Haemostasis Flashcards
What is primary haemostasis?
- endothelial damage
- platelets adhere
- platelets aggregate
What allows platelet adhesion?
Exposed collagen and Von Willebrand factor
What allows platelets to aggregate?
Activated platelets release granules (containing ADP, thrombin and thromboxane A2) that activate coagulation and recruit other platelets
These other platelets aggregate via membrane glycoproteins
Causes of failed primary haemostasis
- problem with platelets: thrombocytopenia or reduced function
- vascular causes
- problems with VWF
What is secondary haemostasis?
a coagulation cascade involving clotting factors to strengthen the platelet clot with a fibrin mesh
How do healthy cells prevent adhesion of platelets?
they secrete nitric oxide and prostaglandins
Describe initiation of secondary haemostasis
Breakage of the endothelium exposes tissue factor which forms a complex with factor VIIa. This complex catalyses the formation of Xa and IXa and forms a small amount of thrombin. Thrombin then activates factors V and VIII.
Describe amplification of secondary haemostasis
With factors VIII and IXa now activated, they form a complex which amplifies the cascade by activating factor Xa
Describe propagation of secondary haemostasis
Factors V and Xa form a complex which activates prothrombin to thrombin. Thrombin cleaves fibrinogen into soluble fibrin monomers.
What does thrombin do other than cleave fibrin?
activate platelets
natural anticoagulants
protein C is converted to activated protein C by a thrombin-thrombomodulin complex located on the surface of endothelial cells.
Activated protein C in association with its cofactor protein S cleaves and inactivates the cofactors FV and FVIII.
The primary target of the anticoagulant protein antithrombin is thrombin, although it can also inactivate other coagulation proteases in the cascade, including FIXa, FXa, FXIa, and FXIIa.
How is fibrin broken down into FDPs?
tissue plasminogen activator (tPA) cleaves plasminogen into plasmin which breaks down fibrin
VWF is involved in primary haemostasis. So how does it cause a prolonged APTT when VWF is deficient?
VWF carries factor 8 so it causes indirect deficiency
is warfarin immediately anti-coagulant?
no initially it is pro-thrombotic due to its action on protein C and S
What effect does heparin enhance?
unfractioned: potentiates anti-thrombin
LMWH: anti-thrombin binds to factor 10
Give some vascular causes of failed primary haemostasis
age, steroids, henoch-schonlein, scurvy, inherited collagen disorders
What is henoch schonlein purpura?
an autoimmune vasculitis seen in children after a viral infection where there are IgA deposits on blood vessels
How does henoch schonlein purpura present?
rash (legs)
abdominal pain
arthritis/arthralgia
glomerulonephritis.
What causes thrombocytopenia?
reduced production when there is a bone marrow problem
increased destruction in DIC, ITP and hypersplenism (eg liver disease)
What is immune thrombocytopenic purpura (ITP)?
autoimmune condition of unknown cause that presents as a purpuric rash and increased tendency to bleed.
seen acutely in children (after virus) and chronically in adults
What factors will reduce platelet function?
drugs like aspirin and NSAIDS
renal failure
Is VwF deficiency usually acquired or inherited?
inherited
What is Von Willebrand disease?
an AD condition that results in low levels of VwF. Generally mild ie. menorrhagia, epistaxis…
Are single or multiple clotting factor deficiencies usually acquired?
single = inherited
multiple = aquired
What are the causes of multiple clotting factor deficiency?
complex coagulopathy eg DIC
liver disease
vitamin K deficiency
What is disseminated intravascular coagulation (DIC)?
Excessive and inappropriate activation of the haemostatic system when you have had massive tissue damage with loads of tissue factor produced activating clotting factors. This means thrombus form and get stuck in small vessels causing organ failure
When do you see DIC?
crush injuries RTA ABO mismatch end-organ failure in sepsis obstetric emergency malignancy hypovolaemic shop
Why does liver disease affect secondary haemostasis?
all the clotting factors are produced in the liver
Which clotting factors require vitamin K for carboxylation?
2 7 9 and 10
Give 2 sources of vitamin K
green leafy veg
gut flora
Causes of vitamin K deficiency
- poor dietary intake
- malabsorption in small intestine (eg. Crohns)
- obstructive jaundice stopping bile salts
- HDN
- warfarin therapy
What is haemophilia?
