
100%Lighttransmission
ThrombinTime
Fibrin Clot
XIICoagulation cascade
Intrinsic
ExtrinsicXI
IX
VIII VII
X
V
II
I
Tissue Factor
Cedric Hermans - UCL
PTT / INRaPTTTCA
APTT = activated partial
thromboplastin time
Thyroid dysfunction and coagulationThyroid dysfunction and coagulation
HypothyroïdismHypothyroïdism
Bleeding tendency
HyperthyroïdismHyperthyroïdism
Hypercoagulability
Thyroïd dysfunction and Thyroïd dysfunction and effects on coagulation effects on coagulation
and fibrinolysis : a and fibrinolysis : a systematic reviewsystematic review
J Clin Endocrinol Metab, J Clin Endocrinol Metab, 20072007
Thyroïd dysfunction and effects on coagulation and fibrinolysis Thyroïd dysfunction and effects on coagulation and fibrinolysis : a systematic review: a systematic reviewJ Clin Endocrinol Metab, 2007J Clin Endocrinol Metab, 2007
Overall coagulation and fibrinolytic changes in medium quality studies
Impact of hypothyroïdism severity Impact of hypothyroïdism severity on coagulation disturbanceson coagulation disturbances
ModerateModerateHypothyroïdismHypothyroïdism
HypercoagulabilityIncreased risk of thrombosis
SevereSevereHypothyroïdismHypothyroïdism
Bleeding tendency
Reduction vWF-FVIIIIncreased fibrinolytic activity
Elevated FVIIDecreased fibrinolytic activity
Elevated homocystein
Vascular injury
Primary Haemostasis
- Thrombocytopenia
- Altered platelet function
- Decreased vWF
Secondary Haemostasis (coagulation cascade)
- Reduction FVIII,
- Reduction FVII, FIX, FX, FXII (+ reduced clearance)
Fibrinolysis
- Increased activity
- Reduced activity
Hypothyroïdism Hypothyroïdism and and coagulation disturbancescoagulation disturbances
Effect of thyroïd dysfunction on VWFEffect of thyroïd dysfunction on VWF
FVIII VWF
A1A3
C2
A2A1
C1
Endothelium
T4
VON WILLEBRAND DISEASEVON WILLEBRAND DISEASE
CongenitalCongenital
1 % general population
1/10.000 (severe forms)
Family history
Life-long bleeding history
AcquiredAcquired
Rare
Frequently auto-immune
Hypothyroïdism (found in 6.1 % patients with VWD)
No family bleeding history
Vascular injury
Primary Haemostasis
- Thrombocytopenia (metabolic>immune)
- Vasculopathy
- Increase vWF
Secondary Haemostasis (coagulation cascade)
- Increase FVIII, Fibrinogen, FIX
- Increase turnover - FII, FVII, FX
Fibrinolysis
- Impaired fibrinolysis (hypofibrinolysis)
HyperthyroïdismHyperthyroïdism and and coagulation disturbancescoagulation disturbances
Vascular injury
Primary Haemostasis
- Mucosal bleedings
- Menorrhagia
- Brusing
- Post-op bleeding
Secondary Haemostasis (coagulation cascade)
- Deep haematomas
- Post-op bleeding
Fibrinolysis
- Delayed bleeding
Bleeding symptoms associated with Bleeding symptoms associated with hypothyroïdismhypothyroïdism
Do not forget
- No family history of bleeding disorder- No life-long bleeding history
PointsSymptômes 0 1 2 3
Epistaxis Non ou insignifiant oui Méchage / cautérisation Transfusion
Peau Non ou insignifiant Pétéchies Hématomes Motif de consultation
Saignements lors de blessures mineures Non ou insignifiant Oui (1-5 épisodes /
an) Motif de consultation Chirurgie d’hémostase
Cavité orale Non ou insignifiant oui Motif de consultation Chirurgie / transfusion
Système digestif Non ou insignifiant oui Motif de consultation Chirurgie / transfusion
Extraction dentaire Non ou insignifiant oui Suture / hémostase locale Transfusion
Chirurgie Non ou insignifiant oui Ré-intervention Transfusion
Ménorragies Non ou insignifiant oui Consultation, pilule, fer
Chirurgie / transfusion
Hémorragie du post-partum Non ou insignifiant Oui (substitution en fer) Transfusion, curetage Hystérectomie
Hématomes musculaires Non ou insignifiant oui Motif de consultation Chirurgie / transfusion
Hémarthroses Non ou insignifiant oui Motif de consultation Chirurgie / transfusion
En général, si score > 3 c/o hommes et > 5 c/o femmes, bilan?
