haemostasis and thrombosis Flashcards
- Haemostasis literally means “to stop bleeding”.
- A — process (as opposed to pathological) whereby —- is initiated and terminated that occurs to seal a break in the vasculature (i.e. — ).
- Presented as separate processes but the whole haemostatic
mechanism is integrated and is essential to protect the — of the vasculature. - — is coagulation in a — setting that leads to localised intravascular clotting +/- blood vessel occlusion.
physiological
blood cogualtion
blood vessels
integrity
thrombosis
pathological
blood vessels:
* Intima, media and adventitia
* Intima lined by — , – layer of — cells
– Rests on membrane of — and —
* Media — muscle and —
* Adventitia — and —
* Once activated, the endothelium expresses — molecules ( — ) and — (—)
* Undisturbed endothelium express — and — (PGI2) which cause — and — platelet aggregation
endothelium
single
endothelial cells
elastin n collegen
smooth muscle n collagen
cologne n fibroblast
adhesion moleucyles aka selectins and von Willebrand factor (vWF)
nitric oxide and prostacyclin
vasodilation and inhibit platelet aggregation
the 3 main phases of haemostasis are:
vasoconstriction
platelt plug formation
blood coagulation
1- vasoconstriction:
* — damage
→ – & – release
→ – vasoconstriction
* Adrenal glands release —
→ – vasoconstriction
2- plates plug formation in primary haemostasis: ( activation –> adhesion — > aggregation. ) :
* Platelets adhere to exposed—, secrete— contents and –
* Platelet-collagen binding is mediated by – , which binds to the — receptor on platelets
* Initial platelet activation is via — which binds to — ( aka — )
* Intracellular signalling cascade:
* Release of intracellular — → activation of — → release of — (TXA2) → — + —
* Adenosine Diphosphate (ADP) released during — further — platelets
* Fibrinogen binds to platelets via —-
endothelial
endothelin n thromboaxane
local
adrenaline
systemic
collagen
secret granule content and aggregate
VWF
Gp1b
thrombin
PARs ( protease activated receptor )
calcium
phosphoilpiase A2
thromboxane A2
vascontrictn+ platelet aggregation
paletet acitvation
activates
GPIIb/IIIa
- vWF: — — with several jobs
1. Promotes — to — at site of vascular injury
2. Carrier protein of – , prevents FVIII undergoing rapid — - Made by — cells,— , and —
- Stored in:
o Platelet — granules
o – Weibel-Palade bodies
→ Released upon platelet or endothelial cell activation - Contains binding sites for — & —
- After vascular injury vWF binds to the exposed — becomes — exposing more — and binds more platelets
mutlimetric glycoprotein
platelt adhesion to sub endothelium
FVII
protleysis
endothelial cells , megakarocytes , and platelets
alpha
endothelial
collagen and platelet GP1b
exposed collagen
unwound
biding site
ii
disorders of primary haemostasis:
* —
* Platelet:
– —
– —
* —
which all can be inherited vs acquired
Vascular endothelium
Thrombocytopenia
Platelet Function Defects
von Willebrand Disease
the last phase of haemostasis is — which occurs in — haemostasis:
* i.e. Activation of the —
→ — Generation
→ End point is — Formation
* — proteolyses — to form—
* Tissue injury
→ Exposure of blood to cells expressing — → initiates – ( — pathway)
* Intrinsic pathway activated by:
– — factors (e.g. kallikrein), and
– through — feedback of Thrombin generation
( the process of blood coagulation is intiation amplification propagation and clot formation )
factors:
* Factor I = –
* Factor Ia = –
* Factor II = –
* Factor IIa = —
* Factor III = –
* — Factor Screen (IFS) = Factors VIII, IX, IX and XII
* — Factor Screen (EFS) = Extrinsic + Common Pathways = VII + (II + V + X)
blood cogaulation
2ndary
Clotting Cascade
Thrombin (Factor IIa)
Fibrin Clot
thrombin
fribongoen
to form: insoluble Fibrin monomers
tissue factor tf
coagulate via extrinsic pathway
contact
+ve
check slide 17 so important ( so basically prothorbim II becomes thrombin and then becomes fibrinogen I and then fibrin clot XIII)
* Factor I = Fibrinogen
* Factor Ia = Fibrin
* Factor II = Prothrombin
* Factor IIa = Thrombin
* Factor III = Tissue Factor
intrinsic
extrinsic
steps of blood cogautlion:
1. initiation: ( the ignition )
* Initiation – – + –
* FVIIa– — affinity bind with –
* Results in activation of –
and —
* – with its cofactor FVa
generates a small burst of – .
