W9: Thrombotic Disorders :((( Flashcards
normal haemostasis: what happens in 3 steps
- injury to BV, collagen exposed, platelet adhesion
- platelet activation, secretion & aggreg
- fibrin strands trap cells forming a stable thrombus
thrombotic pathology assoc w/ platelet plug formation
arterial thrombosis
MI, ischaemic stroke, (PAD - peripheral arterial disease)
bc atherosclerosis occurs in arteries
thrombotic pathology of coag step
venous thrombosis
DVT
bc of stasis
arterial thrombosis caused by inapprop activation of platelets - why?
atherosclerosis only in arteries (high pressure - corners, branches_
rupture of plaque exposes lipids which are thrombogenic
arterial thrombosis: S&S depend on location…
ischaemic stroke: disruption of blood supply to brain
MI: disruption of blood supply to heart muscle (coronary arteries)
(PAD - leg arteries)
signs vs symptoms
physician measures vs pt reports
symptoms of MI
Central chest pain, that may radiate to the jaw & arms, SoB, sweating, nausea/vomiting.
signs of MI
Tachycardia, low grade fever, pale clammy skin, hypo or hypertension, altered heart sounds.
diagnosis of MI
ECG, elevated troponin levels (protein released by damaged heart muscle), elevated creatine kinase levels (released by damaged heart muscle).
treatment of MI
Thrombolytic therapy, anti-platelet therapy, b-blockers, PCTA, CABG
prognosis of MI
23% ppl die before reaching hospital
5% die each year thereafter
ischaemic stroke = blockage of which arteries?
carotid/cerebral
ischaemic stroke symptoms
FAST
ischaemic stroke signs
Muscle weakness, paralysis, loss of sensation
ischaemic stroke diagnosis
Clinical (from S&S) but neuroimaging necessary to distinguish haemorrhagic vs ischaemic (CT or MRI).
ischaemic stroke treatment
Thrombolytic therapy, anti-platelet therapies, carotid endarectomy.
ischaemic stroke prognosis
Complete neurologic recovery occurs in ~10%.
Use of affected limb usually limited, & most deficits that remain after 12 months are permanent. Subsequent strokes often occur, & each tends to worsen neurologic function.
~20% pts die in the hospital; mortality rate ↑ w/ aging.
why does inapprop activation of coag in the veins (Venous thrombosis) occur?
virchow’s triad:
stasis
endothelial damage
hypercoagulability (Genetic variation- makes blood more “clotty”)
causes of venous thrombosis
Commonly occurs in the deep veins of the legs (DVT)
Often caused by immobility eg. bed rest / post-surgery, long flights / car journeys
venous thrombosis S&S
sympt: pain in leg
signs:
Tenderness, swelling, redness, heat (unilateral). Fever, general malaise, ↑ WBC & erythrocyte sedimentation rate (measure of inflammation)
Embolism of venous thrombi travel to heart but gets stuck in lungs bc vessels smaller (capillaries)
diagnosis of dvt
Ultrasound, venogram (x-ray w/ contrast dye), elevated D- dimers (by-product of fibrinolysis)
treatment of dvt
Anti-coagulation, thrombolytic therapy
prevention of dvt
Exercising the legs, wearing support stockings, prophylactic anti-coagulation (heparin)
prognosis of dvt
3% risk of fatal pulmonary embolism (PE)
what increases ur long term tisk of venous thromboembolism (VTE)?
thrombophilia - can be acq or gen
what are the 7 inherited causes of thrombophilia?
Antithrombin deficiency
Protein C deficiency
Protein S deficiency
Factor V Leiden
Prothrombin 20210A
Dysfibrinogenemia
May-Thurner Syndrome
Most inherited causes of venous thrombosis result from hypercoagulability.
Often deficiencies in the inhibitors of coag
name some inhibitors of coag
anti-thrombin III
protein C & protein S (activated by thrombomodulin)
plasminogen
anti-thrombin III
Inactivates serine proteases (e.g. thrombin)
Prod by liver
Slowly degraded by thrombin
Heparin increases ATIII activity (works 2000-4000x faster)
protein C & protein S inhibit…
FV & FVIII
plasminogen inhibits…
fibrin
actions of protein C & S
Thrombin binds thrombomodulin (TM)
Protein C (enzyme) binds thrombomodulin & is activated by proteolytic cleavage by thrombin
Protein S (cofactor) and endothelial phospholipid (PL) bind complex
APC (activated protein C) cleaves FV or FVIII (inactivating them)
anti-thrombin III def
Autosomal dominant disorder (chr 1).
