Week 3 (Clotting) Flashcards
Heparin
Anticoagulant
binds antithrombin, which binds factor Xa, thus inhibits thrombin
IV only, rapid action
Can cause heparin induced thrombocytopenia (HIC)
LMWH
enoxaparin and dalteparin
anticoagulants
same but better than heparin
Direct thrombin inhibitors
lepirudin and bivalirudin
anticoagulants
IV only
Factor Xa inhibitor
Fondaparinux
anticoagulant
subcu
fewer side effects than heparins
Warfarin
anticoagulant
inhibits vitamin K (thus factors II, VII, IX, X)
metabolized by CYP2C9
New oral anticoagulants
Dabigatran (prodrug, direct thrombin inhibitor)
Rivaroxaban (direct Xa inhibitor)
Alteplase
thrombolytic
plasminogen activator
Anti-platelet drugs
Aspirin (COX inhibitor)
Clopidogrel, Ticlopidine, Prasugrel, Ticagrelor (inhibit ADP-P2Y binding)
Dipyrimadole (inhibits adenosine deaminase and PDE, increases cAMP)
Abciximab, Eptifibatide (antibodies that prevent fibrinogen cross linking)
Things that happen when platelets activate
Integrin activation granule secretion (2ndary messengers, coag proteins) cytoskeletal rearrangements
Platelet adhesion
GPIb (braking) and GPIIb/IIIa (arrest) on the platelet adhere to collagen via vWF
this binding activates the platelet
platelets co-adhere via fibrinogen bridges -> primary platelet plug
Coagulation cascade
Extrinsic (PT): Tissue factor + VII -> common pathway
Intrinsic (PTT): XI -> IX -VIII/vWF-> common pathway
Common: X -V-> II (Thrombin)
Fibrinogen -II-> Fibrin -XIII-> cross-linked
PT and PTT
PT: extrinsic, VII and common (also vitK, warfarin, liver disease)
PTT: intrinsic, XI, IX, VIII, vWF, and common (also lupus anti-coag and heparin)
PTT also uses XII/contact factor, but is not physiologically important
1:1 mixture separates factor deficits from inhibitors
Both prolonged: X, V, II, fibrinogen, severe liver disease or vitK def, DIC, lupus
Fibrinolytic system
tissue plasminogen activator (tPA) frees up the plasminogen in the clot, which degrades fibrin
Also: antithrombin (heparin),, Thrombomodulin (Protein C)
Immune Thrombocytopenia Purpura (ITP)
auto-antibody against platelets
petechiae, bruising, epistaxis
Childhood: abrupt severe thrombocytopenia, often antecedant virus, most recover well
Adult (women 20-40yo): insidious, most do not recover well
RBC, WBC usually normal,, see large platelets on smear
Heparin Induced Thrombocytopenia
Immune disease (transient) moderate thrombocytopenia assoc with thrombotic events (venous and arterial) (paradoxical bc on heparin) labs: PF-4-Heparin elisa Tx: stop heparin, begin anti-coag
Thrombotic Microangiopathy
schistocytes on smear
DDX: TTP, HUS, DIC, others
Thrombotic Thrombocytopenic Purpura (TTP)
labs: microangiopathic hemolytic anemia and thrombocytopenia
also: organ dysfunction (renal, mental status, fever)
schistocytes on smear
ADAMTS13 deficiency (regulates vWF/platelet interactions (cleaves vWF polymer), platelet string)
Tx: plasma exchange (also maybe steroids)
Platelet function defects
Congenital absence of:
GPIb: Bernard Soulier syndrome (abn adhesion)
GPIIb/IIIa: Glanzman’s thrombasthenia (abn clumping)
Hemophilia
Deficient VIII (A) or IX (B)
X-linked
hemarthrosis, deep muscle bleeds
long PTT and normal PT (corrects on 1:1 mix)
Vit K deficiency
Factors II, VII, IX, X, Protein C,S
can be caused by liver disease, newborns, malabsorbtion, drugs
elevated PT and (less so) PTT
Hemolytic uremic syndrome (HUS)
Like TTP, except NO mental status change, more renal disease, more in kids
often triggered by E coli (stool culture)
vWF Disease
autosomal dominant
mucocutaneous bleeding, menorrhagia
Type 1: reduced levels
2: mutated protein,, 3: absent protein
HPC (stem cell) transplants
best case= identical twin, then HLA-matched sibling (in this case, all GVH is due to minor HLA mismatch,, any polymorphic factor that can generate an immune response)
Threatable things: leukemias, thalassemias, SKID, much more (NOT Hemophilia)
Nowadays try for non-myeloablative chemo bc less harmful to person, more lymphocyte specific, good for non-neoplastic things