– Not sufficient to generate large
amounts of fibrin because FXa quickly inactivated by —
* Thrombin back-activates to – the process
2- amplification , propagation , and clot formation: ( this is thrombin mediated +ve feedback loop , accelerator )
* — burst back-activates FV, FVIII, FXI (Amplification)
→ FXIa activates — → ==
→ FIXa-FVIIIa = — Complex (—) → Tenase complex further activates – → –
→ FXa-FVa = — complex
→ Explosive generation of thrombin (–→ —)
→ Converts – (FI) to – (FIa)
→ Fibrin cross-links – to form —
→ Leading to—
* — then stabilises the —
* These reactions occur on a — bearing surface – cell membrane
* Generally on the surface of activated—
* The product of one reaction becomes the— in the next reaction
TF + factor VII
high
TF
factor X and factor IX
FXa
thrombin
TFPI
amplify
thrombin
FIX
FIXa
tenase
propagation
fx–> fxa
prothrombinase
Prothrombinase complex
fll –> flla
fribonogen —> fibrin
platelt
from platelt plug
clot formation
Factor XIII
fibrin clot
phospholipid
platelt
enzyme
- feedback inhibiton:
- TF-VIIa is inhibited by —
- Antithrombin (AT)– forms in — complexes with — and Factors —
– The anticoagulant Heparin works by — the activity of AT - Thrombin, after binding with Thrombomodulin, activates
Protein C (aPC) - Protein C, with cofactor Protein S, inactivates FV and FVIII
fibrolysis - removal of — : - Generation of sufficient amounts of fibrin is followed by binding of fibrin to — (—- )
- Activates — → – formed at site of —
- – broken down in to – (FDPs, e.g. – )
- Fibrinolysis inhibited by
— & —
TFPI (tissue factor pathway inhibitor)
active
Thrombin and Factors IX, X and XI
enhancing
activates
Protein C (aPC)
FV and FVIII
insoluble fribin
tPA ( tissue plasminogen activator )
plasminogen
plasmin
fribrin clot
fibrin
fibre degradation products as D dimer
inhibited bt : PAI-1 and alpha-2-antiplasmin
check slide 25
disorders of primary haemostasis include:
disorders of secondary haemostasis include:
disorders of coagulation and haemostasis classification:
bleeding disorders:
* Inherited
– —
– — A / B
– Other
* Acquired
– —
–—
– – Disease*
–—*
thrombotic disorders:
* Venous
– —
– –
– — Thrombosis (e.g. CVST, splanchnic vein)
* Arterial
– –
– –
– —
– Other
primary :
* Vascular endothelium
* Platelet:
– Thrombocytopenia
– Platelet Function Defects
* von Willebrand Disease
2ndary:
clotting factor deficiencies
inherited:
Inherited
– Von Willebrand Disease
– Haemophilia A / B
acquired:
– Medication-related
– Immune
– Liver Disease*
– DIC
DVT
PE
unusual site
MI
stoke
ishameic limb
- Haemophilia A is an — disorder characterised by deficiency of and is an – bleeding disorder
- Severely affected patients suffer recurrent — bleeds, typically into —
- Traditional therapies for bleeds include giving — (DDAVP) to release endogenous stores, or infusing exogenous clotting factor concentrates (usually recombinant). rFVIII can be given as —-
- Previous contamination of plasma-derived concentrates has led to
— and —infection. - Emicizumab is a bispecific antibody which mimics the function of — and can be given 2-4 weekly as —.
