Lupus Anticoagulant

Lupus Anticoagulant
By:Jennifer Kirkland (Lambe)

Antiphospholipid
Antibody Syndrome
* Antibodies to phospholipids or plasma proteins bound to phospholipids
o Lupus anticoagulant antibodies
o Anticardiolipin antibodies
o Anti-ß2- glycoprotein I antibodies
* Other antibodies: prothrombin, annexin V, phosphatidylserine, phosphatidylinositol
o These antibodies are not standardized for clinical use and their clinical utility is not well characterized

Lupus anticoagulant
* Lupus anticoagulant
o Describes a group of antibodies which react with cardiolipins, other phospholipids, ß2-glycoprotein I, or proteins other than ß2-glycoprotein I
-AND-
o possess “lupus anticoagulant” activity

What is lupus anticoagulant activity?

* Ability to interfere with coagulation testing (in particular, the tests which are phospholipid dependent) leading to prolonged values
* Despite the “anticoagulant effect” in vitro, these antibodies actually cause coagulation in vivo, in the form of arterial and venous thromboses

Lupus anticoagulant:
Actually a Misnomer
* Associated with clotting, not anticoagulation
* More than one antibody is associated with lupus anticoagulant activity
* Only about 50% of individuals with a lupus anticoagulant meet the American College of Rheumatology criteria for the classification of lupus (SLE)

Definitions
* Cardiolipin= mitochondrial phospholipid
o Causes a biologic false positive test for syphilis
* ß2-glycoprotein I -(not a phospholipid but a plasma phospholipid binding protein)
o In early 1990s, discovery that some anticardiolipin antibodies require the presence of ß2-glycoprotein I in order to bind to cardiolipin
o Patients with SLE or the antiphospholipid syndrome require ß2-glycoprotein I in order to bind to cardiolipin
o Most ß2-glycoprotein I-dependent anticardiolipin antibodies recognize ß2-glycoprotein I equally well whether bound to cardiolipin or bound to other anionic phospholipids

Additional info on LAs
* Anticardiolipin antibodies and Anti-ß2- glycoprotein I antibodies may not possess lupus anticoagulant properties
* Specificity of anticardiolipin antibodies for antiphospholipid syndrome increases with titer and is higher for the IgG than for the IgM isotope
* There is no definitive association between specific clinical manifestations and particular subgroups of antiphospholipid antibodies


Effects of antiphospholipid antibodies on coagulation
* Actually has opposing effects on coagulation
Procoagulant Effects
* Inhibits activated protein C pathway
* Up-regulates TF pathway
* Inhibits antithrombin III activity
* Disrupts annexin V shield on membranes
* Inhibits anticoagulant activity of ß2-glycoprotein I
* Inhibits fibrinolysis
* Activates endothelial cells
* Activates and degranulates neutrophils
* Enhances expression of adhesion moleculres by endothelial cells and adherence of neutrophils and leukocytes to endothelial cells
* Potentiates platelet activation
* Enhances platelet aggregation
* Enhanced binding of ß2-glycoprotein I to membranes
* Enhanced binding of prothrombin to membranes
Anticoagulant Effect
* Inhibits activation of factor IX
* Inhibits activation of factor X
* Inhibits activation of prothrombin to thrombin
o “Microenvironment of cell membranes in vivo may promote greater inhibition of anticoagulant pathways and therefore thrombosis.”
o Ultimately, we don’t really know the mechanism by which thrombosis is promoted over anticoagulation

Criteria for detection of lupus anticoagulant antibodies
* Lupus anticoagulant
1. Must prolong coagulation in at least one phospholipid-dependent coagulation assay with the use of platelet poor plasma
+ Extrinsic (dPT)
+ Intrinsic (aPTT, dilute aPTT, KCT, colloidal silica clotting time)
+ Final common pathway (dRVVT, Taipan venom time, Textarin and Ecarin time)

2. Failure to correct the prolonged coagulation time by mixing the patient’s plasma with normal plasma (1:1)
3. Correction of the prolonged coagulation time after addition of excess phospholipid or platelets that have been frozen and then thawed (they release phospholipids)
4. Rule out other coagulopathies with the use of specific factor assays if the confirmatory test is negative or if a specific factor inhibitor is suspected

