Rami Khouzam, MD

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

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

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

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

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

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

Medications:

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

PE: (Pertinent)

Neck: No JVD, No Bruit

CVS: S1S2 Regular rhythm @ 60 Systolic murmur II/VI over LSB, No g,r

Lungs: CTA bilat., No w, c, r

Ext: No e, c, c

Medications:

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

What’s missing?

Clinical Use

Market share

Mechanical60%

Bio40%

>60.000 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

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)

Tissue Valves(Biologic)

Heterograft

Porcine

1- Carpentier-Edwards porcine

2- Medtronic-Hancock porcine

3- Biocor 4- Intact

5- Mosaic

Bovine Pericardial

Carpentier-Edwards pericardial

Tissue Valves

Homograft

Cryopreserved aortic homograft

Autograft

Pulmonary autograft

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)

Virchow’s triad/ tetrad

1- Vascular endothelial surface abnormality

2- Stasis of blood flow 3- Abnormalities within circulating blood

4- Artificial surface

Components of Virchow’s vary according to:

a) Etiology, presence, duration, and extent of VHD

b) Prosthetic materials used

c) Position of valvular insertion (aortic, mitral, both)

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)

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)

Natural history of PHV thrombosis... Potential fate: 1- Partial/ complete lysis 2- Organization: platelets, fibrin & neutrophils (48 hrs) monocytes (phagocytes:engulfing

RBCs & platelets) (1st week) SMCs & CTM (2nd week) 3- Re-endothelialization

Dream valve in Dreamland

Ideal prosthetic valve: - Normal hemodynamic profile - Lives forever - Nonthrombogenic

(Ideal valve … like Ideal husband Still DOES NOT EXIST)

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 Earle’s medium 1999 and decellularized

Cebotari S, et al. Circ. 2002

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

General Considerations1- Age

2- Anticoagulation

3- Child-bearing potential

4- Chamber/annulus size

5- Concomitant CABG

(tissue may be better)

6- Psychosocial

7- Patient preference

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 < 65 y, MVR < 70 y

IIb Thrombosed tissue valve replacement

III CI or unwillingness to take warfarin

ACC/AHA Guidelines 2001

Tissue Valves

I CI or unwillingness to take warfarin

I AVR > 65 y and no risk factors

IIa Anticipated noncompliance with coumadin

IIa MVR > 70 y and no risk factors

IIb Thrombosed mechanical valve replacement

IIb < 65 y

III Renal failure, hemodialysis, hypercalcemia

III Growing adolescentsACC/AHA Guidelines 2003

General

Risk factors

1- Atrial fibrillation

2- Previous thromboembolism

3- Hypercoagulable state

4- LV dysfunction (controversial)

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

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

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

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

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

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

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

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

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

Rat Poison…

or

Wonder Drug?

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

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

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

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 γ- carboxylation of the coagulation factors

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

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

Side Effects

Hemorrhage

Necrosis of the skin or other tissues

Purple Toes Syndrome

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

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

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

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

"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

So are we seeing the last days of warfarin?

Only the future will tell...

Recommendations

From the 6th ACCP Consensus Conference

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

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

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

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

Warfarin + Aspirin

Recommendations from the 6th Consensus Conference on Antithrombotic therapy:

Mechanical valve + thromboembolic event despite adequate anticoagulation

Caged ball or caged disk valve

Mechanical valves + additional risk factors: Prior thromboembolism Atrial fibrillation Large left atrium Coronary heart disease Left atrial thrombus Ball valve > 1 mechanical prosthetic valve Mechanical prosthesis in the mitral position

Stein, PD, Alpert, JS, et al. Chest 2001

PHV in Nonagenarians Study: 35 (aged 90-<100 years old) had PHV

between 1986 & 2000

30-day mortality: 17.1%

2-year survival: 74.3%

No operative mortality

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

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

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

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

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

Coumadin