Coagulation, Platelets, Bleeding Disorders, Thrombosis/Fibrinolysis Flashcards
vessel injury results
vasoconstriction exposure of subendothelium -collagen/vWF -recruitment of platelets -primary platelet plug TF:FVIIa -thrombin gen -form of fibrin clot Fibrinolysis/wound healing
platelet adhesion
exposure of collagen which binds to vWF which binds GP1b on platelets
platelet aggregation
GP11b/IIIa
(fibrinogen receptor)
changes confirmation and enables binding
___ activates X and IX, which generates ___
TF:FVIIa activates X and IX, which generates THROMBIN
thrombin activates…
VIII
V
^ generate more thrombin
XIII
^crosslinks fibrin monomers
___ crosslinks fibrin monomers
XIII
a transglutaminase, activated by thrombin
vitamin K synthesizes…
II VII IX X C/S
vitamin K sources
green leafy veggies
bacterial synthesis in gut
vitamin K is sctivated by ______ to its reduced form
vitamin K is sctivated by epoxide reductase to its reduced form
_____ is a cofactor for the γ-carboxylation of glutamic acid residues on various proteins required for blood clotting
vitamin K
____ inhibits vitamin K epoxide
WARFARIN inhibits vitamin K epoxide
____ –> plasminogen to plasmin –> fibrin to fibrin degradation products
tPa
released from endothelium
common path
fibrinogen, prothrombin (II), V, X
intrinsic path
common path + VIII IX XI XII
extrinsic path
common path +
VII
lab test for intrinsic system
PTT
lab test for extrinsic system
PT
thrombin time
conversion of fibrinogen to fibrin clot
which two components of the coagulation cascade are not reflected in PT or PTT
vWF
XIII
platelets
origin
anucleate cells derived from megakaryotes in bone marrow
platelets
production regulation
GM-CSF, IL3, IL6, TPO
platelet circulation
circulating in INACTIVE state
7-10 d
alpha granules of platelets
fibrinogen
thrombospondin
vWF
V
PF4
beta thromboglobulin
platelet derived growth factor (PDGF)
P-selectin
platelet factor 4 (PF4)
heparin antagonist, promotes fibrin clot
P-selectin
adhesion of activated platelets to phagocytes
beta thromboglobulin
recruits fibroblasts
PDGF
recruits fibroblasts
dense granules of platelets
ADP
ATP
^platelet activation/recruitment
5HT
^vasoconstriction
Ca
^cofactor for clot
plasma membrane of platelets
GPIb
GPIa/IIa
GPIIb/IIIa
thrombin receptor
phospholipids
P-selectin
Fc receptor
vWF
binds to collagen in sub endothelium of damaged vessel wall
binds to GP1b on platelets
collagen in damaged vessel wall binds to platelet via
GPIa/IIa
platelet activating agents
EPI, ADP, collagen, thrombin
thromboxane A2, arachidonic acid
shape change of platelets
discoid to spherical w/ development of long pseudopods
tensase complex
IX, VIIIa, Xa
prothombinase complex
Xa, Va, II
PFA - 100
measures adhesion/aggregation
anti coagulated whole blood under high sheer rate passes thru aperture w/ 2 membranes coated in either collagen/EPI or collagen/ADP
closure time = time to clot form between 2 membranes
affected by thrombocytopenia/some anemia
bleeding time test
abnml in pt w/ mucocutaneous bleeding
vW disease, platelet disorders
Bernard Soulier disease
GP1b (vWF receptor)
- abnml adhesion/agglutination
- prolonged bleeding time
Glanzmann’s thrombasthenia
GPIIb/IIIa (fibrinogen receptor)
- abnml aggregation and PFA-100
- prolonged bleeding time
congenital thrombocytopathies
abnml platelet fxn
Bernard/soulier disease
Glanzmann’s thrombasthenia
acquired causes of thrombocytopathy
drugs (ASA, NSAIDs)
uremia
myeloproliferative disorders/myelodysplastic syndromes
aspirin MOA includes (reversible or irreversible) COX inhibition
aspirin MOA includes IRREVERSIBLE COX inhibition
–> dec thromboxane –> dec aggregation
NSAIDS MOA includes (reversible or irreversible) COX inhibition
NSAIDS MOA includes REVERSIBLE COX inhibition
–> dec thromboxane –> dec aggregation
congenital thrombocytopenias
May-Hegglin anomaly Wiskott-Aldrich syndrome Thrombocytopenia w/ absent radii (TAR) Epstein's/Alport syndrome Megakaryocytic hypOplasia/aplastic anemia
