An Inspiring Suicide

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Rami Khouzam, MD
An Inspiring Suicide
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Interesting Historical Facts(Blood Transfusion)

• 1492 Pope Innocent VIII, in Rome, had an
  apoplectic stroke and went into a coma. His
  physician advised a Blood transfusion. Employing
  crude methods, the Pope did not benefit and died
  by the end of that year
• 1665 1st recorded successful blood transfusion
  occurred when physician Richard Lower managed to
  keep dogs alive after transfusing blood from
  other dogs

Blundell's blood transfusion apparatus, 19th
century
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• 1667 Jean-Baptiste Denis in France reported
  successful transfusions from sheep to humans
• 1678 Transfusion from animals to humans was
  deemed to be unsuccessful, and was outlawed by
  the Paris Society of Physicians because of
  reactions, many resulting in death

Blood transfusion apparatus, American 1920 1955
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• 1818 James Blundell, a British obstetrician,
  performed the first successful transfusion of
  human Blood to a patient for the treatment of
  postpartum hemorrhage. Using the patient's
  husband as a donor, he extracted a small amount
  of Blood from the husband's arm and, using a
  syringe, he successfully transfused the wife
• 1873-1880 Physicians in the US are documented to
  have transfused milk (from cows and goats) to
  humans

Bottle from blood transfusion apparatus 1914-1918
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• 1901 Karl Landsteiner an Austrian physician, and
  the most important individual in the field of
  Blood transfusion, documented the first three
  human Blood groups A, B O
• 1908 French surgeon Alexis Carrel devised a way
  to prevent Blood clotting. His method was joining
  an artery in the donor, directly to a vein in the
  recipient with surgical sutures. He first used it
  to save the life of the son of a friend, using
  the father as donor. This procedure, not feasible
  for Blood transfusion, paved the way for
  successful organ transplantation, for which
  Carrel received the Nobel Prize in 1912

Alexis Carrel
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• 1932 The first facility functioning as a Blood
  bank was established in a Leningrad Russia
  hospital
• 1970s blood transfusion had become the basis of
  much of modern medicine and voluntary blood
  donors now play an important role as co-health
  workers with medical professionals around the
  world

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Index Case

• 46 yo caucasian gentleman with HTN
• HIV and HCV
• S/P AVR with a bioprosthetic valve (Carpentier
  Edwards) in 2001, following fungal endocarditis
• Presents for a regular clinic F/U
• Currently doing fine, denies any C/O

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Medications

• - Coumadin 9.5 mg qd
• - Atenolol 25 mg qd
• - Zantac
• - HIV meds Zerit/ Epivir/ Kaletra

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PE (Pertinent)

• Neck No JVD, No Bruit
• CVS S1S2 Regular rhythm _at_ 60
• Systolic murmur II/VI over LSB, No g,r
• Lungs CTA bilat., No w, c, r
• Ext No e, c, c

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Medications
?

• - Coumadin 9.5 mg qd
• - Atenolol 25 mg qd
• - Zantac
• - HIV meds Zerit/ Epivir/ Kaletra

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Whats missing?
?
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• Prosthetic

Valves
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Clinical Use
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• gt60.000 cardiac valve replacement/ year in the US
• Mechanical valves expected to last 20-30 years
• Tissue valves
• 30 of heterograft
• 10-20 of homograft
• fail in 10-15 yrs
• Vongpatansin, et al. NEJM 1996

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Mechanical Valves

• 1- Starr-Edwards caged-ball
• 2- Medtronic-Hall tilting-disc
• 3- St. Jude Medical bileaflet
• 4- CarboMedics bileaflet
• 5- Omniscience tilting-disc
• 6- Bjork-Shiley (previously used in the US,
  continued to be used in other areas)

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Tissue Valves(Biologic)

• Heterograft
• Porcine
• 1- Carpentier-Edwards porcine
• 2- Medtronic-Hancock porcine
• 3- Biocor 4- Intact
• 5- Mosaic
• Bovine Pericardial
• Carpentier-Edwards pericardial

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Tissue Valves

• Homograft
• Cryopreserved aortic homograft
• Autograft
• Pulmonary autograft

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Pathophysiology and mechanisms of Thrombosis