Bleeding score
Vascular injury
Primary Haemostasis
- Platelet count
- Platelet function- PFA-100- Platelet aggregation studies
- Von Willebrand factor levels (antigen-activity)
Secondary Haemostasis (coagulation cascade)
- APTT
- Prothrombin Time
- Fibrinogen level
- Thrombin Time
Fibrinolysis
- Difficult to evaluate
- ELT- RoTEM
Bleeding workBleeding work--up inup inpatients with patients with hypothyroïdismhypothyroïdism
Thryoid surgeryThryoid surgery•• The thyroïd gland is a richly vascularized organThe thyroïd gland is a richly vascularized organ
•• Patients with acquired hemostatic defects usually have a negativPatients with acquired hemostatic defects usually have a negative e personal and family bleeding historypersonal and family bleeding history
•• Up to 3 % of patients with thyroïd disease undergoing thyroïd suUp to 3 % of patients with thyroïd disease undergoing thyroïd surgery rgery have been found to have coagulation bleeding abnormalitieshave been found to have coagulation bleeding abnormalities
•• PrePre--operative coagulation screening should include : full blood counoperative coagulation screening should include : full blood count, t, APTT, PFAAPTT, PFA--100, vWF levels100, vWF levels
•• In case of VWF deficiency, treatment with DDAVP (0.3 µg/kg) and In case of VWF deficiency, treatment with DDAVP (0.3 µg/kg) and Tranexamic acid (Exacyl, 1 g 3x/day) is recommendedTranexamic acid (Exacyl, 1 g 3x/day) is recommended
Coagulation and endocrine disorders
HypercortisolismVenous thrombosis
Elevation FVIII – PAI-1
Growth hormone excessPossible mild hypercoagulable state
HyperthyroïdsmHypercoagulable state
Hyperprolactinaemia? Increased risk of thrombosis
HypothyroïdismHypocoagulable state
Acquired VWD
HypocortisolismPossible bleeding diathesis
Acute adrenal failure : suspect APS – adrenal vein thrombosis
Endocrine disorders and coagulationEndocrine disorders and coagulation
•• Hormones influence the haemostatic systemHormones influence the haemostatic system
•• Studies on the relation between the haemostatic system Studies on the relation between the haemostatic system and endocrine dysfunction have important methodological and endocrine dysfunction have important methodological limitationslimitations
•• Well designed clinical studies are necessary to assess the Well designed clinical studies are necessary to assess the clinical relevance of coagulation abnormalities in patients clinical relevance of coagulation abnormalities in patients with endocrine disorderswith endocrine disorders
When should endocrine disorder be When should endocrine disorder be suspected in patients with coagulopathysuspected in patients with coagulopathy ??
SignsSigns Endocrine disorderEndocrine disorderBleeding and decreased VWFBleeding and decreased VWF Hypothyroïdism ?Hypothyroïdism ?
Arterial thrombosisArterial thrombosis Subclinical hypothyroïdism ?Subclinical hypothyroïdism ?
Venous thrombosisVenous thrombosis Cushing disease ?Cushing disease ?Hypothyroïdism ?Hypothyroïdism ?
ConclusionsConclusions•• Various abnormalities of blood coagulation have been reported anVarious abnormalities of blood coagulation have been reported and d
are common in patients with thyroid dysfunction.are common in patients with thyroid dysfunction.
•• Patients with hypothyroPatients with hypothyroïïdism have a bleeding tendency although the dism have a bleeding tendency although the haemostatic profile depends on the severity of the disease.haemostatic profile depends on the severity of the disease.
•• Patients with hyperthyroPatients with hyperthyroïïdism are at risk of thrombodism are at risk of thrombo--embolic events.embolic events.
•• Most coagulation abnormalities are du to direct action of thyroïMost coagulation abnormalities are du to direct action of thyroïd d hormones on the synthesis/release of various haemostatic factorshormones on the synthesis/release of various haemostatic factors..
•• Correction of the levels of thyroïd hormones is accompanied by aCorrection of the levels of thyroïd hormones is accompanied by acorrection of the haemostatic balance.correction of the haemostatic balance.
ConclusionsConclusions
•• Acquired von Willebrand disease should be suspected in Acquired von Willebrand disease should be suspected in all patients with hypothyroall patients with hypothyroïïdism and bleeding symptomsdism and bleeding symptoms
•• Screening for coagulation disturbances is recommended Screening for coagulation disturbances is recommended before thyrobefore thyroïïd surgeryd surgery
