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Coagulation

11/19/12
by

Tiffany T

on 29 March 2014

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Transcript of Coagulation

Intrinsic
Extrinsic
Endothelial Injury
Hyper-
coagulability

Abnormal Blood Flow
Virchow's Triad
Thrombosis
anticoagulant
antithrombin III binds heparin-like molecule, inactivating thrombin and factors Xa and IXa
tissue factor pathway inhibitor inactivates tissue factors VIIa and Xa
thrombin binds thrombomodulin or thrombin receptor, 1) releasing PGI2, NO and adenosine diphosphatase to inhibit platelet aggregation and 2) activating protein C to mediate proteolysis of factors Va and VIIIa
procoagulant
vWF binds broken collagen and the attached platelets are held together by fibrinogen
exposure of membrane-bound tissue factor activates extrinsic coagulation sequence
Thrombosis (platelet coagulation) causes heart attacks and most strokes, and pulmonary embolism.
Aspirin - irreversible COX inhibitor that acetylates to inactivate COX
Platelets release thromboxane (TXA2) for thrombosis, and endothelia release prostacyclin (PGI2) for anticoagulation

activated platelets:
degranulate
change shape
express 3 receptor types
fibrinogen & vWF (gpIIb/IIIa)
monocytes & neutrophils (wound healing)
clotting factor complees (Va, VIIIa)
XIIa
XIa
IXa
Xa
IIa
(thrombin)
Ia
(fibrin)
Va
In artery:
MI
stroke
PAD
In veins:
deep vein thrombosis
pulmonary embolism
Vasoconstriction
reflex constriction
endothelin release from endothelium causes vasoconstriction
Primary
Hemostasis
Secondary
Hemostasis
Thrombus & Antithrombotic
Events
platelet adhesion onto vWF on collagen
shape change of platelet
platelets release granules (ADP, TXA2)
recruitment of more platelets
aggregation (hemostatic plug)
1. endothelium releases tissue factors
2. aggregated platelets express phospholipid complex
3. thrombin activation
4. fibrin polymerization
release of 1) t-PA (fibrinolysis) and 2) thrombomodulin (blocks coagulation cascade)
trapped neutrophil
trapped RBCs
polymerized fibrin
(protease)
Blood cell Turnover:
RBC - 4 months
platelets - 1 week
WBC - 6-12 hours
damage to tissue outside vessel
tissue thromboplastin = tissue factor (TF) + phospholipid
PT test
warfarin
(accelerator)
Platelet Disorders
Vitamin B12 and Folate Deficiency
Drug-induced
Thrombocytopenia
or from infections
Immune Thrombocytopenia Pupura (ITP)
Aplastic anemia
Leukemia and Cancer
Myelodysplastic Syndrome
Antibodies to Platelets
Alloantibodies
Immune Complex Deposition
chronic (adults, women under 40 yo, relapses, primary or secondary to HIV, SLE, B cell neoplasm or CLL, insidious onset) or acute (children, equal sexes, self limited, secondary to acute viral infection, rapid onset)
primary autoimmune
IgG to platelet gps (IIb-IIIa or Ib-IX); opsonins for phagocytes to destroy platelets in spleen (splenectomy helps)
spleen is congested w/ prominent germinal centers - normal sized spleen
more and larger megakaryocytes in bone marrow
abnormally large megakaryocytes in peripheral blood
do not transfuse; give glucocorticoids, IVIG/anti-D (need spleen and Rh+), splenectomy, rituximab
SLE and B cell Lymphoma
Post-transfusion, neonatal
Quinine, heparin, sulfa
HIV, infectious mononucleosis, Dengue fever
HIV-associated immune thrombocytopenia - most common hematological manifestation of HIV; impaired production (HIV-infected megakaryocytes prone to apoptosis) and increased destruction (abs against gp IIb-III complexes on platelets produced by dysregulated B cells); HIV receptors also on platelets allowing direct platelet infection
drug-induced immune thrombocytopenia
HIT usually not severe, onset in ~ 5-7 days; can cause bleeding AND thrombus (b/c platelets activated). IgG binds heparin-coated platelets (bind PF4). Platelets activated and aggregate causing thrombus formation in presence of thrombocytopenia.
