Hemostasis Flashcards
Platelet plug formation
1) exposed collagen on subendothelial surface
2) GpIa/IIa and vWF binds, GpIbIX binds vWF
3) Platelet binds
4) Collagen activates PG synthesis within platelets –> TXA2 –> release of ADP, serotonin, fibrinogen, enzymes from intracellular granules
5) Released ADP and TXA2 causes platelet aggregation
6) GpIIbIIIa exposed, which binds fibrinogens, which binds other platelets
Fibrin clot formation (extrinsic)
1) vessel injury exposes TF - coagulation cascade
2) VIITF –> VIIa-TF
3) IX –> IXa and X –> Xa
4) Prothrombin –> thrombin (also catalyzed by Va)
5) Fibrinogen –> fibrin –> cross-linking
Intrinsic pathway
1) thrombin –> also VIII –> VIIIa
2) XI –> XIa
3) IX –> IXa
4) X –> Xa (also catalyzed by VIIIa)
etc
Clot termination
1) endothelial cells produce thrombomodulin, antithrombin, TFPI, tissue plasminogen activator 1, urokinase, plasminogen activator inhibitor, annexin 1
2) thrombomodulin binds thrombin, activates protein C and S, inactivates Va and VIIIa
3) Antithrombin inhibits factors VIIa, XIa, IXa, IIa (thrombin)
4) TFPI: inhibits protease, mainly VIIa/thrombin
5) plasminogen –> plasmin, cleaves fibrin clot
Immune thrombocytopenic purpura pathophys
- increased platelet destruction due to abnormal IgG (commonly against GpIIbIIIa) - removed in RE system
- idiopathic, may be seen with diseases like SLE
- normal lifespan 7-10d, ITP few hours
- insidious onset - petechial hemorrhage, easy bruising, menorrhagia
ITP Tx
Prednisolone
High dose IVIG for life-threatening hemorrhage
Immunosuppressive drugs
Rituximab
Splenectomy (if refractory disease)
Platelet transfusion (only lasts few h - ineffective)
Secondary thrombocytopenia pathophys
Increased platelet destruction HIV infection H. pylori CLL, Hodgkin's lymphoma AIHA SLE Drug-induced post-transfusion
Aspirin-induced thrombocytopenia pathophys
Inhibition of COX1 and 2 –> reduced TXA2 synthesis
consequent impairment of platelet aggregation
von Willebrand disease pathophys
Most often autosominal dominant with variable penetrance
Normally produced in megakaryocytes and endothelial cells
Roles:
- promotes platelet adhesion to subendothelium at high shear rates
- carrier for VIII
Typically see mucocutaneous bleeding
Rarely see hemarthrosis/muscle hematoma
Hemophilia A pathophys
VIII deficiency
synthesized in liver/endothelium
Tx hemophilia A
factor VIII replacement
DD-arginine vasopressin with fluid restriction
Hemophilia B
Factor IX deficiency
vitamin K dependent
Tx: recombinant IX replacement
Vitamin K deficiency pathophys
Fat-soluble vitamin
Obtained from green vegetables & gut bacteria
Inadequate diet/malabsorption/inhibition by drugs (warfarin)
Role in gamma-carboxylation of glutamic acid in coagulation factors (allows factors to bind Ca and attach to platelet PL)
Liver disease hemostatic disease pathphys
Vitamin K-dependent factor deficiency (II, VII, IX, X, protein C)
factor V, fibrinogen deficiency (severe)
thrombocytopenia from hypersplenism/ immune complex-mediated platelet destruction
Dysfibrinogemia
DIC (disseminated intravascular coagulation) pathophys
Widespread intravascular deposition of fibrin with consumption of coagulation factors and platelets
Consequence of abnormal release of procoagulants, endothelial damage, or platelet aggregation due to:
- infection
- malignancy
- hypersensitivity
- widespread tissue damage (surgery, trauma, burn)
Overwhelm normal removal
Excessive fibrin monomer formation - binds fibrinogen, leading to coagulation defect
Intense fibrinolysis by thrombin –> coagulation defect
Heparin use thrombocytopenia pathophys
HIT
PF4 in alpha granules secreted upon platelet activation –> binds heparin –> complex is immunogenic
IgG-heparin-FP4 binds platelet surfaces, causes platelet activation, degranulation and platelet aggregation
1-5% patients
4-14 days after initiation of therapy
Lupus anticoagulant pathophys
Antiphospholipid Ab associated with venous/arterial thromboses
Activates and stimultaes coagulation cascade
- pathologic thromboses of arteries and veins
- possible placental infarct and pregnancy loss
Associated with antiphospholipid antibody syndrome
Anticoagulant IN VITRO
Procoagulant IN VIVO
Primary hemostasis PE
Mucocutaneous bleeding
Secondary hemostasis PE
Deep tissue bleeding
Hemarthrosis, muscle hematoma
Elevated PTT
Problem in the intrinsic pathway
- Factor 8, 9, 11, 12, vWF deficiency
- 12 does not cause bleeding
- 11 rare
- 8/9 X-linked
- 8 carried by vWF so would be low in 8 def/VWD
Coagulation factor inhibitor - lupus anticoagulant, heparin, acquired factor 8 inhibitor
Followup with mixing study (50:50)
- if corrected: factor def
- if remains elevated: inhibitor present
Elevated PT
problem in extrinsic pathway
factor 7 deficiency
Elevated PTT and PT
