Transcript Bleeding & Clotting Disorders

Bleeding & Clotting
Disorders I
Richard E. Freeman MD
2013
Overview
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The Players
Factor Deficiencies causing bleeding
Dissolving the Clot
The Clinical Presentation
Other Causes of Bleeding
Hypercoagulability
The Precarious Balance
• Bleeding
• Bleeding Diathesis
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Clotting
Hemostasis
Coagulation
Thrombophilia
the anticoagulants vs. the procoagulants
• Hemostasis:
– cessation of blood loss from a damaged
vessel
• Other Terms
– bleeding disorders = bleeding diathesis =
coagulopathies
– diathesis [Gr. Diathenai – to predispose] : A constitutional
predisposition to certain diseases or conditions
Clots Stop Blood Flow
Phases of Clot Formation
I.
VASCULAR INJURY & SPASM
constriction of injured blood vessel
– injury releases tissue factors, platelets
release serotonin (vasoconstrictor), and
activates extrinsic pathway
II.
PLATELET PLUG FORMATION
collagen in vessel exposed by injury.
von Willebrand factor (vWF) needed to
bridge platelets and collagen.
– Calcium (Ca 2+) needed
Phases of Clot Formation
III. COAGULATION CASCADE
INTRINSIC AND EXTRINSIC PATHWAYS
formation of cross-linked fibrin polymer clot
“fibrin clot”
IV. DISSOLUTION OF CLOT
vascular spasm
collagen fibers
platelet
plug
platelet plug formation
fibrin
clot formation
The Players
Complex Interactions
• ALL OF THESE MUST FUNCTION
NORMALLY for EFFECTIVE CLOT
FORMATION and HEMOSTASIS
– Vascular endothelial cells
– Platelets
– Clotting factor cascade
– Blood flow & shear
– Antifibrinolysis
Blood Content & Hemostasis
• Plasma – Unclotted liquid part of blood
– 90% Water
– 10% Dissolved and suspending particles
• Organics: Proteins
– albumin 53%-LIVER
– globulins 43%
» Antibodies-RE SYSTEM
» Compliment & Kinin System (Inflamation)
» Clotting Factors-LIVER AND ELSEWHERE
– Fibrinogen 4%
• Inorganics: salts
• Blood Cells
– RBCs – Erythrocytes
– WBCs – Leukocytes
– Platelets – Thrombocytes
•ENDOTHELIAL
CELLS
Three Layers of the Blood Vessel
• Tunica intima:
endothelial cells (EC)
& subendothelium
• Tunica media:
• smooth muscles &
extracellular matrix
• Tunica adventitia:
fibroblasts & cellular
matrix(loose
connective tissue)
The Endothelial Cell (EC)
• 1. Intact, healthy EC produces and is “teflon”
coated with prostacyclin (PGI2)
• – RESTING STATE
– A vasodilator
– Inhibits platelet adhesion
– Acts in opposition to the platelet thromboxane A2
• 2. EC coated w/ heparin sulfate which activates
anti-thrombin III in plasma & stops thrombosis
• 3. Synthesis of Factor VIII – vonWillebrand
factor
– vWF synthesized in platelets & EC
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•PLATELETS
The Amazing Platelet
• 1. Secrete procoagulants which promote clotting
• 2. Secrete vasoconstrictors causing vascular
spasm in injured blood vessels
• 3. as they aggregate they undergo
degranulation releasing:
– serotonin (vasoconstrictor),
– ADP (attractant)-calls for more platelets to help,
– thromboxane A2 –(clot promoter)
• 4. form temporary platelet plugs to stop bleeding
• 5. dissolves blood clots that have outlasted their
usefulness
• 6. inflammation and remodeling
Platelets
Life of a Platelet
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MEGAKARYOCYTE (“mama” cell)
fragmentation in marrow
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thrombopoietin (TPO) stimulates production
produced in liver, bone marrow & kidney
1/3 sequestered to the spleen
2/3 into circulation (150-450,000 per microliter of
blood).