• () Charged surfaces favor thrombus formation
• (-) Charged surfaces thromboresistant
• Artificial surfaces with a net charge highly
  adsorptive of plasma proteins ( blood cells) e.g
  Fibrinogen (1st. Protein)

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Virchows triad/ tetrad

• 1- Vascular endothelial surface abnormality
• 2- Stasis of blood flow
• 3- Abnormalities within circulating blood
• 4- Artificial surface

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Components of Virchows vary according to

• a) Etiology, presence, duration,
• and extent of VHD
• b) Prosthetic materials used
• c) Position of valvular insertion (aortic,
• mitral, both)

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Aortic valve

• Blood flow typically rapid
• Acceleration high shear stress
• ? - platelets activation
• - RBCs membranes damage
• - ADP release
• - ? platelet activation and aggregation
• ( contribution of coagulation factors 2ry)

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Mitral valve

• Blood flow comparatively slow
• (esp. if MS, LAE, MR and LV dilatation)
• ? stasis and ? contact of coagulation factors
  with damaged endocardial or prosthetic surface
• (contribution of platelets 2ry)

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Natural history of PHV thrombosis...

• Potential fate
• 1- Partial/ complete lysis
• 2- Organization
• ?platelets, fibrin neutrophils (48 hrs)
• ?monocytes (phagocytesengulfing RBCs
  platelets) (1st week)
• ?SMCs CTM (2nd week)
• 3- Re-endothelialization

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Dream valve in Dreamland

• Ideal prosthetic valve
• - Normal hemodynamic profile
• - Lives forever
• - Nonthrombogenic
• (Ideal valve like Ideal husband
• Still DOES NOT EXIST)

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Tissue-Engineered Heart Valve (TEHV) In Study...

• With human marrow stromal cells on the trileaflet
  heart valves fabricated from rapidly absorbable
  polymers
• Hoerstrup SP, et al. Circ. 2002
• Cultivated human venous endothelial cells onto
  cadaver human allografts (homografts) that had
  been preserved in antibiotic-enriched Earles
  medium 1999 and decellularized
• Cebotari S, et al. Circ. 2002

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• Aortic valve interstitial cells to repopulate
  aortic valve leaflets that had been
  decellularized aortic valve leaflets
• Morphological and mechanical properties similar
  to human native heart
• Bertipaglia, et al. Ann. Thorac Surg. 2003

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Selection
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General Considerations

• 1- Age
• 2- Anticoagulation
• 3- Child-bearing potential
• 4- Chamber/annulus size
• 5- Concomitant CABG
• (tissue may be better)
• 6- Psychosocial
• 7- Patient preference

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Mechanical Valves

• I Expected long life span
• I Mechanical valve in another position
• IIa Renal failure, hemodialysis,
• hypercalcemia
• IIa Requiring warfarin for risk factors
• IIa AVR lt 65 y, MVR lt 70 y
• IIb Thrombosed tissue valve replacement
• III CI or unwillingness to take warfarin
• ACC/AHA Guidelines 2001

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Tissue Valves

• I CI or unwillingness to take warfarin
• I AVR gt 65 y and no risk factors
• IIa Anticipated noncompliance with coumadin
• IIa MVR gt 70 y and no risk factors
• IIb Thrombosed mechanical valve replacement
• IIb lt 65 y
• III Renal failure, hemodialysis,
  hypercalcemia
• III Growing adolescents
• ACC/AHA Guidelines 2003

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Anticoagulation
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General

• Risk factors
• 1- Atrial fibrillation
• 2- Previous thromboembolism
• 3- Hypercoagulable state
• 4- LV dysfunction (controversial)

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The History of Warfarin

• Farmers in the northern prairie states of Canada
  and the USA began planting sweet clover plants
  imported from Europe
• Although the sweet clover proved to be
  nutritious, it also brought a fatal disease of
  cattle herds
• Sweet clover disease affected cattle
  relentless, spontaneous bleeding

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Coumadin (Warfarin) How Farmers With Moldy Hay
and An Attempt at Suicide Transformed the Face of
Medicine