Problem in the common pathway/ fibrinogen Common: 1, 2, 5, 10 Multiple factors: 12, 11, 9, 8, 7 - hemophilia A (8), B (9) - vitamin K: 2,7, 9, 10 - liver disease (TT not prolonged) - DIC
give vit K to differentiate between liver disease & vitamin K
Key questions for hematologic problem
Bleeding site Age of onset Consistency of bleeding problem Spontaneous or provoked by trauma Previous medical procedures/transfusions Severity
Cause of mucocutaneous bleeding
Thrombocytopenia
Platelet dysfunction
von Willebrand disease
Causes of hemarthroses, hematuria, intramuscular/intracerebral/retroperitoneal hemorrhages
Severe hemophilia A/B
Severe deficiencies of factors 7, 10, 13
Severe type 3 von Willebrand disease
Afibrinogenemia
Causes of bleeding from stump of umbilical cord/habitual abortions
Afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, factor XIII deficiency
Petechiae
<3 mm
non-blanching
Often appear in clusters
purpura
3-10 mm
non-blanching
Ecchymosis
> 1 cm
bruise/contusion
non-blanching
Hematoma
Localized collection of blood outside vessels, within tissue
raised swelling
Hemangioma
Abnormal buildup of blood vessels in the skin/interal organs
Senile purpura
extremely common in old age
age-dependent deterioration of the vascular supporting structure
bruising on the dorsum of the hands and forearms
serious bleeding does not occur
Type I vWF disease
reduced vWF
common
m/c bleeding
Type 2 vWF disease
dysfunctional vWF protein
uncommon
m/c bleeding
type 3 vWF disease
no vWF and associated factor 8 deficiency
rare
severe m/c bleeding
can see joint/muscle bleeding
Mild hemophilia
6-40% factor 8/9
bleeding only with trauma or surgery
can present in adulthood
Moderate hemophilia
1-5% factor 8/9
bleeding usually with trauma or surgery
can be spontaneous
Severe hemophilia
<1% factor 8/9
bleeding spontaneously or with minor trauma
presents at a young age
vWF treatment
1) Desmopressin - release endogeneous stores (WPB)
- usually 3-5x rise in vWF and factor 8 in type 1, but not in types 2 and 3
2) exogenous vWF - donor plasma, usually for types 2/3, also give factor 8
Hemophilia A tx
mild - desmopressin
recombinant factor 8
Platelet characteristics
New platelets are larger
Up to 1/3 are sequestered in the spleen - 90% if splenomegaly
Normal life span 7-10 d
Removal: 50% by the spleen, 33% by the liver, 17% by bone marrow/lymph node/other tissues
Platelet contents
alpha granules: proteins associated with adhesions and clotting
dense granules: calcium, ADP/ATP, serotonin
no nucleus!
Normal platelet function
1) adhesion to vascular wall
2) secretion of granular contents
3) aggregation
Procoagulant activity
Vascular healing
Platelet adhesion
1) GpIaIIa engages exposed collagen in subendothelium
2) subendothelial microfibrils bind vWF, which binds platelet GpIbIX
3) platelets become more spherical, extrude pseudopods, form a monolayer
Platelet - secretion of granular contents
1) collagen exposure activates TXA2 synthesis
2) activation of phospholipase C –> increased calcium concentrations within platelet –> granules released
3) releases ADP, serotonin, fibrinogen, enzymes
4) triggers further conformational change and activation
Platelet aggregation
1) GpIbIX binding –> activation of GIIbIIIa, exposing binding sites for fibrinogen
2) fibrinogen binds platelets to one another
3) ADP and TXA2 (also a potent vasoconstrictor) recruit other platelets
Platelet procoagulant activity
Phospholipid required for 2 steps of clotting cascade
Membranes of activated platelets provide phospholipid surface
Bound fibrinogen helps localize clot
Qualitative platelet disorders
Congenital - platelet receptor deficiency, release/secretory defects, Granule content/storage pool disease
Acquired - drugs, systemic conditions (renal failure, cardiopulmonary bypass), hematologic disease
PFA-100
Platelets - add agonist –> measure light transmission
If platelets aggregate and sink to the bottom, 100% light transmission at the top
will be abnormal in someone taking ASA/NSAIDs, vWF disease, congenital platelet function defects
Platelet disorders - reduced production
Congenital: rare
Acquired:
- nutritional - B12/folate
- infiltrative
- marrow failure
- medication
Thrombocytopenia - sequestration
hypersplenism
1) congestive
2) reactive - infections, autoimmune hemolysis
3) infiltrative - benign (CT disease), malignant (hematologic)
Thrombotic thrombocytopenic purpura (TTP)
Thrombotic microangiopathies
Microvascular occlusive disorders
Triggered by: HUS, congenital/autoantibody causes of ADAMTS13 deficiency (familial TTP)
Normally ADAMTS13 cleaves large vWF; uncleaved –> attracts platelets
Classic pentad for TTP
Thrombocytopenia Microangiopathic hemolytic anemia Fever Neurologic symptoms and signs Renal impairment
Untreated - mortality 90%
TTP treatment
emergency!
Plasma exchange
Aspirin
Corticosteroids for refractory disease/relapse
Platelet transfusions are CONTRAINDICATED