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LIFE SPAN 7 TO 10 DAYS
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(RBCs 90-120 days, WBCs 1 day)
ASA (aspirin) thus effect lasts this long
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irreversible acetylation of cyclooxygenase 1
Cell Lines
Platelet-Chemistry
• ACTIN-MYOSIN
– Contraction – pulls clot together
• SURFACE: GP IIb/IIIa glycoprotein
– Important in adhesion and aggregation
• DENSE GRANULE:
– Calcium, ADP, Serotonin
• ALPHA-GRANULE:
– Growth factor, fibrinogen, Factor V, von
Willebrand factor (vWF), fibronectin, betathromboglobulin, heparin antagonist (PF4),
thrombospondin
PLATELET
PLATELETS
-FOUR MAJOR FUNCTIONS
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1. ADHESION ACTIVATION
2. AGGREGATION
3. SECRETION
4. PROCOAGULANT ACTIVATION
1. ADHESION ACTIVATION:
– platelet on subendothelial matrix (surface)
– glycoprotein IIb/IIIa surface receptor binds vWF in subendo
matrix
2. AGGREGATION:
– cohesion of platelets
– fibrinogen binds activated glycoprotein IIb/IIIa
receptor
• Inhibited by
– abciximab IV (ReoproR), tirofiban (AggrastatR),
eptifibatide (IntegrelinR) all IV; used in angioplasty; often
used along with aspirin and heparin*
– ADP-receptor involved in GP IIb/IIIa-fibrinogen
interaction and possibly also the vWF site
• Inhibited by
– clopidogrel (PlavixR), ticlopidine (TicilidR) inhibit; both
given PO*
*all treat and prevent arterial thrombosis
3. SECRETION:
• release of plt. granule proteins
– ADP, serotonin, adhesive protein (fibronectin,
others), Factor V, thromboxane A2
– many growth factors (smooth muscle etc)
• may be involved in restenosis post PTCA
4. PROCOAGULANT
ACTIVITY:
• enhancement of thrombin generation
– assembly of the clotting cascade on the
platelet surface
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GP-IIb/IIIa Receptor
• CLOTTING FACTOR
CASCADE
Coagulation: the common pathway
Factor X
• THE OBJECTIVE
• is to convert the
plasma protein
fibrinogen into fibrin,
a sticky protein that
adheres to the walls
of a vessel and also
traps additional
platelets and RBCs
like a spider’s web
Fibrin Polymerization-
Coagulation Cascade
• TWO reaction pathways (roads)
– INTRINSIC PATHWAY uses only clotting factors found
inside the blood itself (plasma, platelets) 3- 6 seconds
– EXTRINSIC PATHWAY initiated by clotting factors released
in damaged vessels (tissue factor or thromboplastin)
and perivascular tissues -15 seconds
• Roman numerals indicate the order discovered,
however some numbers are not used:
– Factor IV is Ca++; Factor VI is activated Factor V
Coagulation Cascade Pathways
Extrinsic
Pathway
Common Pathway
EXtrinsic = In Tissue
INtrinsic = In Blood
Common = Yields fibrin
CLOT
THE INTRINSIC
PATHWAYthe reaction
amplification
cascade
Table 18.9
PROCOAGULANT
“CLOTTING FACTORS”
Synthesis
• ALL synthesized in the LIVER except
– von Willebrand Factor in megakaryocytes and
endothelial cells
• vWF is involved in
– PLATELET ACTIVATION
– Maintaining normal factor VIII levels
Vitamin K
• Vitamin K-dependent procoagulants
– II (Prothrombin), VII, IX, X
• Vitamin K-dependent anticoagulants
– Warfarin-dicoumarol (COUMADIN)
– Vit K antagonist
– Inhibits Vit K epoxide reductase
• (recycles oxidized Vit K – after K has been used in
carboxylation of clotting factor production)
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“THE REGULATORS”
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PROTEIN C & S
ANTITHROMBIN
TISSUE FACTOR PATHWAY INHIBITOR
PLASMINOGEN->PLASMA
PROSTACYCLIN ( PGI2)
PROTEIN C & PROTEIN S
Protein C & Protein S
• ACTION: inactivates Factor Va and VIIIa
• “Natural anticoagulant” – keeps system in balance
• Protein C:
– vitamin K-dependent serine protease enzyme
• Thrombomodulin (on endothelial cell surfaces) and
Thrombin stimulate Protein C and when activated
by Protein S- inactivates Factor V
• .see flow diagram
thrombin +
thrombomodulin on
endothelium turns
off clotting cascade
by activating
Protein C.