To rule out a lupus anticoagulant antibody
* Two or more assays that are sensitive to these antibodies must be negative (one should be based on low phospholipid concentration and they should evaluate distinct portions of the coagulation cascade)

Diagnosis of antiphospholipid antibody syndrome
* Clinical Criteria
o Vascular thrombosis (Venous or arterial: blood vessels, brain, kidneys, lung GI tract, placenta etc)
o 1 or more deaths of normal fetuses at or after 10th week of gestation,or 1 or more premature births at or before the 34th week of gestation; or 3 or more unexplained consecutive spontaneous abortions before the 10th week of gestation

* Laboratory criteria
o Anticardiolipin antibodies
+ Anticardiolipin IgG or IgM antibodies present at moderate or high levels in the blood on two or more occasions at least 6 weeks apart
o Lupus anticoagulant antibodies
+ LA detected in the blood on 2 or more occasions at least 6 weeks apart (?12 weeks)

Antiphospholipid syndrome
* Primary
o No other evidence of another autoimmune disease
* Secondary
o Associated with autoimmune or other diseases, most commonly SLE
* Sneddon’s syndrome: clinical triad of stroke, livedo reticularis, and hypertension may represent undiagnosed antiphospholipid syndrome.


Epidemiology
* Antiphospholipid antibodies are found among young, apparently healthy control subjects at a prevalence of 1 to 5% for both anticardiolipin antibodies and lupus anticoagulant antibodies
o Meta-analysis
+ LA= 11.1 Odds ratio for venous thrombosis compared with 3.21 with anticardiolipin Ab
o Multivariant analysis
+ Odds ratio for venous and arterial thromboembolism is 4.4 with LA and 1.2 with anticardiolipin
* Prevalence increases with age

Prevalence of LAs in patients with SLE
* Anticardiolipin antibodies= 12-30%
* Lupus anticoagulant antibodies= 15-34%
* B2glycoprotein I antibodies=20%
o Antiphospholipid syndrome may develop in 50 to 70% of patients with both SLE and antiphospholipid antibodies after 20 years of follow-up
o Up to 30% of patients with SLE and anticardiolipin antibodies lacked any clinical evidence of the antiphospholipid syndrome over an average follow-up of seven years

Prospective study
* In a recent prospective study involving individuals with antiphospholipid antibodies, the incidence of thrombosis per year was:
o 1% in individuals with no history of thrombosis
o 4% in patients with systemic lupus erythematosus
o 5.5% in patients with a history of thrombosis
o 6% in individuals with high titer IgG anticardiolipin antibody (>40 units).

Functional Assays of Lupus Anticoagulants
* aPTT
o Some manufacturers offer aPTT reagent which contains a low amount of phospholipid, therefore it is more sensitive for lupus anticoagulant
o Conditions causing acute phase reactants associated with increased fibrinogen and factor VIII, may shorten the aPTT and mask a weak LA
* Prothrombin Time:
o patients with LA will have a normal PT unless they are receiving oral anticoagulants or they develop an inhibitor to prothrombin (PT reagents contain more phospholipids than PTT reagents)

* DRVVT (screening)
o Activates factor X which in the presence of PL, calcium, and factor V activates prothrombin, leading to the formation of a fibrin clot
o Dilution of the venom yields a clotting time in which concentration of the PL reagent is the rate limiting step (there is low amount of phospholipids)
o Inhibition by LA leads to prolongation
o After positive screen, perform the mixing study- if does not correct then:
* DRVVT (confirm)
o Adds a higher amount of phospholipids to neutralize the lupus anticoagulant
o Ratio is derived from the screen clotting time divided by the confirmatory clotting time
o If ratio exceeds the established cutoff, then lupus anticoagulant is in the specimen

Tissue thromboplastin inhibition test (TTI)
o Modified PT assay
o Thromboplastin, which is rich in phospholipid, can be diluted so that its concentration becomes the rate limiting step
o Inhibition of prothrombinase by a LA will cause prolongation of the PT assay
o Due to the various PL and its concentration in the reagent, the test varies in its sensitivity and specificity

STACLOT LA: Hexagonal II Phase Phospholipid Assay
* Two part aPTT screening assay for LA
* Patient’s plasma is mixed with buffer (screening test) or hexagonal phase phosphatidyl ethanolamine (confirmatory test) to neutralize any lupus anticoagulant present
* Mixtures are incubated with normal plasma to correct any coagulation factor deficiency
* Measure aPTT in both mixtures
* If specimen contains LA, the aPTT of the confirmatory test will be significantly shorter than that of the screening test