- Haemophilia B is characterised by deficiency of — ; inheritance and clinical features are similar to haemophilia A
- Transmission of serious — with factor – in the past.
- clinical significant of coagulation factor n haemophilia:
1- normal range : — Clotting Factor
Normal blood coagulation
2- mild haemophilia : – Clotting Factor
Bleeding problems usually
associated – extractions, – , – accident. Often not diagnosed until – in life
3- moderate haemophilia: — Clotting
Factor
Bleeding usually associated with — –knock/ deep cut. Can present like — haemophilia
4- severe haemophilia: — Clotting
Factor , Bleeding is – and often — into joints, muscles, and any site including brain.
Usually diagnosed in— of life.
x linked recessive
Factor VIII
inherited
spontaneous
joints
desmopressie
bleed prophylaxis
HIV and hepatitis C
FVIIIa
prophylaxis
IX
viral infection
factor VIII
50-150 %
5-50%
tooth , surgery , severe
2-5 %
injury
severe
>1%
frequent and spontaneous
first year
von Willebrand Factor (vWF)
* A – glycoprotein
* Chromosome –
* Produced by — and –
* In circulation it is bound to — – half-life usually —
* Half-life of Factor VIII is reduced to – when not bound to –
* Binds to exposed –
* Binds to — via — receptor
* Binds — when activated
von Willebrand disease (vWD):
* — (mostly)
* Causes secondary ↓ Factor VIII and impairs —
* Mainly bleed — (not joints)
* Treat with — (mild) / — ( severe )
* Can be defects in quantity or quality of the VWF
* Type 1 – — deficiency (Autosomal — )
* Type 2 – variety of — defects in VWF multimers
* Type 3 – virtually — VWF (mimics – , autosomal — )
* May have – APTT
large
12
megakarocyte and endothelium
factor VIII
12 hours
2 hours
vWF
collagen
platelt via GPIb receptor
thrombin
autosomal dominat
platelt function
post trauma
desmopressin
vWF concentrate
partial
dominant
qualitative
absent
haemophilia A and is recessive
prolonged
acquired bleeding disorders:
* Medication-Induced
– — (e.g. VKA, DOAC, Heparin)
– —- Agent (e.g. Aspirin, Clopidogrel)
* Acquired Haemophilia (rare)
* Acquired von Willebrand Syndrome (rare):
– — -mediated
– — (e.g. due to shear stress from tight aortic stenosis)
* Coagulopathy of – Disease*
*— *
anticoagulation
anti platelt
immune
mechanical
liver
DIC
thrombosis - classification by location:
Venous:
* —-
– Lower Limb
– Upper Limb
* —
* — Thrombophlebitis
* — Thrombosis:
– Splanchnic Veins
* Portal Vein
* Splenic Vein
* Hepatic Vein
* Mesenteric Veins
– Cerebral Vein & Sinus Thrombosis
(CVST)
– Retinal Veins
Arterial:
* —
* Ischaemic —
* Peripheral Artery —
*— Thrombosis:
– Cardiac Thrombus
– Renal Artery Infarction
– Splenic Infarction
– Mesenteric Artery Infarction
– Retinal Artery Occlusion
deep vein thrombosis
pulmonary embolism
(both of these have less common sites as: Upper Limbs, Cerebral Veins, Splanchnic Veins (Mesenteric
Veins, Hepatic Veins, Portal Vein)
superficial
unusual site
myocardial infraction
ishaemic stroke
occlusion
unusual site
VENOUS THROMBOEMBOLISM (VTE)
* VTE = – + –
* Acute venous obstruction by –
* Important causes of morbidity and mortality
DVT
* Incidence 1/1000
– 1/100 elderly
– 1/10,000 young adults
* PC: Pain, swelling, erythema
* DVT fatal in approximately 2.5-5%
of cases within 1 month of
diagnosis
PE
* Incidence 1/3000
* PC: SOB, pleuritic chest pain,
tachycardia, tachypnoea,
haemoptysis
* PE fatal in approximately 5-10% of
cases within 1 month of diagnosis
- VTE risk factors and virchows triad:
abnormal — : immobility travel prior VTE surgery and trauma
— include:
increasing age
Pregnancy and Puerperium
OCP and HRT
Cancer
Antiphospholipid Antibody
Syndrome
Myeloproliferative Disease
Trauma
Inherited Thrombophilia*
endothelial damage as : — and –
