Computational Journalism at Columbia, Fall 2013, Lecture 8: Social Network Analysis
Lecture 8, fall 2014
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Transcript of Lecture 8, fall 2014
Lecture 8
Thrombophilia
Thrombophilia
• Arterial Thrombosis • Stroke and myocardial infarc:on are major causes of death ▫ Every 45 seconds someone in the US suffers a new or recurrent stroke ▫ 800,000/year
� Every 34 seconds someone in the US suffers a new or recurrent MI � 1.5 million/year à ~ 1/3 will die
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Atherosclerosis
• Atherosclerosis – thickening of the arterial wall – primary cause of coronary artery disease and cerebrovascular disease – Arterial wall thickens to form an atherosclero:c plaque – Reduces the blood supply to the organ (heart and brain – most common)
• Atheroma – accumula:on of intracellular and extracellular lipid in the in:ma of large and medium sized arteries
Atherosclerosis • Mechanism
1. A lesion begins as a faTy streak (preatheroma) that protrudes into the in:ma • LDL enters the in:ma – modified by oxida:on and aggregates within the extracellular
in:ma space • Smooth muscle cells, T-‐lymphocytes , and macrophages migrate into the area –
macrophages phagocy:ze the oxidized lipids • Proteoglycans, collagen and elas:c fibers migrate into the area
2. Fibro-‐faTy lesion forms – diffuse in:mal thickening occurs • Atheromatous plaque
3. Complicated plaque • Eggshell briTleness, ulcera:on of the luminal surface, micro-‐emboli released into the
blood stream, decreased blood flow results in more thrombus forma:on
Pathogenesis
1. Chronic inflammatory response of the vascular wall to endothelial injury or dysfunc:on
2. Elevated plasma LDL levels causing the deposit of LDL in the subendothelium of blood vessels
3. Oxida:on of transmigrated LDL
4. Ac:va:on of endothelial cells
5. Recruitment of monocytes/macrophages which ingest ox-‐LDL through scavenger receptors
6. Forma:on of foam cells – faTy streaks
7. Prolifera:on of smooth muscle cells
8. Deposi:on of extracellular matrix proteins
Atherosclero:c Plaque
• Coronary Atherosclerosis
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Mechanism of Arterial Thrombosis
8 hTp://www.drugs.com/health-‐guide/images/205452.jpg
CORONARY ARTERY DISEASE
1. Artery narrowed by cholesterol containing atheroma – note how the tube which the blood flows through has been narrowed and restricted
2. Once the surface of the vessel is damaged, platelet clot accumulates restric:ng flow – this may resolve or worsen
3. Platelets may accumulate so that blood flow is limited by the clot and this causes starva:on of oxygen death of muscle and a heart aTack
Pathogenesis of coronary heart disease (CHD)
Thrombophilia ▫ Venous Thrombosis ▫ DVT/PE à ~ 900,000 to 2,000,000/year ▫ 60,000-‐100,000 individuals will die of DVT/PE ▫ 10-‐30% will die within one month of diagnosis ▫ ~25,000 of these deaths result from VTE contracted in hospitals ▫ >25X the number of deaths from MRSA ▫ >Combined total deaths from BC + AIDS + MVA
• Ironically – fatal PE caused by DVT may be the most common preventable cause of hospital death in the US – only 1/3 of hospitalized paBents with risk factors for VTE receive preventaBve measures
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Mechanism of Venous Thrombosis
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• Most common manifesta:ons – Deep vein thrombosis – Pulmonary embolism – Postphlebi:c syndrome
• Mechanism – Endothelial damage
• Trauma, surgery • TF • Thrombin genera:on • Primary hemosta:c plug with fewer platelets
• Venous stasis – Red clots
Nature, 451(21) Feb 2008
What Causes a Thrombus to Form? Venous Thrombogenesis