An x-linked condition characterized by problems with blood clotting due to deficiency in either coagulation factor VIII (haemophilia A which is 5x more common) or factor IX (haemophilia B).
Where does haemophilia affect?
joints (knee and ankle) and muscles (quad)
What is a target joint?
bleeding into joints means iron sitting in the joint irritates the synovium and stimulates neovascularisation. These fragile vessels are more likely to bleed again.
How would haemophilia present in a coagulation screen?
APTT would be prolonged with normal PT as it affects the intrinsic pathway.
If both APTT and PT are prolonged what is the problem?
multiple clotting factor deficiency
then check d-dimers (high in DIC, not in liver disease)
What is the problem is only the prothrombin time is abnormal?
factor 7 deficiency due to liver disease (rare to be inherited)
What is a venous thrombosis?
a fibrin-rich clot in a low pressure system that occurs due to the coagulation cascade
What is the MOA of heparin?
has an immediate effect
unfractioned: potentiates antithrombin (monitor with APTT)
LMW: affects factor Xa
What increases the risk of venous thromboses?
Virchow’s triad: stasis, hypercoagulability and vessel wall (valve)
What is the MOA of warfarin?
Vitamin K antagonist
- blocks the ability of vitamin K to carboxylate the dependent clotting factors and reducing their coagulant activity.
Name an
a) oral direct thrombin inhibitor
b) oral Xa inhibitor
a) dabigatran
b) rivaroxaban
What is an arterial thromboses?
a platelet-rich clot in a high-pressure system triggered by epithelial rupture due to atherosclerosis
What is the MOA of aspirin?
inhibits cyclo-oxygenase which is necessary to produce thromboxane A2 (platelet agonist).
What are some side-effects of aspirin?
bleeding, block prostaglandin production, GI ulceration, bronchospasm
What is the MOA of clopidogrel?
ADP receptor antagonists
What is the MOA of dypridamole?
phosphodiesterase inhibitor so reduces cAMP (activates platelets)
How long do anti-platelets need to be stopped before elective operations?
7 days prior
What is microangiopathic haemolytic anaemia (MAHA)?
a group of diseases that cause damage to small blood vessels resulting in intravascular haemolysis. red cell fragments are seen on blood film
Causes of MAHA
DIC, TTP, HELLP syndrome, APS, malignancy, cardiac valve, lupus, paroxysmal nocturnal haematuria
What is paroxysmal noctural haemoglobinuria?
an acquired disease where there is a defect on the surface of red blood cells (because one stem cell develops a mutation) and the blood cells are destroyed by the complement system
Which test differentiates immune from acquired haemolytic anaemia?
coomb’s (direct antibody)
Which NOAC is used in patients with impaired renal function?
apixaban
When do you need to monitor LMWH?
pregnancy and renal impairment
How do you monitor
a) unfractioned heparin?
b) LMWH?
c) warfarin?
a) APTT
b) anti-Xa assay
c) INR
Do NOACs need to be monitored?
no
A 17 year old woman presents to the emergency department with a 2 day history of diarrhoea. On examination, she looks unwell and has purpura. Her full blood count shows haemaglobin 9.8g/dL (normal range 12-16.0), white cell count 14.4x109/L (normal range 4-11.0), platelet 46x109/L (normal range 150-400), and her creatinine is 587umol/L (normal range 44-80). A blood film shows marked red blood cell fragmentation and polychromasia.
Haemolytic uraemic syndrome due to e. coli 0157
Warfarin treatment for a
a) patient with one DVT
b) patient with +1 DVT
should last how long? with what target?
a) 3 months, INR at 2.5
b) life-long, INR at 3.5
What happens to platelet count in DIC?
it is low
A woman is known to carry a mutation in the factor VIII gene that causes X-linked haemophilia. She has experienced haemorrhage following surgery. Why?
normal X inactivation
50% of the patients liver cells will have the mutant X chromosome as the only active one. She has, therefore reduced capacity for making factor VIII.
When can blood transfusion be given?
when Hb is less than 8
Does warfarin or heparin act on the intrinsic pathway?
heparin
lowers APTT
Will heparin or warfarin cause prolonged PT?
warfarin