Staclot-LA
* Phospholipid antibody positive= difference in the clotting times between the two tubes is greater than + 8.0 seconds.
* The aPTT reagent in this assay contains a heparin inhibitor which makes the test system insensitive to heparin levels up to 2.0 U/mL.
* False positive results may occur in patients with high titer Factor VIII inhibitors

Summary
* Lupus anticoagulant causes thrombosis
* Lupus anticoagulant is a group of antibodies that bind to phospholipids or phospholipid binding proteins
* Due to the heterogeneity of the phospholipid antibody, there is no single test that is confirmatory for all phospholipid dependent antibodies.

References

* Kaolin clotting time
o Sensitive for LA when no additional PL is used
o LA is identified when the KCT fails to correct after the addition of even large amounts of plasma
o Problems with the KCT, owing to the particular nature of kaolin, is that it is unsuitable for some photo-optical devices, which makes full automation difficult
* Taipan (Oxysuranus scutellatus) venom activates prothrombin in the presence of PL and Ca2+
* Textarin (Pseudonaja textiles) acts similarly but requires the presence of factor V
* Specificity of both of the above tests can be improved by mixing tests and/or confirmation with the use of ecarin, an enzyme purified from the venom of Echis carinatus, in conjunction with the Textarin test

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Antiphospholipid Antibody Syndrome in Children

Antiphospholipid Antibody Syndrome in Children
By:Jill Glassberg Azok
Grand Rounds
January 23, 2009

Case: OL

* HPI: 2 yo female with Trisomy 21, Tetralogy of Fallot
o 7/9/08: surgical repair of TOF
o 7/31: re-exploration of surgical wound due to wound dehiscense, cultures +pseudomonas
o 7/31: developed rash on buttocks, trunk, described as “red, circular spots”; initially thought to be Candida
+ Over the next 2 wks, developed petechiael rash of her trunk, feet
+ Rash became diffuse erythroderma with resolution of petechiae
o 8/15: returned to OR for exploration of sternal wound due to fever, respiratory distress, and rash; no evidence of infection
o 8/22: returned to OR sternal non-union
+ cultures +corynebacterium and enterococcus facaelis


* PMHx
o DOL 3: TE fistula repair
o DOL 9: modified BT shunt
o Post-op course complicated by thrombus in iliac and aorta, requiring thrombectomy
o Hypothyroidism
o Trisomy 21
o Tetralogy of Fallot with pulmonary atresia
o Chronic lung disease requiring tracheostomy and ventilator
Labs
* Lupus anticoagulant: positive
* Russel viper venom test: negative
* Cardiolipin antibody: positive
o IgM: indeterminate, IgA/IgG: negative
* Beta-2-Glycoprotein-I
o IgM: negative, IgA/IgG: positive
* Phosphatidylserine antibodies
o IgA, IgG, IgM-negative
* Skin biopsy
o Marked hemorrhage in the superficial dermis; prominent fibrin thrombi with white blood cells occluding the vessels of the superficial vascular plexus.
o Given the occlusion and lack of inflammation around the vessels, we favor the extravasation of red blood cells is secondary to the occlusion and not secondary to a vasculitis.

Hospital Course
* Diagnosed with Catastrophic Antiphospholipid Antibody Syndrome: Treated with IVIG 5mg/kg
* 8/26: Decreased perfusion, increased lactate, decreased urine output, firm abdomen, guaic positive stools
o KUB: pneumatosis with possible portal venous gas formation
o Taken To OR for concern for necrotizing enterocolitis;
o Exploratory laparotomy and ileocolic resection
o Small intestine had diffuse areas of necrotizing enterocolitis with poor perfusion
o Right colon and the transverse colon were distended with evidence of full-thickness injury and vessel thrombosis
o Returned to CICU on inotropic support, broad spectrum antibiotics, both chest and abdomen were open
* 8/28 worsened clinically: Back to OR
o Small bowel was necrotic with multiple areas of full-thickness injury.
o The remaining portion of the colon down to the level of the rectus was also necrotic.
o Thrombi in the distal vessels and at the end branches of the mesenteric vessels
o She had a complete colectomy with resection of most of her small bowel
* 8/29: family decided to withdraw care: patient expired
* Autopsy: Cause of death listed as catastrophic antiphospholipid antibody syndrome