• The name Warfarin was created from Wisconsin
  Alumni Research Foundation and the rin from the
  word coumarin
• According to the Wisconsin Alumni Research
  Foundation, one snowy morning in 1933 a farmer
  named Ed Carlson showed up at the lab of Dr. Karl
  P. Link

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• The farmer had with him a dead calf and a milk
  can of blood that would not coagulate
• The farmer had been feeding his cattle sweet
  clover hay. Storage had caused the sweet clover
  hay to spoil and eating it had killed the calf
• Link and his colleagues discovered that coumarin
  in the hay was being chemically transformed into
  dicoumarol

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• 1921 Schofield, a veterinary pathologist in
  Alberta, reported that the disease was caused by
  consumption of spoilt sweet clover hay

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• 1940 The mystery of why spoilt hay caused the
  disease was solved by Karl Paul Link his
  co-workers in mouldy hay, coumarin is oxidised
  to 4-hydroxycoumarin and then coupled with
  formaldehyde and another coumarin moiety to form
  dicoumarol, an anticoagulant

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• 1941 Dicoumarol was patented and was
  therapeutically used as an anticoagulant

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• 1951 a navy recruit unsuccessfully attempted
  suicide with 567 mg of warfarin. His surprising
  full recovery induced research into the
  anticoagulant potency of warfarin in humans

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• 1954 Warfarin was introduced commercially and
  Clinicians quickly discarded dicoumarol in favor
  of "rat poison"
• In that same year President Eisenhower was
  treated with warfarin following a heart attack
• Today warfarin is the standard treatment for
  long term oral anticoagulant therapy

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• Link "My rule is, never overstate your case in
  print. It's better to understate it and let the
  facts speak for themselves."

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• Rat Poison
• or
• Wonder Drug?

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• Brand names Coumadin (USA) and Marevan (UK) and
  as its generic version Warfarin Sodium
• It is sold as colored tablets, each color
  indicating the strength of the dose

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• By the way
• If you can't remember the name Warfarin just use
  the chemical name
• 4-Hydroxy-3-(3-oxo-1-phenyl-butyl)-chromen-2-one

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• Another large application as rat poison
• Effective in controlling Norway (Brown) rats and
  house mice
• Rodents continue to consume it until its
  anticlotting properties have produced death
  through internal haemorrhaging

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• Warfarin is a vitamin K antagonist. It produces
  its anticoagulant effect by interfering with the
  vitamin K cycle
• It interacts with the KO reductase enzyme so that
  vitamin KO cannot be recycled back to vitamin K
• This leads to a depletion of vitamin KH2,
  limiting the ?- carboxylation of the coagulation
  factors

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Efficacy

• 1983 A system of standardising the PT in oral
  anticoagulant control was introduced by the World
  Health Organisation (WHO)
• The INR is calculated
• INR (patient PT / control PT) ISI
• ISI International Sensitivity Index and is the
  correction factor which includes effects of the
  reagent used

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• Interactions with other drugs
• Drugs which potentiate the anticoagulant effect
  include anabolic steroids, cimetidine,
  fluconazole, miconazole, metronidazole,
  propanolol, tetracycline, flu vaccine, aspirin
  Cranberry.
• Other drugs inhibit the action of warfarin and
  include barbiturates, rifampin, carbamazepine,
  cholestyramine and even high-vitamin K-content
  foodstuff

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Side Effects

• Hemorrhage
• Necrosis of the skin or other tissues
• Purple Toes Syndrome

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• Other adverse reactions fever, urticaria, taste
  perversions, rash, dark urine, sores in mouth or
  throat priapism
• Pregnancy relatively contraindicated. Fatal
  hemorrhage to fetus in utero birth malformation
  ??
• Narrow Therapeutic Range (NTR) drug

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The Future

• Alternatives acenocoumarol (nicoumalone)
  phenindione very rarely used
• Warfarin (branded or generic) remains the most
  widely used oral anticoagulant
• Coumadin achieved sales of over 400 million in
  1999. For the last 50 years, warfarin has
  dominated the market of oral anticoagulants

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• New drug Exanta (Ximelagatran) by AstraZeneca.
  The first investigational oral anticoagulant to
  reach Phase III trials in more than 50 years
• Works by interfering with thrombin Direct
  Thrombin Inhibitor (DTI)
• Avoids stringent dietary restrictions or the need
  for constant laboratory tests to ensure safe
  levels of medicine. Fewer interactions with food
  and other drugs