DVT + PE
thrombus
blood flow
hypercogualtion
surgery n trauma
1- inherited thrombophilia:
* Rarely tested. If done, should be under guidance of a Haematologist
* Most frequent indication is for otherwise-unprovoked — with a strong — history, particularly in 1st degree relatives
2- acquired risk factors for VTE hospitalisation:
* —-Acquired VTE is the #1 preventable cause of death in
hospitals
* 60% of all VTE occur during or within 90 days of hospitalisation
* RR of VTE x8 if hospitalised with a medical illness
* Potentially preventable
* All hospitalised patients should undergo risk assessment for VTE
and bleeding and be given thromboprophylaxis if appropriate
* Assessment should take into account: diagnosis, mobility status,
whether previous history of VTE, etc.
* Thromboprophylaxis dose should be appropriate for patient’s weight
and renal function
3- acquired risk factors for VTE cancer:
Multiple Mechanisms
* Tumour-related
– Site of cancer
* Gastric, pancreatic & brain highest
– Mass compromising venous return
– Activation of coagulation with
metastatic disease
* Treatment-Related
– Major surgery
– Central lines
– Chemotherapy
– Hormonal therapy
– Hospitalisation & immobility
Treatment Considerations
* Anticoagulate for min 6/12 or as long
as active disease / ongoing treatment
of malignancy
* LMWH 1st line, superior to Warfarin
– e.g. Tinzaparin 175iu/kg
* Recent studies have shown DOACs to
be non-inferior to LMWH at preventing
recurrent VTE
– e.g. Edoxaban, Rivaroxaban, Apixaban
– But higher bleed rates in certain
groups, e.g. GI Malignancy
– Caution re: drug interactions, chemo-
induced thrombocytopenia
4- acquired risk factors for VTE in hormone association:
Pregnancy
* Normal clotting factor levels
change during pregnancy
* Increases RR for VTE x5-8
* Risk rises during pregnancy,
peaks post-partum and normalises
after 6 weeks
* Left-sided DVT most common due
to position of uterus
* Treatment of VTE is with LMWH –
does not cross placenta
Combined OCP
* Increases RR x3
* Highest risk with highest rate of
synthetic oestrogen
* Typically occurs in first 4 months
of COCP use
* No increased risk with
progesterone-only forms of
contraception (e.g. POP,
Implanon, Mirena coil)
* HRT oral oestrogen increases RR
x2 (but transdermal oestrogen ok)
* Tamoxifen
Other
venous thrombosis
family history
hospital
5- acquired risk factors for VTE in antiphisphilpid antibody syndrome APS:
* aka — syndrome
* Can overlap with –
* Warfarin superior to DOACs in treating thrombosis in APS
* Need Clinical AND Laboratory Criteria to make a diagnosis
Clinical Criteria
* Thrombosis or Pregnancy-related
morbidity
* Thrombosis – either arterial or
venous
* Pregnancy related morbidity
– recurrent miscarriage (3
consecutive first trimester), or
– fetal loss in 2nd or 3rd trimester, or
– premature birth because of pre-
eclampsia
Lab Criteria
* ≥1 positive lab test on 2 separate
occasions at least 12 weeks apart
* Tests show the presence of
antibodies to phospholipid binding
proteins
1. Lupus anticoagulant – clue is
prolonged APTT
2. Anticardiolipin antibodies
3. Anti-Beta-2 glycoprotein 1
antibodies
6- acquired risk factor for vte others:
Surgery
* 1 in 3 VTE-related deaths occur
following surgery
* RR x2-3 if surgery in a patient with
cancer
* Strong evidence for prolonged
thromboprophylaxis after elective
hip or knee replacement surgery
Travel
* Relates to duration, reduced
mobility and poor venous return
* Long haul flight >4 hours
Myeloproliferative disorders
* e.g. Polycythaemia vera,
essential thrombocytosis
* Raised Hb, Plts
Paroxysmal Nocturnal
Haemoglobinuria (PNH)
highes
SLE
VTE diagnosis :
Clinical Suspicion DVT or PE?