stop heparin, may give direct thrombin inhibitor (argatroban) and change to warfarin if anticoagulation is necessary
alloimmune
secondary autoimmune
disseminated intravascular coagulation
thrombotic microangiopathy
mechanical injury
ineffective hematopoiesis
bone marrow replacement
bone marrow failure
nutritional
thiazides, alcohol
HIV, measles
selective impairment of platelet production
mucocutaneous bleeding (purpura, petechiae, ecchymosis)
mechanisms:
quantitative defects (thrombocytopenia)
decreased production (give platelet transfusion)
decreased survival
sequestration
dilution
qualitative defects of platelet fn
Platelet Count
automated counter (may miss large/small platelets and clumps)
peripheral smear (can see unusual shapes and sizes; more time and $)
thrombocytopenia: <100,000 platelets/ul
Bleeding Time (BT)
can screen VWD, severe fibrinogen deficiency, qualitative platelet abnormalities
determines platelet interaction w/ endothelium and may also see if there are too few platelet to form adequate clot (~ <50K)
platelet function analyzer (PFA-100) now routinely used in place of BT
Bone marrow biopsy may rule out leukemia as cause of ITP or thrombocytopenia in general
HIV/hepatitis testing
TTP: ADAMST13 antibody assay/activity
Clotting Factor Disorders
deep tissue bleeding
hematoma - localized collection of clotted blood (may occur in deep skin, organ, or open space), blanchable?
pulmonary embolus - clot breaks from deep vein in lower extremity and lodges in pulmonary artery, decreasing blood supply to lung and reducing oxygen exchange
Prothrombin Time (PT) - tests fn of extrinsic and common pathway of coagulation cascade; used to monitor warfarin therapy; INR (International Normalized Ratio) standardizes PT measurements from differing reagents
Activated Partial Thromboplastin time (aPTT) - tests fn of intrinsic and common pathway of coagulation cascade; used to monitor heparin therapy; less sensitive to common pathway than PT; elevated in Hemophilia A, (sometimes in VWD, DIC)
aPTT and PT mixing studies - mix 1:1 with normal plasma, if aPTT/PT corrects, there is factor deficiency (if not, inhibitor is present)
vWF panel (ristocetin cofactor analysis of amt and fn - agglutination means no vWF disease, vWF ag amt, factor VIII activity, vWF multimer analysis; PT, aPTT and platelet count may be normal)
DIC (disseminated intravascular coagulation)
pathogenesis: microangiopathy, widespread fibrin thrombi (clot) generation (causes infarcts and hypoxia; chronic DIC (cancer), damage to RBCs trapped in thrombus (hemolysis)), consumption of platelets and clotting factors (bleeding is acute DIC; placenta complication), and plasmin generation & fibrinolysis activation
almost always secondary to another disease process
abruptio placenta, acute promyelocytic leukemia AML3, mucin-secreting adenocarcinoma, g(-) septicemia (meningococcemia), and major trauma, severe burns, extensive surgery (release of thromboplastin)
initiated by release of tissue factor (activates extrinsic pathway) or endothelial damage (exposes collagen and activates intrinsic pathway)
involves kidneys, heart, lung, liver, CNS
bleeding > clotting
fibrin degradation products (FDP) - protein fragments from plasmin acting on fibrin or fibrinogen; more sensitive than D-dimer for determining degree of fibrinolytic activity; can be quantified and tacked in disease processes where fibrinolysis exceeds thrombosis
D-Dimer - reflects fibrinolysis of cross-linked fibrin; useful for assessing DVT
increased FDP*** and aPTT/PT, decreased Plt and coagulation factors, schistocytes
manage with fresh frozen plasma infusion to reverse active bleeding and/or cryoprecipitate, which is plasma fraction enriched for fibrinogen, FVIII and vWF (can use both in combination and mabye transfuse with blood or platelets too)
Infections
Meningococcemia and septicemia
Drug Reaction
Scurvy and Ehler Danlos Syndrome
defective collagen weakens vessel wall

