Disorders of Coagulation Flashcards
Factor levels vs phenotype for hemophilia
6-30% activity - Excessive bleeding with trauma. No spontaneous bleeds.
2-5% activity - Excessive bleeding with minor trauma. Rarely spontaneous bleeds.
<1% activity - Spontaneous bleeds, hemarthroses.
What is the threshold of factor activity to make a diagnosis of hemophilia?
<50%
Approximately how many cases of congenital hemophilia are due to de novo mutations?
~30%
Factor VII deficiency
Aka Alexander’s disease. Autosomal recessive.
Prolonged PT rather than PTT, as in hemophilia A or B
Often presents with spontaneous GI or CNS bleeds.
Factor XI deficiency
Rarely called Hemophilia C. Autosomal recessive.
Often have dental bleeding, but may also have postpartum/postsurgical hemorrhage.
Fibrinogen deficiency
Divided into afibrinoginemia (AR), hypofibrinoginemia (AD), and dysfibrinoginemia (AD)
Prolonged PT and PTT
Characterized by umbilical cord bleeding, epistaxis, but also infertility, poor wound healing, and prothrombosis.
Prothrombin deficiency
Autosomal recessive
Prolonged PT, PTT, and thrombin time
Similar sx to other hemophilias
Factor V deficiency
aka Parahemophilia. Autosomal recessive.
PT and PTT are prolonged.
Sx are widely variable – aSx to life threatening. Platelet dysfunction also seen due to dysfunction of alpha granules in platelets.
Factor X deficiency
Autosomal recessive.
Prolonged PT and PTT.
Treated with Coagadex, a recombinant Factor X replacement.
Factor XIII deficiency
Rares of all hemophilias. 95% of cases caused by deficiency in A subunit.
PT and PTT are normal.
Different phenotype: Initial clotting followed by failure of clot maturation/fibrin crosslinking. Defect in tertiary hemostasis rather than secondary.
Dx by clot solubility testing.
Factor XII deficiency
Really not clinically relevant
PTT prolonged but no clinical bleeding symptoms in the vast majority of cases.
A diagnosis of reassurance more than anything else – to explain the prolonged PTT.
Acquired hemophilias often require therapy with. . .
. . . bypassing agents or xenologous factors (often porcine)
Principal of commercially available coagulation tests
Measure viscosity or optical density over time.
Principal of commercially available factor activity assays
Clot based assays: Pt plasma mixed with known deficiency plasma. Degree of correction measured using standard PT/PTT assays. Must compare with standard curve of known deficient plasma mixed with standard plasma.
Chromogenic assays: Measured by color change as a result of factor Xa activity.
Bethesda assay
Assay for type and titer of inhibitors.
One Bethesda unit: Amount of inhibitor that will inactivate 50% of factor.
Type I inhibitor: Linear inhibition. Alloantibody against exogenous factor.
Type II inhibitor: Does not completely inhibit. Often seen in autoantibodies against self factor.
Commercially available bypassing agents for hemophilia
Activated factor VII (acute bleeding or periop management in pts with hemophilia – VERY prothrombotic, very expensive)
Activated prothrombin complex concentrate. Contains factors II, IX, X, and mainly activated factor VII.
Emicizumab
Bispecific antibody that mimics factor VIII by engaging factors IXa and X.
Great for patients with acquired inhibitors to exogenous factor VIII, since it mimics the function without being targeted by the alloantibody.
Hemophilic arthropathy
Result of repetitive hemarthroses within a joint
Similar to osteoarthritis with joint degeneration, subchondral cysts, etc. Potentially sequellae of iron deposition.
Design of gene therapies for hemophilia B
Adenoviral vector with gene under hepatic-specific promoter and infused into a liver-associated vein