Protein C w/ Protein
S (a cofactor)
turn off various
Factors
Protein C & S deficiency
• Spontaneous Thrombosis/thromboemboli
• Suspect in young person with DVT/Stroke
with significant risk factors
• Most will be need Lifelong Anticoagulant
therapy
FACTOR V - LEIDEN
• MUTATIONS OF FACTOR VA –
–resistant to APC (activated protein C)
–Factor V Leiden mutation (present in 20
– 60% of pts with spontaneous venous
thromboembolism
–5% of European decent, rare in Asian
and African decent
ANTITHROMBIN III
• Serine protease inhibitor
• Active at all times
• Degrades:
– Thrombin, Factors IXa, Xa, XIa, XIIa,
• Enhanced by Heparin sulfate
• Deficiency- leads to thrombophilia
active
AT-III binds
Thrombin
inactive
AT-III
activated
AT-III
TISSUE FACTOR PATHWAY
INHIBITOR (TFPI)
• limits the action of tissue factor (TF)
• inhibits excessive TF-mediated activation
of FVII and FX
PLASMIN-fibrinolysis
Fibrinolysis: Dissolution of Clot
• Plasminogen
Plasminogen a
– t-Plasminogen activator (t-PA)
• cleaves plasminogen into the activated form: a two
chain disulfide
• Plasminogen ----kallikrein----Plasmin
• PLASMIN DISSOLVES THE CLOT
– limits fibrin clot to avoid ischemia in tissue
– localizes clot to prevent widespread thrombosis
DISSOLVING
THE BLOOD
CLOT
D-dimer
PROSTACYCLIN (PGI2)
• Produced by endothelial cell via PGH1
• chiefly prevents formation of the
PLATELET plug
• inhibiting platelet activation
• Antagonist to Thromboxane (TXA2)
• Vasodilator
– epoprostenol –FLOLAN
• primary pulmonary hypertension
Control MechanismsBLOOD FLOW AND SHEAR
• DILUTION of procoagulants by flowing blood
• Removal of activated Factors via RE cells
• Stasis promotes clotting
Antithrombotic Mechanisms-summary
• INTRINSIC REGULATION OF CLOTTING CASCADE
– ANTITHROMBIN III
– PROTEIN C/PROTEIN S
– TF PATHWAY INHIBITOR
• TISSUE FACTOR (thromboplastin or factor III)
• MODULATION OF VESSEL AND PLATELET REACTIVITY
– PROSTACYCLIN (PGI2) – repulses platelets
– nitric oxide- Vasodilation
• INHIBITION OF PLATELET RECRUITMENT
– Ecto-ADPase (CD39) – inactivated ADP
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REMOVAL OF FIBRIN CLOT (CLOT BUSTERS )
– Fibrinolysis– tPA and plasminogen
Prevention of Inappropriate Coagulation
• Platelet repulsion (PGI2; nitric oxide-- vasodilation)
• Dilution of activated factor
– Nitric oxide-vasodilator more blood flow
– STASIS IS THE ENEMY
• in low flow states may see thrombosis
• Circulating anticoagulants
– antithrombin-III (circulating protease inhibitor)
• inhibits thrombin & Factor X
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two big players in common pathway !!!!