Antiphospholipid Antibody Syndrome
* Multisystem autoimmune disease
* Most common cause of acquired thrombophilia
* History
o 1906: antiphospholipid antibody discovered in patients with syphilis, complement-fixing antibody that reacted with extracts from bovine hearts
o 1952: Conley and Hartmann described circulating anticoagulant in patients with Lupus
o 1963: Bowie associated the anticoagulant with thromboembolic events
* Epidemiology
o Most common in young to middle-age adults
o Can occur in children and elderly
o More common in females

* Diagnosis
o At least one antiphospholipid antibody
o At least one clinical manifestation
* May be primary or secondary


CLINICAL CRITERIA
1. Vascular thrombosis: One or more clinical episodes of arterial, venous, or small vessel thrombosis, in any tissue or organ.
2. Pregnancy morbidity

A. One or more unexplained deaths of a morphologically normal fetus at or beyond the tenth week of gestation, with normal fetal morphology documented by ultrasound or by direct examination of the fetus, or

B. One or more premature births of a morphologically normal neonate at or before the thirty-fourth week of gestation because of severe preeclampsia or eclampsia, or severe placental insufficiency, or

C. Three or more unexplained consecutive spontaneous abortions before the tenth week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded


LABORATORY CRITERIA

1. aCL of IgG and/or IgM isotype in blood, present in medium or high titer, on two or more occasions at least 6 weeks apart, measured by a standardized ELISA for β2-GPI–dependent aCL.

2. Lupus anticoagulant present in plasma, on two or more occasions at least 6 weeks apart, detected according to the guidelines of the International Society on Thrombosis and Hemostasis (Scientific Subcommittee on Lupus Anticoagulant/Phospholipid-Dependent Antibodies), in the following steps:

A. Prolonged phospholipid-dependent coagulation demonstrated on a screening test (eg, activated partial thromboplastin time [aPTT], kaolin clotting time, dilute Russell's viper venom time, dilute prothrombin time, Texarin time)

B. Failure to correct the prolonged coagulation time on the screening test by mixing with normal platelet-poor plasma

C. Shortening or correction of the prolonged coagulation time on the screening test by the addition of excess phospholipid

D. Exclusion of other coagulopathies (eg, factor VIII inhibitor or heparin) as appropriate

Clinical Manifestations
* Vascular thrombosis: arterial and venous
* Skin: Levido reticularis
* Recurrent pregnancy loss
* Neurologic: TIA, stroke, migraine, chorea, seizures, optic neuritis
o Sneddon Syndrome: stroke, levido reticularis, hypertension
* Cardiac: Coronary artery disease, premature atherosclerosis, vegetations
* Renal: thrombotic microangiopathy, renal vein thrombosis, renal infarction, renal artery stenosis with hypertension, increased allograft vascular thrombosis, and reduced survival of renal allografts
* Pulmonary: PE, pulmonary hypertension
* GI: Budd-Chiari syndrome, intestinal ischemia and infarction, colonic ulceration, esophageal necrosis and perforation, hepatic infarction, acalculous cholecystitis with gallbladder necrosis, and mesenteric and portal vein thrombosis
* Hematologic: thrombocytopenia, TTP/HUS, hemolytic anemia

Antiphospholipid antibodies
* Antiphospholipid antibodies present in young, healthy controls
o Studies of healthy blood donors
+ Lupus anticoagulant in 8%
+ IgG anticardiolipin in 6.5%
+ IgM anticardiolipin in 9.4%
+ <2% of healthy blood donors with elevated anticardiolipin antibody still had elevated level 9months later
o Incidence increases with age and coexisting chronic disease
* Among patients with thrombosis, prevalence of antiphospholipid antibodies is 4 to 21%
* Increasing risk of thrombosis among those with higher antibody titers