treat scurvy with Vit C
Perivascular Amyloidosis
Senile Purpura
Cushing Syndrome
Henoch Schonlein Purpura (HSP)
deposition of circulating immune complexes w/i vessels throughout body (systemic vasculitis)
no treatment; just observation
children mainly
purpura, arthritis, abdominal pain
Factor VIII Deficiency
X-linked recessive mutations (may occur in females because of X inactivation)
aka hemophilia A, classic hemophilia
recurrent deep tissue bleeds
hemophilic arthropathy (chronic disability from bleeding into joint, hemoarthrosis)
infection
1/3 cases due to new mutations
extrinsic pathway intact, but fibrin deposition (fibrinogenesis) inadequate and clot removal (fibrinolysis) inadequate because high thrombin levels are needed to activate fibrinolysis inhibitor
manage with good health care maintenance (dental care, vaccination, avoid impact injuries in sports) and factor replacement therapy (treatment vs prophylaxis)
Factor IX Deficiency
Von Willebrand Disease (vWD)
Defective Production
(liver diseases and malnutrition)
Pathologic Inhibition (antibody)
Vitamin K Deficiency
Excessive Consumption of Platelets
most common hereditary coagulation disorder
vWF deficiency (needed for platelet adhesion)
mucocutaneous >>> deep tissue bleeds
Ristocetin test
ristocetin causes vWF binding to gp1b on platelets
No agglutination is abnormal -> no vWF = vWD
Types
1 (quantitative, true deficiency, low vWF Ag levels, aut. dom)
2A (qualitative, fn-al defect, normal vWF Ag levels, aut. dom)
3 (quantitative, true deficiency, very low vWF Ag levels, aut. rec)
Manage mainly by observation. If surgery/bleeding:
DDAVP (release stored vWF from endothelium)
Factor VIII replacement
platelet transfusion
Factors that depend on Vitamin K to become functional: II, VII, IX, X, proteins C & S
warfarin inhibits epoxide reductase (converts vitamin K to active form)
causes
fat malabsorption (Vit K is fat-soluble)
broad spectrum antibiotics (endogenous flora synthesize Vit K)
coumarin anticoagulants (warfarin)
liver disease (storage site)
newborn born outside hospital and didn't receive Vit K injection (hemorrhagic disease of the newborn)
Manage with Vit. K supplementation and treating underlying cause
VIIa
Factor Xa inhibitors
Thrombin inhibitors
warfarin (aka coumadin)
inhibits vitamin K epoxide reductase
blocks gamma-carboxylation of glutamate in prothrombin, VII, IX, X, protein C & S (blocking synthesis of these Vit K-dependent factors decreases prothrombin levels)
racemic mix; potency: S>>R
Na salt; 100% bioavailability
long plasma t1/2 (36 hrs)
oral (std dose 5-10 mg)
slow onset and offset
crosses placenta (NOT for pregnant) and causes hemorrhage and serious birth defects affecting bone and blood proteins
skin necrosis aka WISC in 1st week b/c venous thrombosis from less protein C activity
effect monitored via PT and INR
adjustment of PT: 1 wk
therapeutic range defined in terms of INR (recommended INR is 2-3)
reverse action by stopping drug and, if bleeding, give Vit K1 (phytonadione), fresh frozen plasma, prothrombin cplx concentrates & rFVIIa
rivaroxaban
oral
fast onset of action
liver metabolism by CYP3A4 (drug interactions)
no routine monitoring needed
antidote: Xa
antithrombin (AT or AT III)
serine protease inhibitor (serpin)
inactivates IIa, IXa, Xa
protein C
Vit K-dep. serine protease
activated by thrombin to APC
degrades cofactor Va & VIIIa
protein C deficiency may display increased thrombosis
Protein S
Vit K-dep. glycoprotein
free form is cofactor to Protein C
Endogenous Anticoagulants
VIIIa
XIIIa
blood vessel damage
collagen and platelets
PTT test
heparin
Stabilized Fibrin
Coagulation Cascade
Anticoagulants
Procoagulants
Vit K
Thrombolytic Drugs
IV for pulmonary embolism w/ hemodynamic instability, DVT, and ascending thrombophlebitis w/ severe lower extremity edema
for management of acute MI
directly degrade thrombi ('clot-busters') - not for prevention
IV (systemic vs localized)
primarily for arterial thrombi in heart or brain or venous thrombi causing pulmonary embolus
aka plasminogen activators or fibrinolytic agents

