Coag Part 3/3

multifactorial
(chronic/acute, uncontrolled plt activation, blood coag control protein deficiencies, uncontrolled suppression of fibrinolysis)

emboli formation
venous thromboembolism (VTE)

DVT, pulmonary embolism (PE), arterial thrombosis

age, diet, immobilization, lipid metab disorders, pregnancy, femoral/tibial fracture, surgeries, smoking

MPN, liver disease, leukemia,
PNH, chronic inflam diseases, antiphospholipid syndrome (APS)

plt activation
high plasma viscosity

reduced production of coag reg proteins

APL, DIC risk

plt activation

diabetes, cancer, infection, autoimmune

deficiency: AT, protein C, free protein S
AT resistance, Prothrombin G20210A
hyperfibrinogenemia

APC resistance:
FV (R506Q) GOF mutation in FV gene

mutation causes FII elevation

APC resistance
FV Leiden mutation
Prothrombin mutation G20210A
LAC profile
AT, PC, PS, activity
fibrinogen

immunoglobulins (IgG or IgM) that bind protein-PL complexes (non specific inhibitors)

lupus anticoagulants (LACs)
anticardiolipin (ACLs)
anti-β2-GPI

antiphospholipid syndrome (APS)

1-2% random pop, 5-15% pts with thrombosis,
mostly transient following infections (alloimmune) or arise as autoimmune abs in autoimmune diseases (50% SLE)

TT

Do Hepzyme and repeat PTT

assay for heparin

If dabigatran is present, discontinue;
if not, do mix test plasma :1:1 with NP PTT on mixture

Do mix test plasma 1:1 with NP PTT on mixture

assay for LAC

mix test plasma 1:1 with NP
incubate 37C 1-2 hrs and repeat PTT

assay for factor def

assay for specific factor inhibitor or LAC

guanine to adenine mutation a 3'UTR

mutation elevates prothrombin level, 2-3-fold increase in thrombosis risk to heterozygotes

worldwide 0.3-2.4%
in familial thrombosis 5-18%

molecular genetic assay

activity <70% of normal

liver disease, nephrotic syndrome, prolonged heparin therapy, contraceptives, and in DIC

>90% quant
(low AT antigen level)

activity <65% normal

1.5-11.5-fold increase in thrombosis (DVT and PE)

results in neonatal purpura fulminans (deadly if left untreated)

challenges with coumadin therapy in heterozygous PC def
(coumadin-induced skin necrosis)

generalized and uncontrolled activation of hemostasis systemic triggered by systemic disease

MAHA, microthrombi formation but hemorrhage is major issue

consumptive coagulopathy or defribrination syndrome, engages the whole hemostasis from vessels up to fibrinolytic system

pattern on PBS/CBC report
thrombocytopenia, prolonged PT/PTT/TT, low fibrinogen, increased FDPs (esp D-D)

TF release, endotoxin,
endothelium exposure during vasodilation,
circulating immune complexes, secretion of proteolytic enzymes,
toxins, acidosis, PLT activation

endothelium damage (trauma)

septicemia, bacterial infection

heat stroke

HIT, AHTR, graft rejection

APL, AMML

snake venom

diabetes mellitus

thrombocythemia, vascular surgery

RI 150,000-450,000/ uL
DIC <150,000/ uL

schistocytes (MAHA) in 50% DIC cases
leukocytosis common

RI 11-14 s
DIC >14 s

RI 25-35 s
DIC >35 s

fibrinogen <80mg/dL, elevated FDPs, soluble fibrin monomer all prolong TT

RI 0-240 DDU or 0-500 FEU
DIC >240 DDU or >500 FEU
(often 10,000-20,000)

RI 220-498 mg/dL
DIC <220 often higher bc fibrinogen is an APR

<50%
use to monitor plasma, AT concentrate

decreased
useful for analyzing systemic fibrinolysis;
observe specimen management protocols

positive
hemagglutination assay

<30%
FV and FVIII rise in inflammation, assays may give misleading results

an immune response against plts following exposure to therapeutic heparin (UFH or LMWH) displayed as thrombocytopenia

risk of thrombosis
(0.5-5% with UFH, less with LMWH)

DVT, PE, MI, stroke, limb ischemia, skin lesions at sites of injection

mortality 30%
of those who survive 20% req amputation

an IgG ab that recognizes plt factor 4 (PF4)-heparin complex
IgG:H:PFP4 complex

heparin

binds FcyRIIa (CD32) on plts

binds to Ecs: inflammatory rxn involving monocytes, PMNs, and mq

plt activation
thrombosis
inflammation

plt ct every 48h after heparin therapy
30-50% decrease in plt ct post-heparin vs pre-treatment

by degree of fall in platelet count:
resultant plt ct may be normal but <150,000/ uL however, HIT pts rarely develop bleeding

primary HIT: plt ct declines 5-10 days after heparin initiation
if pt was heparinized <120 days before, plt fall occurs faster (within hours)
delayed HIT: may show up 30 days after cessation of heparin therapy

thrombosis in heparin-treated pts with thrombocytopenia
pts who show thrombocytopenia but no thrombosis at discharge must be monitored for 30 days after initial plt ct fall