– Thrombi begin in regions of slow/disturbed blood flow Damaged veins, valve cusp pockets
– Inherited/acquired hypercoagulable states important – Stasis is a major risk factor – Variable response to thrombus
• Classical signs/symptoms DVT • Minimal signs/symptoms
DVT/PE
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Venous Clot
Thrombosis (Blood Clots)
Intracoronary Clot
DVT
PE
Intracranial Bleed Hemorrhagic Stroke
Hemorrhage (Bleeding)
Gross specimen, coronal sec:on of brain, large subcor:cal hypertensive ICH
Chronic venous ulceration Very difficult to manage
Post phlebitic syndrome
Pain (dull and aching), leg cramps, heaviness, itching and altered sensation
Arterial versus Venous Thrombosis Arterial Thrombosis Venous Thrombosis
� Arterial thrombosis � Occur under high shear condi:ons � Rich in platelets � Involved disrupted atherosclero:c
plaque � Platelet adhesion, ac:va:on, and
aggrega:on prior to ac:va:on of coagula:on cascade
� White clots
� Myocardial infarcBon and stroke � AnBplatelet agents
� AnBfibrinolyBc and anBthromboBc agents
• Venous thrombosis – Under low shear stress – Fewer platelets involved – TF generates thrombin prior to
platelet ac:va:on – Red clot
– DVT, PE – AnBcoagulaBon agents for
venous thrombosis
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Arterial vs Venous Clot
hTp://www.emedicinehealth.com/slideshow_pictures_deep_vein_thrombosis_dvt/ar:cle_em.htm
hTps://www.med.unc.edu/wolberglabl/scien:fic-‐images/arterial%20thrombosis.jpg/view
Virchow’s Triad
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Thrombosis
Stasis
Changes in Blood Composi;on
Vascular Injury
Arterial Rudolph Virchow
Post-‐operaBve state CasBng/splinBng Sedentary state Leukostasis syndrome (AML) Congenital heart disease
Central line, Sepsis Trauma, APA Chemotherapy/toxins Hyperhomocysteinemia
Inherited thrombophilia Acquired thrombophilia
Virchow’s Triad
Thrombosis involves 3 interrelated factors: 1. Abnormali:es of the blood vessel wall 2. Abnormali:es in blood flow 3. Abnormali:es in the blood cons:tuents
• Cells -‐ Erythrocytes, leukocytes, platelets • Plasma proteins
Risk Factors
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• Mul:ple risk factors—mul:-‐factorial process – Hereditary – Acquired
• Mul:-‐hit hypothesis – Most hereditary and acquired risk factors have a rela:vely small
individual effect – Risk is greatly increased when two or more risk factors combine
• Classifica:on of Thrombophilia – Inherited – Acquired—Physiologic, Environmental
Thrombophilia
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• Acquired or inherited causes
• Venous and arterial events
• Occurs when the cloqng system is ac:vated 1. Excessive genera:on of prothrombo:c factors 2. Failure in the regulatory mechanisms to down-‐
regulate the coagula:on cascade 3. Inhibi:on of the fibrinoly:c system
Thrombophilic Risk Factors
Congenital Risk Factors Mechanism
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¤ Protein C ¤ Protein S ¤ AT
¤ FVL ¤ PG20210 ¤ FVIII ¤ Homocysteine (acquired also)
¨ Non-‐modifiable
Prothrombotic
Inhibitory
Acquired Risk Factors
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¨ Acquired risk factors ¤ Pregnancy ¤ Malignancy ¤ Surgery ¤ Immobiliza:on ¤ Hormone therapy (HRT, OCT) ¤ An:phospholipid an:bodies ¤ Trauma ¤ Obesity
¨ Physiologic risk factors ¤ Gender (hormonal changes) ¤ Age –Increases ~1%/year of age
n Childhood = 1/100,000 n 40 years = 1/1000 n 75 years = 1/100
¨ IdenBfy a populaBon at risk but have low predicBve value for individuals
Modifiable
Non-‐modifiable
Prevalence of Risk Factors
0%
5%
10%
15%
20%
25%
% Risk
FVL PG AT PC PS FVIII
Risk Factor