* Lupus anticoagulant: most specific
o Functional assay, measures ability to prolong clotting time
o aPTT, Russel viper venom test, kaolin clotting time
o Meta-analysis showed the odds ratio of lupus anticoagulant for stroke: 11 compared to 1.6 for anticardiolipin
* Anticardiolipin antibodies- most sensitive
* Anti-b2 Glycoprotein I antibodies
* Other antibodies of unclear significance: prothrombin, annexin V, phosphatidylserine, phosphatidylinositol, phosphatidylcholine
* Some anti-cardiolipin antibodies require presence of the plasma phospholipid-binding protein b 2-glycoprotein I in order to bind to cardiolipin
* People with syphilis or infectious diseases, antibodies bind directly to anticardiolipin, independent of /inhibited by b 2-glycoprotein-I
* Autoimmune anticardiolipin antibodies directed against phospholipid-binding protein, not phospholipid itself

Pathogenesis Theories
* Interfere with phospholipid-binding proteins involved in the regulation of the clotting cascadeprocoagulant
* Activation of endothelial cellsincreased expression of cell-surface adhesion molecules and increased secretion of cytokines and prostaglandins
* Oxidant-mediated injury of vascular endothelium
* Platelet activation

Drug Induced aPLs
* Mediations reported
o Phenothiazines
o Phenytoin
o Hydralazine
o Procainamide
o Quinidine
o Dilantin
o Ethosuximide
o Alpha-interferon
o Amoxicillin
o Chlorothiazide
o Oral contraceptives
o Propranolol
* Usually transient
* Associated with IgM
* Rarely associated with thrombosis
* Mechanism unknown

Significance of aPLs
* No history of thrombosis and positive aPL: Risk of new thrombosis <1%
* History of thrombosis and positive aPL: Risk of new thrombosis >10% in first year if anticoagulation stopped within 6 months

A systematic review of secondary thromboprophylaxis in patients with antiphospholipid antibodies
Ruiz-Irastorza G Database of Abstracts of Reviews of Effects 2008

* Sixteen studies were included (n=1,740)
* Thrombosis recurrence rates among untreated patients: 19 to 29% per year
* Rates of major bleeding varied widely, ranging from 0.57 to 10% per year. Seventy-four per cent of bleeding episodes occurred in patients with an INR ≥3.0
* Eighteen deaths were reported to be directly related to recurrent thromboses and one due to bleeding. Ten patients in one study died as a result of the presenting thrombosis
* Patients with definite APS and arterial and/or recurrent thrombosis are at high risk of recurrent events. Most thrombotic events in patients on warfarin occur at an INR <3; recurrences are infrequent among those with an INR of 3.0 to 4.0. Patients with venous embolism or stroke and a single positive aPL that does not persist are at relatively low risk of recurrent thrombosis.
* Recommendations: after a first venous thrombosis, patients with APS should be treated with warfarin at an INR of 2.0 to 3.0; those with arterial or secondary thrombosis should be treated with warfarin at an INR >3.0. Patients with venous thrombosis or stroke and a single positive aPL test should be retested, and should be treated no differently from other patients unless the antibody persists.

Pediatric Antiphospholipid Syndrome: Clinical and Immunologic Features of 121 Patients in an International Registry
* 121 cases of antiphospholipid antibody syndrome in children in the European registry
o Mean age of onset: 10.7 years
o Slightly more common in females, 1.2:1
o 60 (49.5%) had underlying autoimmune disease
o 72 (60%) had venous thrombosis
o 39 (32%) had arterial thrombosis
o 81% had positive anticardiolipin antibodies
o 67% had positive anti-b2-glycoprotein I antibodies
o 72% had positive Lupus anticoagulant

Unique to Pediatric Population
* Lack of prothrombotic risk factors which are present in adults, ie cigarette smoking
o Frequency of vascular thrombosis lower
* Increased incidence of infection-related antiphospholipid antibodies
o Parvovirus B19, cytomegalovirus, varicella-zoster virus, HIV, streptococcal and staphylococcal infections, gram negative bacteria, mycoplasma pneumoniae
* Higher frequency of Evan’s syndrome, Raynaud’s, migraines, and chorea
* Decision-making for long term anticoagulation

Neonatal APS
* Due to transplacental passage of maternal aCL, disappear over 6months
* In pediatric age group, neonatal period highest risk for thrombosis
o Decreased Protein C, Protein S, and antithrombin
o Elevated Factor VIII and von Willebrand factor
* Despite this, very low risk of thrombosis