May-Hegglin anomaly
AD, lg platelets, dole bodies in wbc
Wiskott-Aldrich syndrome
XLR, eczema, immune dysfunction
Thrombocytopenia w/ absent radii (TAR)
AR
abnml hand/wrist
cardiac lesions
Epstein’s/Alport syndrome
AD, interstitial nephritis, deafness, lg platelets
Megakaryocytic hypOplasia/aplastic anemia
stem cell disorder
may be acquired
acquired causes of thrombocytopenia (dec production)
infiltrative process (malignancy)
viral (parvovirus, hepatitis)
drugs (chemo, alcohol, abs, anticonvulsants, antipsychotics)
Radiation
acquired causes of thrombocytopenia (inc destruction)
- heparin (HIT)
- immune thrombocytopenia purport (ITP)
- Thrombotic thrombocytopenia purpura (TTP)
- Hemolytic Uremic Syndrome (HUS)
- Disseminated intravascular coagulation (DIC)
- Antiphospholipid antibody syndrome (APLA)
- HELLP syndrome/pre-eclampsia
- Hypersplenism
immune thrombocytopenia purport (ITP)
AI disorder
Ab:Ag complex on surface of platelet targets it for removal of RES
comm cause: anti-GPIIB/IIIA Abs
ISOLATED platelet destruction
tx: immune modulation (steroids, IVIG, anti-D, Rituximab), TPO, splenectomy, adjunctive therapy for bleeding
Thrombotic thrombocytopenia purpura (TTP)
- adults
- fever, thrombocytopenia, microangiopathic anemia, acute renal failure, neurologic dysfunction
- dec activity of ADAMTS13 (vWF cleaving factor –> multimers of vWF build up –> platelet obstruction)
-normal PT/PTT
Tx: plasma exchange
ISOLATED platelet destruction
immune thrombocytopenia purport (ITP)
Hemolytic uremic syndrome (HUS)
- children
- diarrhea infection often E. coli strain
- MAHA, thrombocytopenia, severe renal failure
- normal PT/PTT
Tx: supportive care (usu resolves on its own)
Disseminated intravascular coagulation (DIC)
- consumptive coagulopathy
- thrombocytopenia, xs fibrinolysis, reduced coagulation fx –> hemorrhage, thrombosis, multiorgan failure
causes: endotoxin, SEPSIS, tissue factor release, tissue injury, proteases, toxins, malignancy, obstetrical complications, - bleeding/thrombosis
- prolonged PT/PTT, TT, dec fibrinogen, inc d-dimer
___ is not measured by either PT or PTT, but it stabilizes _____, so could prolong PTT if low enough
vWF:Ag is not measured by either PT or PTT, but it stabilizes factor VIII, so could prolong PTT if low enough
____ deficiency is a late step not involved in PT or PTT
FXIII deficiency
inc PT, normal PTT
think VII
PT is normal, PTTT is inc
think VIII, IX, X, XI, XII
failure of mixing study to correct at 2 hrs implies..
pt has a circulating inhibitor protein
bc mixed pt plasma with pooled normal plasma containing normal coagulation fx
thrombin time
measures conversion of fibrinogen to fibrin
prolonged: afibrinoginemia, dysfibrinoginemia, drugs (heparin)
vWD
- most comm congenital bleeding disorder
- easy bruising, epistaxis, mucocutaneous bleeding, menorrhagia
- usually AD, variable penetrance and expression
- vWF normal range varies w/ blood type (lowest in O, highest in AB)
blood type w/ lowest vWF
O
blood type w/ highest vWF
AB
vWF is stored in ____ (within endothelial cells)
Weibel-Palade bodies
vWF is synthesized in
endothelial cells and megakaryocytes
vWF is stored in ____ (within platelet alpha-granules)
megakaryocytes
vWF is assembled and circulates as
multimers
lg multimers are most active in hemostasis in high shear vessels
each monomer of vWF has binding sites for
VIII
GPIb
collagen
GPIIb/IIA
2 functions of vWF
- mediates platelet-endothelium adhesion
2. stabilizes FVIII
causes of acquired vWD
Abs (SLE, malignancy, myeloma, MGUS, infections, idiopathic)
hypOthyroidism (dec synthesis of vWF)
Cardiac (destruction of vWF (aortic stenosis, congenital heart disease, MV prolapse)
Drugs
dx of vWD
normal PT/PTT (PTT possibly prolonged) CBC/platelet/smear typically normal PFA-100: abnml with EPI and ADP VIII low if LOW vWF-Ag (range differs w/ blood type)
vWD tx