streptokinase - bacterial protein from streptococci that activates plasminogen; potential allergic reaction (no repeated use. only for first MI)
anistreplase - complex of human plasminogen and streptokinase
urokinase - human enzyme made by kidney cells that directly converts plasminogen to active plasmin
tPA
alteplase (r t-PA) - recombinant tissue plasminogen activators that preferentially activate fibrin-bound plasminogen; used in acute ischemic stroke
reteplase (r t-PA) - like alteplase, but less fibrin-specific than t-PA
tenecteplase (mu t-PA) - mutant t-PA that is more fibrin specific than t-PA; longer t1/2; IV bolus
Ideal anticoagulant is:
oral (currently, dabigatran, warfarin, rivaroxaban)
rapid onset/offset of action
wide therapeutic range
predictable therapeutic effect
no good or drug interactions
(coagulation cascade)
(fibrinolysis)
The Disorder Tree
small stimulus -> large rapid response
physical plug
limited location, extent, duration
Blood Vessel Disorders
mucocutaneous bleeding
mechanisms:
increased fragility
defect in blood vessel wall
consumption of platelet and clotting factors by endothelial damage
vasculitis
definitive diagnosis is vascular damage, usually as fibrinoid degeneration
perivascular cellular infiltration with extravasation of red cells
sometimes see granulomatous inflammation with giant cells
in Rocky Mtn Spotted Fever, rickettsial organisms invade endothelial cells of small vessels producing vasculitis responsible for petechiae
Labs
no screening studies
rule out platelet and coagulation factor disorders w/ other studies
test by suspected abnormality (blood culture/CBC, genetic tests, often clinical diagnoses or confirmed with biopsy)
Hereditary Hemorrhagic Telangectasia (HHT)
Requirements
Hemostasis
See Virchow's Triad and The Coagulation Cascade
indirect - interact with antithrombin (AT) to activate it; inactivate thrombin (IIa), IXa, Xa, XIa, XIIa
heparin
parenteral (IV, SC), do not use IM (hematoma risk), short t1/2 (1 hr), preferred for pregnant women, therapeutic levels can be determined by protamine titrations or by anti-Xa units
unfractionated (UFH) - mixture of sulfated mucopolysaccharides extracted from porcine gut or bovine lung; binds endothelial cell surface; closely monitor aPTT or by protamine titration or anti-Xa units; given as IV for treatment and subcutaneous for prevention
low molecular weight (LMWH) - (enoxaparin (mg), dalteparin (anti-Xa units), tinzaparin (anti-Xa units)) inhibit Xa (less effect on thrombin), less frequent dosing, less side effects/toxicity, no routine monitoring of aPTT; weight based dosing with predicatable response; aPTT only measured in obese, pregnant, renal insufficient (anti-Xa unit); peak therapeutic after 4 hrs; subcutaneous; 5 fold lower risk for HIT; less risk for osteporosis
toxicity - BLEEDING esp in elderly and renal failure pts, HIT (abs against heparin/PF4 complex; when UFH >7 days esp surgical pts, venous thrombosis; suspicious when low platelet count, new thrombus, thrombocytopenia). if bleeding or HIT, stop use and replace w/ direct thrombin inhibitor or fondaparinux; also, allergy (to animal products), alopecia, osteoporosis/fracture (long-term use)
reverse heparin - discontinue and give antagonist protamine sulfate (basic). avoid excess protamine (also an anticoagulant), incomplete LMWH neutralization, does not reverse fondaparinux
contraindications: HIT, heparin hypersensitivity, active bleeding, hemophilia, purpura, intracranial hemorrhage, advanced liver/kidney disease, severe HTN, infective endocarditis, active TB, GI ulcer, threatened abortion, visceral carcinoma
avoided in: post-surgery of brain, spinal cord, eyes, lumbar puncture, pregnancy unless clearly indicated
fondaparinux