* History and examination
* Consider — test
– in combination with a clinical risk prediction model
– e.g. — Criteria for DVT or PE
* ultrasound of lower limb veins
* CT Pulmonary Angiogram (CT-PA)
– or Ventilation Perfusion (V/Q) scan
the wells score criteria :
- most risk factor is the sign of dvt as swelling
>6 – probability
2-6 –
<2 – probability
d dimer
wells
high
medium
low
1- post thrombotic syndrom PTS:
* Persistent swollen, painful leg post DVT
* 30-50% of DVT cases
* No evidence that routine wearing compression stockings after DVT
reduces rate of PTS (but may be helpful in individual cases)
* Recent study of — thrombolysis in above knee DVT
also failed to show a significant reduction in PTS
2- management of VTE:
* —- is mainstay of treatment
– — are now first line anticoagulant in most cases
* Apixaban / Rivaroxaban / Edoxaban / Dabigatran
– Patients often commence LMWH initially
– Warfarin is first line in some situations (e.g. APS, recurrent VTE despite
DOAC, patient preference)
* Duration of anticoagulation
– Minimum —
– Consider — duration if deemed unprovoked, particularly in men,
or in the presence of a persistent major provoking factor
* Address provoking factors if identified
3- management of VTE life threating PE:
* PE can be life-threatening (<5% of cases)
* Considered a high risk PE if features of —- instability
present
– Persistent hypotension
– Obstructive shock
– Cardiac arrest
* Consider — as improves outcomes
– e.g. with recombinant tPA (Alteplase)
* No benefit with thrombolysis in less severe cases as bleeding complications outweigh benefits
catheter direct
anticoagulation
DOACS
3-6 months
haemodynamic
systemic thrombolysis
disseminated intravasiclar coagulation DIC:
* Inappropriate, excessive activation of — system
* Consumption of— &— factors
* Not in itself a disease but a manifestation of another disorder
* Presentation
– an — disorder, or
– an —, —- disorder
* Caused by— volume of thromboplastins into the blood stream
– Gram negative septicaemia / hemorrhagic virus
– — malignancy e.g. Acute Promyelocytic Leukaemia (APML)
– Massive trauma
– Obstetric causes (e.g. amniotic fluid embolism)
– Incompatible blood transfusion
– Snake venom
primary events in DIC:
underlying disorder —> — activation of coagulation which will either be widespread —- and — deposition leading to — or consumption of — and — leading to —
haemostat
planet n clotting
presentation:
– an acute hemorrhagic disorder, or
– an indolent, subacute thrombotic disorder
high
disseminated
systemic
intravascular
firbin
thrombosis
plalet and clotting factors
bleeding
disseminated intravascular cogautlion DIC:
* Pathogenesis is due to simultaneous dysregulation of several —
mechanisms:
1. Excessive activation of — :
* Increased — synthesis
* Sustained — generation
2. Downregulation of — pathways:
* e.g. Consumption of — &—
3. Dysregulation of — :
* — Plasminogen Activator Inhibitor Type 1 (PAI-1)
* — tPA & urokinase
* Which inhibits — & contributes to the net procoagulant state
* Management:
– Treat the underlying cause
* e.g. Sepsis → Antibiotics / APML → ATRA + chemotherapy
– Consider blood products if active bleeding / invasive procedure required
– May require anticoagulation
homeostatic
coagulation
tissue factor
thrombin
physiological anticoagulant
antirhobmin n protein c
fibronlysis
elevated
downregualting
inhibits fibrolysis
