Thrombosis and Disease Flashcards
What are coagulation factor deficiencies?
Deficiencies in many coagulation factors can be observed in humans, with varying effects and severity.
The most common are the haemophilias, which affect the sex-linked clotting factors; VIII and XI.
What is haemophilia A?
Factor VIII deficiency (haemophilia A) is the most common clotting factor disease, as not only is it sex linked, it is a hypermutatable gene with many points at which mutation renders the protein ineffectual. As such this affects 1 in 5,000 males. Bleed the patriarchy amiright?
What is haemophilia B?
Factor IX deficiency (haemophilia B) is rare, affecting 1 in 30,000 males.
How are haemophilias characterised?
Because haemophilia can be caused by many different mutations of varying impact, the severity of it is grouped into classes depending on the percentage of the factor made which is active.
What is classed as severe haemophilia?
What is classed as moderate haemophilia?
Patients with 1-5% active factor are classed as moderate haemophiliacs.
This retains the excessive bleeding following trauma, and can also cause joint and muscle bleeding after minor injuries in the location.
What is classed as mild haemophilia?
Patients with 5-40% active factor are classed as mild haemophiliacs. The only symptom of this tends to be increased bleeding after trauma.
It is often not noticed by the sufferer until they are injured, as this approaches normal active factor percentage minima that occurs through normal bodily variation (50%).
What are the current treatments for haemophilia?
Current treatment relies on replacement with extraneous clotting factors purified from blood plasma or produced recombinantly (which is highly expensive and has a short half-life).
This can be used as a treatment on demand, to provide relief when it is needed, or is otherwise used as a prophylaxis to prevent spontaneous bleeding.
What treatments are being developed for haemophilia?
Gene therapy trials for factor IX are currently underway. This is easier than it would be for factor VIII due to its interaction with vWF complicating things, though those trials are being planned.
The IX trials are reporting 4% expression in the high-dose group, with added protein stability gained from protein tagging.
What non-haemophilia coagulation factor deficiencies exist in humans?
Factor XI Deficiency Factor VII Deficiency Factor X Deficiency Factor XIII Deficiency Von Willebrand Disease
What is Factor XI Deficiency?
This is sometimes also called haemophilia C, but has little in common with IX or VIII deficiency as it is not sex linked, being found on chromosome 4.
As such this is a rare disease, except in Ashkenazi Jews, who make up half of all cases. Although there are many mutations which can lead to factor XI deficiency, two common inherited mutations are responsible for 90% of the cases in Ashkenazi Jews.
Less than 10% of factor XI deficiencies produce a severe phenotype. Spontaneous bleeding is therefore rare, and this disease generally manifests as extra bleeding after trauma or surgery. Treated with FFP or cyroprecipitate in emergencies.
What is Factor VII Deficiency?
This is an autosomal recessive disorder, with the gene being found on chromosome 13. It produces mild to severe phenotypes, with the severe forms clinically similar to haemophilia.
Active factor VII levels of 10% are capable of controlling most bleeding episodes, but the phenotype mysteriously often fails to correlate with this statistic, in some cases undetectable factor VII levels have no effect on bleeding.
Treatment relies on prothrombinase complex concentrate (PCC) or recombinant factor VII (again, very expensive and short half-life).
What is Factor X Deficiency?
This too is an autosomal recessive disorder found on chromosome 13, with mild-severe phenotypes similar to haemophilia. Affects 1 in 500,000.
This is treated with exogenous prothrombinase complex concentrates, fresh frozen plasma (FFP) and factor X extract.
What is Factor XIII Deficiency?
This is an autosomal recessive mutation of the gene on chromosome 6. In this disorder clots are likely to form but are quickly degraded by fibrinolysis, which can lead to severe bleeding in any tissue.
This is often treated with factor XIII concentrate or cryoprecipitate.
What is Von Willebrand Disease?
This is the most common inherited factor deficiency of all, occurring in around 1 in 100 people, but mostly with unnoticeable symptoms. The prevalence of clinically significant cases is only around 1 in 10,000. The severity of the case varies hugely depending on the type.
How is Von Willebrand Disease treated?
Treatment of VWD often utilises desmopressin (AKA DDAVP), which stimulates release of vWF from Weibel-Palade bodies, increasing the amount of it present.
It can also be treated with the same factor VIII concentrate used for haemophiliacs due to the vWF that comes in the complex.
What are the categories and symptoms of platelet disorders?
These can be grouped into three categories; thrombocytopenias, non-thrombocytopenias and storage pool deficiencies. These also lead to ineffective clotting and so extra bleeding.
Describe thrombocytopenias.
o Bernard-Soulier Syndrome
Autosomal recessive
Mutations in platelet receptors, GP1bα, GP1bβ or GPIX
o Wiskott-Aldrich Syndrome
X-linked
Platelets and T-cell lymphocytes are defective
Describe Non-thrombocytopenias.
o Glanzmann thrombasthenia
Autosomal recessive
Leads to lack of GPIIb or GPIIIa receptors, and subsequent lack of platelet aggregation
Describe Storage Pool Deficiencies.
o Hernansky-Pudlak Syndrome
Disrupts dense granule storage
o Grey Platelet Syndrome
Absence or reduced size of α-granules