DDAVP (desmopressin)
Factor VIII +vWF concentrates (human plasma)
Recombinant vW
Tx underlying condn if acquired
adjunctive tx of vWF
antifibrinolytics
estrogens
AVOID NSAIDs/aspirin/herbal meds
hemophilia A
XLR
- carrier females can exhibit bleeding phenotype
- VIII deficiency
- inversions/deletions/point mut
hemophilia B
“Christmas disease”
XLR
-carrier females can exhibit bleeding phenotype
hemophilia clinical features
spontaneous hemarthoroses
IM bleeds
intracranial hemorrhage
mucocutaneous bleeds
sx occur within 1st yr of life
surgical bleeding and bleeding w/ trauma
target joints (sites of recurrent hemarthroses w/ hypertrophy of synovial sheath over time/painful arthritis)
severe hemophilia fx levels
<1%
very mild hemophilia fx levels
25-50%
dx of hemophilia
PT - nml
PTT prolonged (VIII and FIX are intrinsic pathway)
mixing studies - nml at 0, 2 hr
factor assay to quantify factor levels
Epsilon amino caproic acid (Amicar)
used for mucosal bleeding to inhibit plasminogen breakdown of the fibrin clot
adjunctive therapy for hemophilia
anti-fibrinolytics epsilon amino caprice acid (amicar) DDAVP Protection, rest, ice, compression, elevation pain cntrl (NOT NSAIDS) Physical therapy Ortho intervention
DDAVP (desmopressin acetate)
releases FVIII and vWF from endothelial cells but only works if the patient makes enough factor VIII to be stored and released as in patients with MILD hemophilia A only.
does NOT work for FIX deficiency.
complications of hemophilia
- arthropathy
- infection
- inhibitors (polyclonal high affinity IgG Abs that neutralize infused FVIII –> bleeding continues. More common in severe hemophilia A)
hemophilia pt w/ inhibitors
tx?
Bypass agents
- recombinant VIIa
- activated prothrombin complex concentrates
Suppression of inhibitors
- immune tolerance induction: daily infusion of high dose factor
- -> desensitization: induce tolerance of VIII or IX, stop prod of VIII or IX
- effective in children but COSTLY
hemophilia C
XI deficiency
- Ashkenazi Jews
- variable bleeding phenotype
- bleeding after dental extraction
- achieve hemostasis w/ prophylactic use of epsilon aminocaproic acid for mucosal bleeding
- FFP or rFVIIa for bleeding
acquired hemophilia
AutoAb to VIII
75% after 50 y/o
–Severe soft tissue bleeds –Less frequent hemarthroses –Spontaneous bleeding –Post-surgical bleeding –Incidental finding of prolonged APTT
tx of acquired hemophilia
tx underlying disease
immunosuppression
tx bleeding (DDAVP, VIII, rVIIa, FEIBA)
FEIBA
prothrombin complex concentrate
DIC testing
no one test, all are abnml
- low platelets (often profound thrombocytopenia w/ bleeding)
- prolonged PT and PTT
- elevated D-dimer and fibrinopeptides
- low fibrinogen
- fragmented rbc (MAHA)
DIC tx
tx bleeding (platelet transfusion, factor replacement (cryoprecipitate/FFP), heparin)
correct underlying disease
liver disease –> bleeding
MOA?
Coagulopathy
- hepatocyte dysfunc (dec V)
- vitamin K deficiency
- fibrinogen
Thrombocytopenia
- hypersplenism
- dec prod and abnml fxn
Failure to clear activated coagulation fx
- DIC
- elevated D-dimers
hepatic cirrhosis is associated w/ ___ coagulopathy
SEVERE
- deficiency of procoagulant proteins (prolonged PT/PTT)
- deficiency of thrombopoietin (thrombocytopenia)
Hemorrhagic disease of the newborn
vitamin K deficiency
- gut relatively devoid of bacteria and hepatocytes are immature
- vitamin K is given IM to all newborns to prevent bleeding in newborn period
young woman w/ menorrhagia
FHx appears AD
vWF disease
Virchow’s triad
- impaired blood flow
- circulating blood coagulation fx and inhibitors
- vascular damage
mesenteric vein thrombosis
abd pain
very ill pt w/ skin necrosis
DIC
inherited thrombophilia causes
ATIII, protein C/S deficiency
APC, V Leiden, prothrombin mut
hyperhomocysteinemia
PAI-1 mut
elevated VIII, IX, XI, lipoproteins
inherited thrombophilia
first thrombosis teen/early 20s
spontenous
high risk situations
