Download - Lecture 8, fall 2014
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Lecture 8
Thrombophilia
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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
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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
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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
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Atherosclero:c Plaque
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• Coronary Atherosclerosis
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Mechanism of Arterial Thrombosis
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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
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Pathogenesis of coronary heart disease (CHD)
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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
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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
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DVT/PE
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Venous Clot
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Thrombosis (Blood Clots)
Intracoronary Clot
DVT
PE
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Intracranial Bleed Hemorrhagic Stroke
Hemorrhage (Bleeding)
Gross specimen, coronal sec:on of brain, large subcor:cal hypertensive ICH
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Chronic venous ulceration Very difficult to manage
Post phlebitic syndrome
Pain (dull and aching), leg cramps, heaviness, itching and altered sensation
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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=PL
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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
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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
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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
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An:cardiolipin An:body ELISA
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