Week 3 (Clotting) Flashcards by Matt Doers

Heparin

Anticoagulant
binds antithrombin, which binds factor Xa, thus inhibits thrombin
IV only, rapid action
Can cause heparin induced thrombocytopenia (HIC)

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LMWH

enoxaparin and dalteparin
anticoagulants
same but better than heparin

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Direct thrombin inhibitors

lepirudin and bivalirudin
anticoagulants
IV only

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Factor Xa inhibitor

Fondaparinux
anticoagulant
subcu
fewer side effects than heparins

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Warfarin

anticoagulant
inhibits vitamin K (thus factors II, VII, IX, X)
metabolized by CYP2C9

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New oral anticoagulants

Dabigatran (prodrug, direct thrombin inhibitor)

Rivaroxaban (direct Xa inhibitor)

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Alteplase

thrombolytic

plasminogen activator

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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)

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Things that happen when platelets activate

Integrin activation
granule secretion (2ndary messengers, coag proteins)
cytoskeletal rearrangements

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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

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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

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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

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Fibrinolytic system

tissue plasminogen activator (tPA) frees up the plasminogen in the clot, which degrades fibrin
Also: antithrombin (heparin),, Thrombomodulin (Protein C)

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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

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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

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Thrombotic Microangiopathy

schistocytes on smear

DDX: TTP, HUS, DIC, others

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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)

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Platelet function defects

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Congenital absence of:
GPIb: Bernard Soulier syndrome (abn adhesion)
GPIIb/IIIa: Glanzman’s thrombasthenia (abn clumping)

Hemophilia

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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

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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)

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Like TTP, except NO mental status change, more renal disease, more in kids
often triggered by E coli (stool culture)

vWF Disease

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autosomal dominant
mucocutaneous bleeding, menorrhagia
Type 1: reduced levels
2: mutated protein,, 3: absent protein

HPC (stem cell) transplants

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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

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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

Week 3 (Clotting) Flashcards

(44 cards)