– heparin-blocks thrombin quickly,
• prothrombin activator, and promotes antithrombin III activity
(supercharges it)
• Source: Mast cells
– Protein C & Protein S
– negative feedback of pathways; important due to
common deficiencies found in pts
• Fibrinolysis removes clot
1.Excessive production of
thrombin,
2.AT-III deficiency
3. Protein C or S
Deficiency
THROMBOSIS
Protein C & S
inhibit this
Diminished thrombin formation
from many etiologies causes
HEMORRHAGE
Tissue
factor
Plasminogen
(-)
Thrombotic Disorders
• Genetic
– Factor V Leiden
mutation
– Protein C deficiency
– Protein S deficiency
– Antithrombin III
deficiency
– prothrombin 20210
mutation
• Acquired
– Antiphospholipid
antibodies
• (Anti-Cardiolipin
antibodies)
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Cancer
Atherosclerosis
Hyper-homocysteinemia
Infection
Stasis
Injury
Hypercoagulability
-more
deaths from clotting than
bleeding
“KILLER CLOTS”
• Myocardial infarction
• Deep venous ThrombosisPulmonary
Emboli
• Cerebral vascular accidents• Thrombotic Emboli-sources
– Carotids
– Heart – Atrial fibrillation, CHF
Deep Venous Thrombosis/
Venous Thrombo Embolism
• VenousThromboEmbolism: DVT and/orPE
– 1:1000 Americans, yearly
– high death rate
• 250,000 Americans/year
– objective of DVT treatment to prevent PE
– 59 % of VTE from current or recent
hospitalization or nursing home
• 24 % hospital-surgery
• 22 % hospital-medical
• 13 % nursing home
VTE risk
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Malignancy
Trauma
Surgery- Extremity
Smoking
Drugs- Birth Control – high estrogen
Congestive Heart failure
Central Venous Pressure (CVP) catheter
Pacemaker/Defibrillator placement
Neurological deficits- CVA, MS, Spinal cord
Superficial vein thrombosis
Hereditary deficiencies- ProteinC/S, antithrombin III
• STASIS, STASIS, STASIS
Hypercoagulability: Risk Factors
• recent surgery
• tissue factor exposure,
especially orthopedic)
• total hip replacement: 25% w/o
prophylaxis (3-4% fatal)
• -reduced 30-50% with prophylaxis
• traumatic hip fx: 50%
• total knee replacement: 60%
• fractures or other traumas
Virchow’s Classic Triad
• THREE MAJOR ELEMENTS
– that promote thrombosis
– Endothelial injury
– Decrease in blood flow
– Imbalance between procoagulants and
anticoagulants
• (Hypercoagulable state)
Endothelial Injury
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Mechanical trauma
Atherosclerosis- (intrinsic pathway)
Endotoxins from bacteria
Proteases & cytokines of inflammation
Immune-autoimmune
Hypoxia
Decrease in Blood Flow
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Heart failure (HF)-causes stasis
Atrial fib/flutter,
Myocardial infarction
Immobilization
• Long travel & long flight –
• “economy class syndrome”
• Casting
• Bedridden (stroke)
Thrombophilia (hypercoagulable)
• GENETIC:
– 5 – 8 % of population has one genetic clotting disorder;
25-50% will have F. V Leiden
• AGE: at onset < 50 yrs.
• IDENTIFIABLE RISK FACTORS: may be none
– Frequently triggered by 2nd risk factor
• FAMILY HISTORY: frequently positive
• PAST HISTORY: recurrent events
• get into trouble when 2nd risk factor is present
INHERITED
Hypercoagulable Disorders
• activated Protein C resistance
– (Factor V Leiden genetic mutation)
– 25% in pt w/ family hx of thrombosis
– 5% of white population;
– #1 cause of inherited thrombophilia
– named for city in Netherlands
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Hyper-homocysteinemia - (under debate)
Antithrombin III deficiency
Protein C deficiency (1:100)
Protein S deficiency
prothrombin 20210 mutation -altered
thrombin production
ACQUIRED
Hypercoagulable Disorders
• ANTIPHOSPHOLIPID ANTIBODY SYNDROME:
– found in some cases of SLE, syphilis, rheumatoid arthritis
• ACQUIRED HYPERCOAGULABLE STATE
– physiologic or thrombogenic stimulus
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acute-phase reactants from inflammation
advanced age (fibrinogen levels increase)
