B3.049 Disorders of Coagulation Flashcards
why is the vascular wall important in hemostasis?
anchor to which platelets bind
mediated by vWf
what are some of the functions of platelets in in hemostasis
form plug
have granules with coag factors
have stores of Ca2+
has a phospholipid surface where secondary cascade gets activated (flip flopping)
what prevents vWF and platelets from interacting in circulation?
not conformationally compatible
what happens to stimulate vWF and platelet interaction?
conformational change
can happen due to chem or phys means
turbulence or cytokines both important
turbulence set off bc of injury to vessel wall
describe the physical characteristics of vWF
large protein; enzyme cleaves large protein into functional units
multiple active domains
anchor platelets to subendothelial collagen
what mediator connects vWF to platelets
Gp1b
what is the function of Gp2b3a?
binds to fibrinogen to help stick platelets together
where is vWF synthesized?
endothelial cells (WP bodies) platelets (alpha granules)
what protein processes vWF multimers?
ADAMTS-13 in plasma
what function outside of platelet adhesion does vWF have?
stabilization of factor 8
without it, factor 8 degrades quickly and you have the appearance of a factor 8 deficiency
what factors initiate clotting in vivo?
TF and factor 7
what is the purpose of factor 7 after the initiation of clotting?
nothing
after initiation, clotting is potentiated by a positive feedback loop stimulated by thrombin
what factors does thrombin activate?
8, 9, 10
these must be stopped to stop fibrin clotting (NOT 7)
what is the function of activated factors?
serine proteases
can cleave downstream factors
which factor is the PT test more sensitive for?
factor 7
what are the vitamin k dependent coag proteins?
2, 7, 9, 10
protein C and protein S
why is vitamin k necessary?
required for post translational gamma-carboxylation of glutamic acid residues, forming gamma-carboxyglutamic acis (gla)
gla binds to Ca2+ in active site and allows protease reactions to proceed
what is the mechanism of warfarin?
inhibits the recycling of vitamin K
inhibits production of functional clotting factors
what is the only mechanism of D-dimer production?
breakdown of CROSS LINKED FIBRIN
had to have had a thrombus
causes of an abnormal PT?
liver disease
vitamin K def
warfarin
how can you distinguish between liver disease or vitamin K def in a patient w abnormal PT?
test 1 liver dependent factor and 1 vitamin K dependent factor separately
what is the function of the INR?
to compare PT values across institutions
causes of an abnormal PTT?
hemophilia A and B vW disease heparin therapy liver disease (severe) vitamin K def (severe) warfarin (if supra-therapeutic)
discuss the diagnostic utility of the D-dimer test
high sensitivity for DIC
low specificity (many many causes for D-dimer elevation)
high negative predictive value for PE
-if you don’t have D-dimer, you don’t have a clotting issue
-if you do have D-dimer that’s not super diagnostically helpful
purpura
bleeding within skin or mucous membranes
petechiae
pinpoint bleeding of skin or mucous membranes
ecchymosis
large confluent area of bleeding within skin, larger than petechiae
hematoma
a collection of blood in organ, space, or tissue
hemarthrosis
bleeding into the joint space
bleeding patterns associated with primary hemostasis issues
skin or mucosal bleeds
purpura, petechiae, ecchymosis
spontaneous bleeding
bleeding pattern associated with secondary hemostasis issues
bleeds into soft tissue, muscle, joints
hemarthrosis
bleeding with trauma
vW disease epidemiology
variable age of onset
m = f
prevalence 1-5 per 1000
type 1 vWf disease
partial quantitative deficiency
autosomal dominant
type 2 vWf disease
qualitative deficiency
types: factor 8 binding issue, binds to gp1b too much, no multimers
varying degrees of clinical manifestations
type 3 vWf disease
complete quantitative deficiency
autosomal recessive
pathologic features of vW disease
prolonged closure time on PFA-100 prolonged PTT (30% of patients) decreased vWf activity (in all types) decreased vWf antigen (types 1 and 3) normal vWf antigen (in type 2)
treatments for vWf disease
humate P, best option: vWf concentrate, blood derivative (pathogen inactivated)
cryoprecipitate: good source of vWf, blood product (not pathogen inactivated)
desmopressin (ADH): stimulates endothelial cells to release remaining vWf stores
classic triad of thrombosis
abnormal blood flow (stasis or turbulence)
hypercoagulability (inherited or acquired)
endothelial injury (hypercholesterolemia)
what causes venous thromboembolism?
inherited risks
OR
acquired risks
what causes arterial thrombosis
platelet and vessel wall abnormalities
most commonly atherosclerosis
acquired risk factors for venous thromboembolism (by risk)
major surgery, trauma history lupus anticoagulant pregnancy cancer hospitalization w/ illness oral contraceptives hyperhomocysteinemia anticardiolipin antibodies hormone replacement obesity
inherited risk factors for venous thromboembolism (by frequency)
Factor 5 leiden (heterozygous) elevated factor 8 hyperhomocysteinemia prothrombin G20210A protein c deficiency protein s deficiency antithrombin deficiency factor 5 leiden (homozygous) dysfibrinogenemia
what is the function of protein C
inactivates 8 and 5
what is the function of protein S
cofactor of protein C
what is the function of antithrombin
inactivates 10, 2, others
what is factor 5 leiden
point mutation leading to decreased proteolytic inactivation by protein C
where does DVT occur
deep veins of legs
pulmonary arteries
cerebral veins, mesenteric veins, hepatic veins
clinical features of DVT
leg swelling
different in calf circumference between legs
redness, warmth, tenderness, palpable cord in calf
diagnosis of DVT
compression ultrasound of proximal leg veins (+ if noncompressible)
D-dimer
venography
prognosis of DVT
PE
post-thrombotic syndrome
clinical features of PE
dyspnea, wheezing chest pain (pleuritic) hemoptysis right sided heart failure (cor pulmonale) hypoxemia
diagnosis of PE
spiral CT- high PPV, low NPV
D-dimer- high NPV, low PPV
ventilation-perfusion (V-Q) scan, pulmonary angiography
prognosis of PE
mortality 15%, usually due to right heart failure
chronic pulmonary hypertension
prothrombin gene mutation
point mutation in 3’ untranslated region leading to increased stability of mRNA
increased prothrombin levels
antiphospholipid syndrome
autoantibodies against phospholipid binding proteins; mechanism of thrombosis not entirely clear
venous and arterial thrombosis
treat w anticoagulation if you have recurrent symptoms
heparin induced thrombocytopenia
autoantibodies against heparin-platelet factor 4 complex cause platelet activation and thrombosis
worse with higher MW heparin types
clinical features of heparin induced thrombocytopenia
4 T's timing- 5-7 days after heparin thrombocytopenia- 50% decrease thrombosis- venous, arterial exclude oTher causes no bleeding
what is DIC
intravascular activation of coagulation without a specific localization and arising from different causes
can cause damage to microvasculature and produce organ dysfunction
clinical features of DIC
bleeding
thrombosis
pathologic features of DIC
hyaline microthrombi of microvessels platelet and fibrin rich thrombi thrombocytopenia prolonged PT and/or PTT decreased fibrinogen elevated D-dimer microangiopathic hemolysis (schistocytes)
management of DIC
manage underlying disorder
blood product as clinically indicated
antifibrinolytic agents- if bleeding predom
heparin- if clotting predom