1:5000
~50% develop clot in lifetime.
25-50x risk of VT.
(affects XIa, IXa, Xa & thrombin)
protein C def
Autosomal dominant/recessive disorder (chr 2) .
1:500.
10-15x risk of VT.
(affects VIIIa & Va)
protein S def
Autosomal dominant / recessive disorder (chr 3).
10x risk of VT.
Prot S levels higher in♂.
Levels drop in pregnancy, contraceptive pill and HRT.
(affects VIIIa & Va)
factor V leiden
a mutation in FV so can’t be inhibited by protein C (activated protein C resistance APCR).
Autosomal dominant disorder (chr 1).
Most common cause of thrombophilia.
80x risk of VT (homozygotes)
3-5x risk of VT (heteros).
APCR more common in pregnancy, contraceptive pill and HRT.
(affects Va)
Prothrombin G20210A allele
Autosomal dominant disorder (chr 11).
Elevated prothrombin levels.
2-3x risk of VT.
Dysfibrinogenaemia
Autosomal dominant disorder (chr 4).
Dysfunctional fibrinogen may cause
thrombosis (10%)
haemorrhage (50%)
asymp (40%).
V. Rare (~200 families)
Variable risk of VT.
may-thurner syndrome
congenital anatomic variation that predisposes to DVT in left leg.
Compression of left common iliac vein by right common iliac artery.
Causes stasis (Virchow’s triad)
11 reasons for acquired thrombophilia
Previous thrombosis
Age
Immobilisation
Surgery
Malignancy
Oral contraceptives
Hormone replacement therapy
Antiphospholipid syndrome
Essential thrombocytosis
Polycythaemia vera
Paroxysmal nocturnal haemaglobinuria
acquired thrombophilia: prev thrombosis
prev DVT is the strongest risk factor, ↑ risk by 5x.
Acquired Thrombophilia: age
less active (stasis of blood in venous system), ↓ prod of inhibitors??
Acquired Thrombophilia: immobilisation
less active (stasis of blood in venous system)
Acquired Thrombophilia: surgery
less active (stasis of blood in venous system)
Most likely in the elderly / obese.
Major abdominal operations
Major orthopaedic operations
Acquired Thrombophilia - malignancy
4x risk. Tumour cells may express TF. Occult cancer should be considered.
Acquired Thrombophilia: oral contraceptives & HRT
Oestrogen therapy:
incr plasma levels of factors II, VII, VIII, IX AND X
decr levels of anti-thrombin III
decr levels of protein S
Prot S levels higher in ♂.
Prot S levels decr in pregnancy, contraceptive pill & HRT
decr levels of tPA
Therefore, careful screening for other thrombophilic risk factors necessary before prescribing.
Acquired Thrombophilia: Antiphospholipid antibody syndrome
Autoantibodies (IgG/IgM) to phospholipid (aPL)
Found in 5% healthy popn.
18% of young stroke patients, 21% of young MI patients
In vivo associated with increased arterial AND venous thrombosis, and recurrent pregnancy loss.
In vitro causes prolonged aPTT!
Acquired Thrombophilia: Essential thrombocytosis or thrombocytheamia
A raised platelet count above normal range of 150-400 x 109/L
Can cause thrombosis (excess platelets) or bleeding (platelet function can be defective).
One of the myeloproliferative neoplasms (MPDs) (excess production of myeloid blood cells):
Essential thrombocytosis (excess platelets)
Polycythaemia vera (excess RBCs)
Chronic Myeloid Leukaemia (excess granulocytes)
Primary myelofibrosis (bone marrow replaced with connective tissue)
Acquired Thrombophilia: Polycythaemia Rubra Vera
Another myeloproliferative neoplasm
Excess production of RBCs
A raised Hct (>48% in females, >52% in males)
A raised HGB (>16.5g/dL in females, >18.5g/dL in males).
Acquired Thrombophilia: Paroxysmal Nocturnal Haemaglobinuria
Lysis of RBCs results in Hb in urine. Due to urine concentration overnight, it appears darker in morning. However, the lysis is occurring all the time.
Defect in forming GPI-anchors, so loss of GPI-anchored proteins from the surface of blood cells
Effects:
Haemolytic anaemia
Venous thrombosis at atypical sites (e.g. Hepatic portal vein)
Bone marrow failure (pancytopenia)
