rami khouzam, md. interesting historical facts (blood transfusion) z 1492: pope innocent viii, in...
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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