Catastrophic APS
* Multiple, simultaneous vascular occlusions throughout body
o Widespread microthrombi in multiple vascular bedsMassive thromboembolism
o Clinical involvement of at least 3 organ systems over days to weeks
o Histopathologic evidence of occlusions of small and large blood vessels
o Most common organs: kidney>lung>CNS>heart>skinmultiorgan failure
o DIC in 25%
o Respiratory failure, stroke, abnormal liver enzymes, renal insufficiency/failure, adrenal insufficiency, cutaneous infarcts
* Precipitating factor in 55%: Most common is infection
* Usually primary APS
* Treatment
o Treat precipitating factor if present
o Anticoagulation
o Steroids
o IVIG
o Plasma exchange
* Mortality > 50%

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Amino Acid Metabolism

Amino Acid Metabolism
by:Hanley N. Abramson
Professor of Pharmaceutical Sciences
Wayne State University

December 2009

Dynamics of Protein And Amino Acid Metabolism
Dietary Proteins Digestion to Amino Acids
Digestion of Proteins
Stomach: Pepsinogen Pepsin (max. act. pH 2)
Small Intestine: Trypsinogen Trypsin
Trypsin cleaves:
Chymotrypsinogen to chymotrypsin
Proelastase to elastase
Procarboxypeptidase to carboxypeptidase
Aminopeptidases (from intestinal epithelia)

Enteropeptidase
Lumen
Amino Acids Oligopeptides
Intestinal Absorption
Oligopeptides
Amino Acids
Peptidases
Blood
Transport
Protein
Incorporation of NH4+ Into Organic Compounds
Carbamoyl
Phosphate
Synthase I
(CPS-I)
Glutamate
dehydrogenase
a-Ketoglutarate
Glutamate
TCA Cycle
mitochondria
Glutamine
Glutamate
Glutamine
Synthase
Mg++
N of glutamine donated to other compounds in synthesis of purines, pyrimidines, and other amino acids
Biosynthesis of Amino Acids: Transaminations
Glutamate a-Ketoglutarate
Oxaloacetate Aspartate
Glutamate-Pyruvate
Aminotransferase
(Alanine Transferase ALT)
Glutamate-Oxaloacetate
Aminotransferase
(Aspartate Transferase AST)
Blood levels of these aminotransferases, also called transaminases, are important indicators of liver disease
Metabolic Classification of the Amino Acids
* Essential and Non-essential
* Glucogenic and Ketogenic
Non-Essential Amino Acids in Humans
* Not required in diet
* Can be formed from a-keto acids by transamination and subsequent reactions
* Alanine
* Asparagine
* Aspartate
* Glutamate
* Glutamine
* Glycine
* Proline
* Serine
* Cysteine (from Met*)
* Tyrosine (from Phe*)
* Essential amino acids
Essential Amino Acids in Humans
* Required in diet
* Humans incapable of forming requisite carbon skeleton
* Arginine*
* Histidine*
* Isoleucine
* Leucine
* Valine
* Lysine
* Methionine
* Threonine
* Phenylalanine
* Tryptophan

* Essential in children, not in adults

Glucogenic Amino Acids
* Metabolized to a-ketoglutarate, pyruvate, oxaloacetate, fumarate, or succinyl CoA
Phosphoenolpyruvate Glucose
* Aspartate
* Asparagine
* Arginine
* Phenylalanine
* Tyrosine
* Isoleucine
* Methionine
* Valine
* Glutamine
* Glutamate
* Proline
* Histidine
* Alanine
* Serine
* Cysteine
* Glycine
* Threonine
* Tryptophan

Ketogenic Amino Acids
* Isoleucine
* Leucine *
* Lysine *
* Threonine
* Tryptophan
* Phenylalanine
* Tyrosine

Amino Acids Formed From a-Ketoglutarate
Transamination or
Glutamate
Urea Formation
Blood Urea Nitrogen
Synthesis of Nitric Oxide
Nitric oxide synthase (NOS)
Nitric Oxide
Conversion of Serine to Glycine
Sulfur-Containing Amino Acids
Homocysteine
Homocysteinuria
High blood levels of homocysteine associated with cardiovascular disease
Methionine Metabolism: Methyl Donation
Pneumocystis carinii infectons
Creatine and Creatinine
Normal Utilization of Phenylalanine ....

Amino Acid Metabolism.ppt

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