Prevalence of Inherited Risk Factors
General Population Selected: 1st Thrombotic Event
Prevalence of Acquired Risk Factors
0102030405060708090
Fractures
Hip
Cancer
APAS
OCT
Pregnancy
HRT
Hcys
FVIII
Risk Factor
Incr
ease
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Congenital Risk Factors Acquired Risk Factors
Who should be tested
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¨ Pa:ents presen:ng with ¤ Venous thrombo:c event before 40-‐50 years of age ¤ Unprovoked or Recurrent thrombosis at any age ¤ Thrombosis at unusual site ¤ Posi:ve family history of thrombosis ¤ Unexplained abnormal laboratory test (PT, aPTT)
¨ Age of first episode
¤ 0-‐12 years Rare ¤ 13-‐45 years Highly probable ¤ 45-‐60 years Probable ¤ 60+ years Possible
Congenital Risk Factors
When to test
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¨ Op:mal Times for Tes:ng
• Asymptoma:c • Not on an:coagulant therapy • Any:me for DNA tes:ng
¨ To establish • Pathologic basis for the thrombo:c event • Dura:on and intensity of therapy • Prophylaxis for high risk pa:ents • To alert the pa:ent's immediate family members to the presence of possible inherited risk factors
Laboratory Assays for Thrombophilia
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• Plasma-‐based assays – AT – PC – PS – APC-‐R – Lupus An:coagulant/An:phospholipid An:bodies
• Dilute Russell Viper Venom Test (dRVVT) • An:cardiolipin An:bodies • An:-‐β2-‐Glycoprotein An:bodies
– Factor VIII – Homocysteine
• DNA-‐based assays – FVL – PG20210 – MTHFR
An:thrombin Deficiency
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• Eggberg, 1965 • Reported the first inherited thrombophilic state • Func:ons as a naturally occurring inhibitor of the coagula:on cascade • Most severe of the inherited condi:ons • Rela:vely uncommon (~1% of first DVT)
• Clinical Manifesta:ons – Increased incidence of venous thrombosis – AT levels <40-‐50% – Ini:a:ng events leading to thrombosis
• Surgery • Trauma • Pregnancy • OCT
Protein C Deficiency
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¨ Griffin, early 1980’s ¨ 75% of individuals will experience one or more events ¨ Thrombosis may be spontaneous ¨ Func:ons as a naturally occurring inhibitor of the coagula:on
cascade ¨ 50% of heterozygotes will experience VTE by 40 years of age
¨ Common Manifesta:ons ¤ DVT ¤ PE ¤ Superficial thrombophlebi:s ¤ Cerebrovascular events ¤ Myocardial events
Protein S Deficiency
¨ Described in 1984, Comp ¨ TOTAL PS circulates in 2
forms: ¤ Bound PS—60%
n C4B-‐BP—nonfunc:onal ¤ Free PS—40%-‐func:onal
¨ Serves as a cofactor for PC ¨ Binds aPC to the
phospholipid surface ¨ 50% of heterozygotes will
experience VTE by 40 years of age
Free PS
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Total PS
C4bBP
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aPC-‐Resistance—Screening assay
• aPC-‐resistance – Dahlbäck et al in 1993 – Func:ons as a natural
an:coagulant – Poor an:coagulant response of
aPC to degrade FVa and VIIIa – Ra:o of 2 aPTT’s—(+/-‐ APC)
__(aPTT plus APC)__ (aPTT minus APC)
• “Screening assay” for FVL muta:on
• http://www.wardelab.com/arc_2.html
Approximately 90% of APC Resistance is caused by a defect in the Factor V molecule, known as the Factor V Leiden gene muta:on
Factor V Leiden—Confirmatory Assay for FVL Muta:on
– Muta:on later described in 1994 by Ber:na et al – Caused by single point muta:on in the FV gene
• A single nucleo:de subs:tu:on of adenine for guanine at nucleo:de 1691 of the FV gene
• Replacement of Arg (R) with Gln (Q) at pos 506 in F.V protein
– Higher risk for thrombosis – Venous thrombosis most common manifesta:on
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PG20210 Muta:on