synthetic pentasaccharide that enhances Xa inactivation (like the antithrombin binding site); long t1/2 (15 hrs) so once daily SC dosing; predictable anticoagulant response; can prevent/treat venous thromboembolism; alternative anticoagulants in pts w/ HIT; less bleeding than LMWH
LMWH
direct - directly bind thrombin active site; primarily used in HIT when heparins contraindicated; can treat or prevent clots (like heparin); bivalent DTIs also bind substrate recognition site
hirudin - bivalent, irreversible DTU from leech saliva
bivalirudin - bivalent, reversible DTI; also inhibits platelet activation; IV; rapid on/off action; short t1/2
lepirudin - recombinant form of hirudin; used in HIT pts; caution when renal insufficient
argatroban - in thrombosis and HIT pts; IV; short t1/2; monitor aPTT; liver clearance (caution in liver disease); increases INRs; inhibits protein C activation and platelet aggregation
dabigatron - oral; fast onset action; not a p450 substrate; contraindicated in renal failure (assess renal fn before giving); no antidote; fetal bleeding reported; no routine monitoring needed
directly inhibits platelet fn, decreasing clotting ability (increases BT)
used to prevent arterial clots
side effects: generally GI erosions and bleeding
dipyrimadole (weakest drug) - weak inhibitor of phosphodiesterase, blocks adenosine uptake; usually combined with aspirin for stroke prevention
ADP receptor antagonists (Thienopyridines) - irreversibly inhibit ADP receptor (P2Y12) on platelets; prevent thrombosis during coronary stent placement; useful when can't use aspirin
clopidogrel (Plavix) - prodrug (slow onset, less adverse effects); avoid using with proton-pump inhibitors (eg omeprazole) due to reduced antiplatelet activity
ticlopidine - adverse effects: GI toxicity, hemorrhage, thrombotic thrombocytopenia pupura (TTP), neutropenia
thromboxane inhibitor
aspirin - irreversibly inhibits TXA2 synthesis via COX1 acetylation; for primary prophylaxis of MI: 325 mg/d
IIIa/IIb receptor antagonists (strongest medication; IV only; blocks final step of platelet aggregation activation and most abundant receptor on platelet and megakaryocyte)
abciximab - chimeric mAb against IIb/IIIa receptor; blocks activation of IIb/IIIa receptor and vibronectin receptor; used in acute coronary syndromes
eptifibatide - analog of fibrinogen delta chain; blocks fibrinogen binding IIb/IIIa receptor
tirofiban - similar to eptifibatide, but smaller
Vitamin K Inhibitors
Platelet Inhibitors
Clotting
Factors
Anti-
plasmin
VII, VIII, IX, X, FFP, cryoprecipitates
plasmin forms from tPA and plasminogen while bound to lysine on fibrin
fibrinolytic inhibitors
aminocaproic acid
lysine analog
competitively inhibits plasminogen activation
adverse effects: thrombosis, hypotension
loading dose to avoid hypotension
used as adjunctive therapy in hemophilia, treat bleeding from fibrinolytic therapy, prophylaxis for rebleeding from intracranial aneurysms
aprotinin
serine protease inhibitor (serpin)
inhibits fibrinolysis by free plasmin
used in high risk pts undergoing coronary artery bypass grafting to decrease bleeding during surgery
adverse effects: potentially fatal anaphylaxis, increased risk of MI, stroke, renal damage
fat-soluble (Vit K1 primarily in leafy green veggies. K2 made by human intestinal flora)
oral or IV, avoid SC and rapid infusion
treat decreased prothrombin activity by excessive warfarin or Vit K deficiency
Vit K1 is given to all newborns to prevent Vit K deficiency (common in premature babies)
Fibrinolytic
Pathway
Surprise! A good video:
~*~*~EXTRA~*~*~
Component Factors
I Fibrinogen
II Prothrombin
III Tissue thromboplastin
IV Calcium
V Proaccelerin
VII Proconvertin
VIII Antihemophilic factor (AHF)
IX Christmas factor, plasma
thromboplastin component
X Stuart-Prower factor
XI Plasma thromboplastin antecedent (PTA)
XII Hageman factor
XIII Fibrin-stabilizing factor
Protein C and S
Plasminogen