Enzyme immunoassays
12C-serotnonin release assay (SRA): confirmatory test

96-well lates coated with H:PF4 or polysulfonate:PF4 complex
Patient’s serum or plasma added, it contains anti-H:PF4 antibody
Incubate, wash, anti-human IgG conjugated with enzyme (e.g., HRP) added
Incubate, wash, add substrate (chromogen), read the plate through a plate reader, color intensity proportional to anti-H:PF4 level, confirmed by extra heparin

coumadin/warfarin
heparin
direct oral anticoags (DOAC)

standard (unfractionated: UFH, indirect, activates AT to inhibit thrombin,F 9a, 10a, 11a, 12a)
low molecular weight (LMWH)
Fondaparinux (F10a inhibitor)

Dabigatran
apixaban, Rivaroxaban, Edoxaban

primarily in hospital
(ER, during surgery, post-surgery)
bridging to Coumadin or DOACs
effect immediate

long term
choice depends on physician, comorbidities, and condition

inhibits at Xa during propagation

inhibits at Xa during propagation and IIa (thrombin) during fibrin formation

inhibits at IIa during fibrin formation

PT/INR
PTT
FXa assay

standard doses are effective with little variability
but do affect lab tests;
sometimes req to see if they are in the system

heparin and coumadin
DOACs reversals are just emerging

by blocking activity of Vit K epoxide reductase req for y-carboxylation of vit K-dependent coag factors (SCZ27910)

to prevent stroke and heart attacks, post surgery/trauma VTE
and recurrence of DVTs and PE

existing factors not affected (still functional)
full effect of coumadin takes 5 days (bridging with UFH, LMWH, or fondaparinux)

with INR
therapeutic range INR 2-3
cardiac valves 2.5-3.5
PT monitored 24 hrs after therapy (checked 2-4 days until INR consistent, checked every 4 wks when stabilized until discontinue)

diet high in vit K reduces drug's effect
(must maintain reg diet, changes in diet=changes in INR)
therefore needs to be monitored regularly

just to reduce INR
stop taking Coumadin,
take oral or injection of vit K

bleeding/emergency/surgery
stop taking coumadin, give IV vit K and bld products which provide usable factors
(prothrombin complex conc, plasma if PCC not avail)

used for DVT, PE, myocardial infarct, etc

1. standard or unfractionated (UFH)
2. low molecular weight heparin (LMWH)

activates AT to inhibit serine proteases (except VIIa)

reduce inhibitory activity against thrombin vs FXa

in fixed doses (have predictable pharmacokinetics) and without the need for dose adjustment based on lab monitoring

LMWH is just as effective as UFH,
easier to administer (pt admin themselves)
easier to monitor

PTT not useful in monitoring (low anti-IIa activity)
occasional chromogenic heparin assay (anti-FXa assay), less HIT risk,
less bleeding, less inhib of plts

does not need AT to inhibit thrombin

prevent conversion of fibrinogen to fibrin
prevent activation of thrombin

direct thrombin inhibitors

oral--Dabigatran (Pradaxa)
IV--Argatroban, bivalirudin, lepirudin

bind both free and clot bound thrombin

does not req routine monitoring
quick acting (1-3 hrs)

may be variable affected, but does not necessarily correlate with drug level

presence of Dabigatran

used for thrombosis pts with atrial fibrillation, VTE

Idarucizumab (Praxbind)

Argatroban, Bivalirudin, Lepirudin

Hirudin (found in salivary glands of medicinal leeches, potent direct thrombin inhibitor)

Apixaban, Rivaroxaban, Edoxaban
directly inhibit FXa (does not need AT)

if renal insufficiencies are suspected
(metabolism can be affected by renal/liver disease)

Andexanet Alfa (AnnexXA)

recombinant human FXa decoy
binds & neutralizes FXa inhibitors & LMWH/pentasaccharide-FXa complexes
given as a bolus followed by 2 hr infusion

by falsely prolonging tests like dRVVT and giving false positive LA;
can use inhibitor-like affect to factor assays giving decreased factor concentration

employs partial thromboplastin time (PTT) reagent with intermediate lupus anticoag (LAC) sensitivity

DTT (VIIa)
DRVVT (Xa)
PTT (XIIa)
Fibrin polymer
Crosslinked fibrin