¨ Poort et al, 1996
¨ Single nucleo:de subs:tu:on G20210A in the 3’ UT region of the prothrombin gene ¤ G → A subs:tu:on at nucleo:de
20210 in prothrombin gene
¨ Results in elevated levels of prothrombin (~30% increase)
¨ No screening test available
¨ Occurs primarily in Caucasians -‐-‐~3% in general popula:on
¨ 2-‐5-‐fold increased risk of VTE
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Homocysteine
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¨ McCully suggested an associa:on between elevated levels of homocysteine in plasma and arterial disease
¨ Most common congenital form due to: 1. (C677T)* in MTHFR gene 2. B-‐cystathionine synthase gene
¨ Acquired form due to deficiencies in Folate, B-‐6, B-‐12
¨ Gene:c tes:ng* is controversial ¤ Homocysteine levels may provide
more informa:on ¨ Normal values increase with age
¤ Higher in males
www.naturaleyecare.com/ar:cles/elevated-‐homocysteine-‐and-‐eye-‐...
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An:phospholipid An:bodies • An:phospholipid an:bodies
– Acquired thrombophilic disorder – An:bodies directed against proteins that bind to phospholipid
membrane surfaces – Autoimmune process
• Subgroups of APLAs – Lupus An;coagulant – An;-‐ Cardiolipin an;bodies – An;-‐Beta-‐2-‐glycoprotein I an;bodies – An:-‐Prothrombin an:bodies – An:-‐Phospha:dylserine an:bodies – An:-‐Phospha:dylethanolamine an:bodies – An:-‐ Phospha:dylinositol an:bodies
hTp://circ.ahajournals.org/cgi/reprint/112/3/e39
Clinical Diagnosis APAS • Acquired disorder which occur in 1-‐5% of the general popula:on • Pa:ent must present with one clinical and one laboratory criteria
• Clinical Manifesta:on – Vascular thrombosis
• One or more clinical episodes of arterial, venous or small vessel thrombosis in any :ssue or organ
– Pregnancy Morbidity • One or more spontaneous abor:ons, severe preeclampsia, eclampsia, death of a normal fetus at or near 10 months gesta:on
• Laboratory Criteria – Posi:ve test in the APA test panel on 2 separate occasions, > 6-‐12 weeks apart
• Lupus An:coagulant • An:cardiolipin An:body • An: –B2-‐Glycoprotein I An:body
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Lupus An:coagulant
• Heterogeneous group of an:bodies (IgG, IgM, or both) that prolongs phospholipid-‐dependent coagula:on tests – Immunoglobulin that acts as a coagula:on inhibitor
– Does not recognize a “specific” coagula:on factor – Retards the rate of thrombin genera:on and clot forma:on in vitro by interfering in phospholipid-‐dependent reac:ons
• Detected in in vitro coagula:on assays only
42
Lupus An:coagulant • Affect 2-‐4% of the U.S. popula:on
• Discovered accidentally—prolonged aPTT found during a pre-‐opera:ve evalua:on
• O|en cause a variety of clinical and laboratory effects
– O|en there are no clinical consequences other than the need to explain the reason for the long APTT
– Minority of pa:ents with LA have a hypercoagulable state manifested by: • Recurrent thromboses • Mul:ple spontaneous miscarriages • Migraine headaches • Stroke
• Rarely pa:ents may experience bleeding – Bleeding due to an:bodies to prothrombin
• Lupus an:coagulants (LA) are a heterogeneous group of an:bodies that cause a variety of clinical and laboratory effects
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Lupus An:coagulant • Results in prolonga:on of phospholipid-‐dependent assays • LA is o|en iden:fied during rou:ne screening with the standard
aPTT – In vitro à results in a prolonged aPTT
• Prolonga:on due to reagent sensi:vity to lupus an:coagulant
• Usually does not result in clinical bleeding – In vivo à usually results in thrombosis rather than clinical bleeding