red = Ca2+ dependent
Also see ~*EXTRA*~
increased vessel fragility due to damage to dermal connective tissue caused by age or chronic sun exposure
Protein wasting due to excessive corticosteroid use
Dilated tortuous blood vessels with a thin wall that bleed easily; BLANCHES
treat with laser/cryotherapy

ectasia - dilation or distension of a tubular structure
green - hereditary; single factor deficiency
purple - acquired; multiple factors deficiency
Amyloid chains (extracellular protein deposit with beta-sheet structure) deposit around blood vessel walls and weaken them (vasculitis)

Increased amount of IgG and IgM in circulation activate C' and attract leukocytes that damage blood vessels

Increased viscosity encourages thrombosis
green - immune
purple - non-immune
deposition of immune complexes in the vessel wall that leads to immune mediated vasculitis
Primary Hemostasis
Secondary Hemostasis
Damage (endotoxin, cytokines, free radicals) to microvasculature endothelium, produces platelet deposition, vasculitis and DIC
give antibiotics/pressors
--------------Purpura--------------
red/purple hemorrhage in skin or mucous membranes that DO NOT BLANCH; >3-10 mm diameter and may be palpable; also seen in platelet disorders
------------------Petechia(e)------------------
red/purple, small, 'pinpoint' spots of hemorrhage (from capillary rupture/leak, and usually in groups) in skin or mucous membranes that DO NOT BLANCH; 1-3 mm size, non-palpable, painless; also seen in platelet disorders
Factor VIII inhibitors
postpartum state
becomes resistant during treatment with Factor VIII with prolonged PTT
manage with judicious use of replacement factor
Lupus anticoagulant (independent reading assignment)
SLE
malignancy
chloropromazine
procainamide
Disseminated Intravascular Coagulation
bone marrow replacement
Thrombotic Microangiopathy
bone marrow replacement
insults that lead to excessive platelet activation, leading to thrombi in small vessels which cause
microangiopathic hemolytic anemia
widespread organ dysfunction
thrombocytopenia
thrombotic thrombocytopenic purpura (TTP)
- associated with deficiency in plasma enzyme
ADAMTS13
(abs against)

which degrades vWF multimers;
fever, transient neurologic defects and renal failure
; manage with
plasma exchange
and adjunct treatment with
glucocorticoids
hemolytic-uremic syndrome (HUS)
- normal levels of ADAMTS13 initiated by shiga toxin of E. coli strain 0157:H7 or due to defect in C' regulatory protein that prevents excessive platelet activation; fever, no neurological symptoms and prominent acute renal failure; manage with supportive care (maybe dialysis) ; antibiotics not recommended
Mechanical Injury
bone marrow replacement
------------Ecchymosis----------
pools of blood in subcutaneous skin later that DO NOT BLANCH (aka bruise); >10 mm size
Hemophilia B
DIC
Hereditary Hypercoagulability Disorders
Cause venous thrombosis (area of low shear stress - veins; often near valve cusps with endothelium intact; high fibrin proportion; trapped RBCs give classic red appearance and lack of venous return causes edema, warmth; embolization risk): Antithrombin III deficiency, Protein C or S deficiency, Factor V Leiden mutation, Prothrombin 20210A mutation, Antiphospholipid Antibody Syndrome. Test for all of these in Inherited Thrombophilia Workup when strong FH of thrombosis and testing would affect clinical decision making.

skin necrosis called dry gangrene usually caused by arterial thrombus (forms at area of endothelial damage - area of high shear stress attracts platelets, which make clot appear white)
Anticoagulant Drugs
work primarily by altering coagulation cascade
so most useful for venous clots (can prevent or treat)
DRUG
LINES

DIC
Full transcript