OCP, pregnancy
surgery, trauma
– hypercoagulable state from other disease
• Malignancy,
• renal- nephrotic syndrome,
• “thick blood”-polycythemia, Sickle Cell
Treatment of Venous
Thromboembolism
• RISK STRATIFY
• LOW risk & clearly identifiable cause
– 3 months oral anticoagulation
• MEDIUM risk
– 6 months oral anticoagulation
• HIGH risk
– life long anticoagulation w/ INR - 2-3
Treatment for Hypercoagulation
• ANTICOAGULANTS:
• heparin, low-molecular heparin, warfarin (Coumadin)
• PLATELET ANTAGONISTS
• INACTIVATES COX –
• necessary for production of Thromboxane A2
– Aspirin –irreversibly
– NSAIDS: reversible inactivation of platelets
• ADP INHIBITIORS
– Ticlopidine-Ticlid
– Clopidogrel-Plavix
• IIB/IIIA INHIBITORS (INHIBIT PLATELET AGGREGATION)
– Abciximab(Reopro), Eptifibatide(Integrilin)
– Tirofiban (Aggrastat)
• FIBRINOLYTIC AGENTS
• Streptokinase, urokinase, tissue plasminogen activators (t-PA)
Heparin-Low molecular weight
• LMWH - depolymerized (fractionated)
– more reliable, predictable
– Monitoring PTT not required
– SQ administration; outpatient therapy possible
– Pregnancy-prophylaxis only- 2 & 3 trimester
– lower risk of thrombocytopenia
– Enoxaparin(Lovenox), Dalteparin (Fragmin)
Coumadin (warfarin)
• reduce clotting of the blood via blocking
the production of Factors VII, IX, X, and II;
competes w/ Vitamin K uptake and
recycling by the liver
• PO, daily
• Indications: DVT/PE, AFib, mechanical
valve replacement
• - must follow PT/INR
• Caution: when using platelet inhibitory Rx
Dabigatran-PRADAXA
• Direct Thrombin inhibitor
– No Protime necessary
• Indications:
– Stroke prevention, DVT Treatment
• Problems:
– Bleeding
– Renal adjustment necessay
INDICATIONS for
THROMBOLYTICS –
”CLOT BUSTERS”
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Acute myocardial infarction (AMI)
Deep vein thrombosis (DVT)
Pulmonary embolism (PE)
Acute ischemic stroke (AIS)
Acute peripheral arterial occlusion
Occlusion of indwelling catheters
Contraindications to Thrombolytics
• history of hemorrhagic stroke < 2 months
• CNS neoplasm, AV malformation, or aneurysm, or
CNS surgery < 2months
• Severe uncontrolled hypertension (over 200/130 or
complicated by retinovascular disease or
encephalopathy)
• ongoing (active) bleeding
• s/p recent significant surgery
• known bleeding disorder
• MI due to aortic dissection
• allergy to agent planned
• many relative contraindications
Thrombolytics – clot busters
• FIBRIN-SPECIFIC AGENTS
– Alteplase (t-PA) Activase, t-PA
– Retaplase (recombinant-PA) Retavase
– Tenecteplase TNKase
• NON–FIBRIN-SPECIFIC AGENTS– Urokinase or Prourokinase (direct
plasminogen cleavage) - nonallergenic
– Streptokinase- allergenic- inexpensive
DISSEMINATED
INTRAVASCULAR
COAGULATION
DIC
DISSEMINATED INTRAVASCULAR
COAGULATION
– Clotting cascade GONE WILD(acute fulminant
process):
– often mediated by
affecting
.
– usually
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Infection (gram negative),
Malignancy,
OB complication – miscarriage, aminotic fluid
Snake Venom
DIC
Clinical:
Hemorrhage - internal and external
Mucosal
“shock”
Petechia/purpura
Labs:
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thrombocytopenia
normal or slightly prolonged aPT
prolonged aPTT
Low Fibrinogen levels
FIBRIN SPLIT PRODUCTS PRESENT
RBC’s – Helmet cells/schiztocytes(fragmented)
– Due to RBC’s being cut up by Fibrin strands
Microangiopathic hemolytic
anemia
• Mechanical shearing
of the RBC as they is
cut by fibrin strands
DIC -TREATMENT
• Treatment should primarily focus on addressing
the underlying disorder.
• Monitor vital signs, assess and document extent
of hemorrhage and thrombosis, correct
hypovolemia, and administer basic hemostatic
procedures-ICU-Transfer
• Platelet and factor replacement.as indicatedFresh frozen plasma
• HEPARIN should be provided to those patients
who demonstrate extensive fibrin deposition
without evidence of substantial hemorrhage