Thrombotic Disorders Flashcards
Tissue Factor Pathway Inhibitor
Complexes with VIIa, TF, and Xa; inactivates Xa
There is no deficiency state of this protein in humans bc it’s incompatible with life
Heparin
Activates antithrombin which inactivates thrombin, Xa, IXa, and XIa
Protein C/S
Thrombin activates Protein C which inhibits Va, VIIIa
Protein S promotes this
Plasminogen
Turns on fibrinolysis
Tissue Plasma Activator (TPA) activates plasmin (general protease, cleaves anything wtih lys residues & fibrin is rich in lysine) which cleaves fibrin
Anticoagulant protein deficiency: homozygous v. heterozygous inheritance
Heterozygous: positive family history
- Increased Venous Thrombosis
- Occasional increased arterial thrombosis
Homozygous: no family history
- Neonatal purpura fulminans: die young of fulminant thrombosis, chroinc DIC if they survive
- Fibrinogenolysis
- Chronic DIC
Activated Protein C Resistance
98% is caused by Factor V Leiden: mutation of Factor V (Arg506 to gln) makes it unable to be cleaved by Protein C
Leads to prolonged PTT
Increased risk of venous thromboembolism, higher risk if you’re homozygous
Synergistic effect if in combination with other defects: protein C, S, ATIII, plasminogen
Hypercoagulable States: Genetic
prothrombin G20210 to A
Mutation in 3’ noncoding sequence of prothrombin gene –> higher concentration of prothrombin but doesn’t impact the structure of prothrombin itself
Risk of venous thromboembolic dz, esp in pregnancy
Acquired hypercoagulable states
So many to list; think of it as the clotting verison of anemia of chronic dz
Inflammatory dz
Nephrotic syndrome
Anticardiolipin syndrome
TTP
Heparin induced thrombocytopenia
DIC
Malignancy, immobilization, OCT, prosthetic valve, PNHmyeloproliferative dz, atherosclerosis, surgery, diabetes
Why do you get hypercoagulable in inflammatory dz?
C4b binding protein increases in inflammatory dz
- binds to protein S and inactivates it –> stops inhibition of clotting
Increased IL-1 and TNF
- both downregulate thrombomodulin, which becomes procoagulant instead of anticoagulant protein at low levels
Why do you get hypercoagulable in nephrotic syndrome?
Loss of glomerular filtration & reabsorption capability leads to excretion of large amounts of protein in the urine including protein S, albumin, antithrombin III, protein C (all have similar MW)
Also this leaves behind a lot of C4B binding protein (bc it has a huge MW and doesn’t get excreted) which binds any protein S that’s left in circulation & inactivates it as an anticoagulant
This can also happen through the GI tract/stool & is called protein-losing enteropathy
What is antiphospholipid antibody syndrome?
Also called lupus anticoagulant, but not necessarily associated with lupus
Associated with: mixed thrombosis: one of the few that’s venous and arterial
Rarely associated with bleeding
Associated with recurrent spontaneous abortions
Possibly secondary to vascular damage from autoimmune dz
Diagnose by testing for antiphospholipid antibodies that interfere with clotting process in vitro but not in vivo; potentially phospholipid is merely associated with the true antigen
TTP
Rare but important; both sporadic and relapsing forms
Congenital defect and/or antibody against vWF cleaving metalloproteinase = ADAMTS-13 gene
Universally fatal without treatment but >90% survival with treatment
FATRN = symptoms: fever, anemia (MAHA), thrombocytopenia, renal insufficiency, neuro symptoms
YOU DO NOT SEE COAG ABNORMALITIES (good way to distinguish from DIC)
What is the treatment for TTP?
Plasma exchange: take out the antibody, replaces missing ADAMTS13
Corticosteroids
Rituximab, vincristine, splenectomy - for refractory cases
HIT
Heparin induced thrombocytopenia
Immunoglobulin-mediated allergic reaction to heparin/platelet factor 4 complex
Thrombocytopenia (<150,000 or 30-50% drop from bsln) 5-14 days after heparin exposure
Can have thrombotic complications but not always
Treatment: stop heparin, use a different anticoagulant
What can you use instead of heparin for anticoagulation when patient has HIT?
STOP heparin, don’t give anything like heparin including LMWH
Do not give warfarin as acute monotherapy
You can give: direct thrombin inhibitors (argatroban, bivalirudin, dabigatran, desirudin) or factor Xa inhibitor (apixaban, fondaparinux, fivaroxaban)