• Abundance of phospholipid – These neutralize the an:body – May explain why bleeding does not occur in vivo
• An:body may be persistent or transient
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Lupus An:coagulant
• All lupus an:coagulants are APAs, but not all APAs are lupus an:coagulants
• Targets specific proteins
• B2GPI • Prothrombin • Proteins C, S • Annexin V
45
Phospholipid AssociatedProteins:•Protein C,S•β2GPI •Prothrombin•and others
Phospholipid Membrane
Antibody:•lupus anticoagulant•anticardiolipin•antiphosphatidylserine•anti b2GPI•anti Annexin V•anti Prothrombin
ANTIBODY-‐MEDIATED THROMBOSIS
Lupus An:coagulant and Thrombosis
The Paradox... How does an anticoagulant in vitro, become a risk factor for hypercoagulability in vivo ? Coagulation Factor/Protein = Phospholipid
CA+2
Calcium Anchor
46
=PL
46
Clinical Significance of the APAs/LA
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• Prevalence in venous and arterial thrombosis • DVT ~32% • Stroke ~15% • Superficial thrombophlebi:s ~9% • Pulmonary embolism ~9% • Fetal loss ~8% • TIA ~7%
• Associated with 2 broad categories of phospholipids an:bodies – An:cardiolipin an:bodies
• Most likely to be clinically significant with high :ters for IgG and IgA – β2-‐GPI an:bodies
• More specific for thrombosis and other clinical complica:ons of the APAS
E:ology of LA
• Exact e:ology of LA is unclear • An:bodies are commonly found in asymptoma:c elderly individuals • Pa:ents with autoimmune disorders • SLE have the highest incidence (20-‐45%) • Pa:ents with HIV infec:on have a high incidence of LA at some :me in the course
of their disease
• A number of drugs are known to induce LA, most notably – Procainamide – Hydralazine – Isoniazid – Dilan:n – Phenothiazines – Quinidine – ACE inhibitors are known to induce LA
48
Lupus An:coagulant and Thrombosis
• LA are one of the most common acquired predisposing causes of thrombosis – cerebral thrombosis – deep venous thrombosis – renal vein thrombosis – pulmonary emboli – arterial occlusions – stroke
• Reports indicate that LA are found in: – 8-‐14% of pa:ents with deep venous thrombosis – 1/3 pa:ents with stroke <50 years of age – Evidence that recurrent thrombo:c events tend to be persistent over :me in
the same pa:ent
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LA in Thrombocytopenia and Pregnancy
• LA and thrombocytopenia – An immune type thrombocytopenia has been observed in a small
percentage of pa:ents with LA – This may be due to reac:ons between an:bodies and platelet
membrane-‐associated phospholipids
• LA and Pregnancy – increased risk of fetal loss due to pre-‐eclampsia, placental abrup:on,
intrauterine growth retarda:on, and s:llbirth – Some evidence suggests that this may be due to an:bodies against the
placental an:coagulant protein, annexin V – Placental infarc:on has been suggested as the cause of the failure to
carry to term but pathological analysis has not definitely supported this conten:on
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Mechanisms of the Reduc:on of Annexin V Levels and the Accelera:on of Coagula:on Associated with An:phospholipid An:bodies
Rand J, NEJM 1997;337:154-‐160
• Annexin V – Phospholipid dependent an:coagulant proper:es on cell
membranes – Placental an:coagulant (shield on placental villi) – Vascular an:coagulant
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Proposed Mechanisms of Thrombosis
• Impaired Fibrinolysis • Inhibi:on of Protein C and S system • Inhibi:on of Prostacyclin release from endothelial cells
• Inhibi:on of Annexin V – Tissue Pathway Down Regula:on
• Inhibi:on of B2GPI – may affect Protein S
52
An:cardiolipin An:body ELISA
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