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• Some analysts believe it could become a 3
  billion-a-year drug
• Ximelagatran
• Currently in clinical trial
• DVT Prophylaxis and treatment
• Arch Int. Med. 2001
• Atrial fibrillation prevention of stroke
• Post-MI 2nry. Prophylaxis
• ESTEEM, Lancet 2003

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• "If Exanta is approved, I think people taking
  Coumadin (warfarin) will switch to it and that
  Coumadin will slowly fade away after 60 years on
  the market," said Dr. Jack Ansell, a researcher
  from Boston University School of Medicine, in a
  Reuters interview

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• So are we seeing the last days of warfarin?
• Only the future will tell...

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Recommendations

• From the 6th ACCP Consensus Conference

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Management of Patients with Prosthetic Heart
Valves

• Anticoagulation
• A) Mechanical Valves
• Systemic embolization
• (Mitral valve 2 x risk of Aortic valve)
• No anticoagulation 4.0 per patient per year
• Aspirin 2.2
• Warfarin 0.7 to 1.0
• Cannegieter, SC et al. NEJM 1995

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Mechanical Valves

• First 3 months
• INR 2.5-3.5
• After 3 months
• Aortic
• Bileaflet or Medtronic Hall INR 2-3
• Risk Factor or other valves INR 2.5-3.5
• Mitral INR 2.5-3.5

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• B) Bioprosthetic Valves
• Major advantage is freedom from anticoagulation
• However, low level anticoagulation (INR 2.0-3.0)
  is recommended in first 3 months to lessen
  thromboembolic complications arising from factors
  such as lack of endothelialization of the suture
  line during the early postoperative period

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Tissue Valves

• First 3 months
• INR 2.5-3.5 (sometimes not done for
• aortic)
• After 3 months
• No risk factor None
• Risk factor aortic INR 2-3
• Risk factor mitral INR 2.5-3.5

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Warfarin Aspirin

• Recommendations from the 6th Consensus Conference
  on Antithrombotic therapy
• Mechanical valve thromboembolic event despite
  adequate anticoagulation
• Caged ball or caged disk valve

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• Mechanical valves additional risk factors
• Prior thromboembolism
• Atrial fibrillation
• Large left atrium
• Coronary heart disease
• Left atrial thrombus
• Ball valve
• gt 1 mechanical prosthetic valve
• Mechanical prosthesis in the mitral position
• Stein, PD, Alpert, JS, et al. Chest 2001

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PHV in Nonagenarians

• Study
• 35 (aged 90-lt100 years old) had PHV between 1986
  2000
• 30-day mortality 17.1
• 2-year survival 74.3
• No operative mortality

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• At a mean of 2.53 years (range. 0.16-7.1 years)
  after PHV survival was 81
• Bachetta MD, et al. Ann Thorac. Surg. 2003

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• In 2000, nonagenarians in the US totaled 1.6
  million and centenarians numbered 72.000
• By 2050 numbers expected to be 8.8 million and
  1.1 million respectively

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PHVs and Pregnancy

• Mechanical PHVs incidence of warfarin
  embroyopathy is low (average 3.9)
• 0-12 wks unfractionated heparin
• 13-38 wks Warfarin OK
• 39-40 wks unfractionated heparin

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• Ten studies 427 pregnancies, incidence was zero
• FDA warning about the use of low-molecular-weight
  heparin during pregnancy
• Pregnancy bioprosthesis associated with SVD
  (structural valve deterioration) 24 during or
  shortly after pregnancy
• SVD at 10 years was 55-76
• Hung L. et al. Circ. 2003

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Summary

• Mechanical PHV Coumadin
• ASA (alone) not enough
• Thrombogenicity caged ball gttilting disk gt
  bileaflet
• Thrombogenicity Mitral area gt Aortic area
• High risk pts Coumadin ASA (81- 100mg)
• Bioprosthetic valves Coumadin x 3 months
• gt x risk factors
• New thrombin inhibitors (Ximelagatran) might
  overthrown Coumadin

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