Long term risks: short stature, hypothyroid, infxn, relapse, new cancers
Alternate sources for cells: cord blood (less GVH, less engraftment,,, Peripheral blood (more chronic GVH, better engraftment)
Physiological coag control
blood flow washes factors away
anti-thrombin (heparin): inactivates enzymes IIa and Xa
Protein C (and S) (vitK dep) degrades cofactors: V and VIII
AT, Protein C,S deficiencies
familial venous thrombosis
risks increase after puberty,, usually clots are “provoked”
Tests: functional AT, PC, PS
PT/PTT will be normal
Factor V Leiden
mild increase risk of venous thrombosis
common in caucasions
Arg506Gln
PTT fails to prolong with added protein C
Factor V is less susceptible to degradation by PC
Prothrombin gene mutation
venous thrombosis
G20210A
elevated thrombin levels
similar risks as FV-Leiden
Antiphospholipid Antibody Syndrome
venous and arterial thrombosis
pregnancy complications / fetal wasting
Labs: evidence of antiphospholipid auto-antibody (“Lupus-like” anticoagulant, anti-cardiolipin)
PT fails to correct with 1:1 mix,, does correct with added phospholipid
may have thrombocytopenia
Dissiminated Intravascular Coagulation (DIC)
widespread activation of thrombin and plasmin mechanisms
consumption of platelets, coag proteins, control proteins,, schistocytes on smear
Caused by: extrinsic clot promoting material, intravascular elaboration of procoagulants, vascular injury (sepsis)
Purpura Fulminans: meningococcal sepsis, severe Protein C deficiency in newborn
Elevated PT and PTT,, also elevated D-Dimer,, low fibrinogen and platelets
Tx: underlying condition
Warfarin-dependent skin necrosis
When warfarin is first started, inhibition of vitK leads to drop in all vitK dependent proteins, including ProC and ProS,, which paradoxically increases thrombosis risk temporarally. This can cause microthrombi and skin necrosis
Things screened for in donated blood
Syphilis, HCV, HIV, West Nile, Chagas, HBV
Things added to preserve donated blood
Citrate (anticoag)
Phosphate (maintain DPG)
Dextrose (metabolism)
Adenine (ATP production)
Direct Antiglobulin Test (DAT)
detects antibody attached to red blood cells \+ in: autoimmune hemolytic anemia drug induced hemolytic anemia hemolytic transfusion rxn hemolytic disease of newborn
Indirect Antiglobulin Test (IAT)
detects antibody in serum
red cell typing, compatibility testing
Also crossmatch
Whole blood transfusion
used for massive blood loss
can be given super rapidly
Matched ABO only
Packed red blood cell transfusion
used for symptomatic anemia in normovolemic pt O is donor, AB is recipient most commonly used Hb 6-8: transfuse if symptomatic Hb less than 6: transfuse
Fresh Frozen Plasma transfusion
contains clotting factors and coag inhibitors
opposite compatibility to RBCs (AB is donor, O is recipient)
Used for plasma protein replacement,, surgery prophylaxis
Plasma exchange in TTP
Cyroprecipitate Transfusion
Mostly to replace Fibrinogen
DIC, liver ds, etc
Platelet transfusion
ABO is less important
used in marrow failure if less than 10k
used prophylaxis for surgery if less than 50k or 100k
Transfusion related fever DDX
FNHTR hemolytic transfusion rxn bacterial contamination TRALI allergic rxn related to underlying disease
Febrile non-hemolytic transfusion rxn (FNHTR)
Antibodies in recipient to the donor WBCs
rapid onset, fever
Hemolytic Transfusion reaction
Immunologic incmpatibility
Acute: ABO error,, intravascular hemolysis
Delayed: low level, undetected antibodies,, extravascular hemolysis
fever, chills, bad,, cytokine storm
Tx: stop transfusion, supportive fluids, etc
Immune transfusion reactions
IgE mediated
usually urticaria (hives)
can be more serious sometimes
Transfusion Induced Acute Lung Injury (TRALI)
Pulmonary edema, hypoxemia, hypotension
antibody mediated, HLA antibodies from the donor
neutrophil specific antibodies
now avoided by not taking plasma from women that have been pregnant,, screened negative for HLA antibodies
