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Rami Khouzam, MD. Interesting Historical Facts (Blood Transfusion) Z 1492: Pope Innocent VIII, in Rome, had an apoplectic stroke and went into a coma.

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Presentation on theme: "Rami Khouzam, MD. Interesting Historical Facts (Blood Transfusion) Z 1492: Pope Innocent VIII, in Rome, had an apoplectic stroke and went into a coma."— Presentation transcript:

1 Rami Khouzam, MD

2 Interesting Historical Facts (Blood Transfusion) Z 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 Z 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

3 Z 1667: Jean-Baptiste Denis in France reported successful transfusions from sheep to humans Z 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

4 Z 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 Z 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

5 Z 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 Z 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

6 Z 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

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

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

9 PE: (Pertinent) u Neck: No JVD, No Bruit u CVS: S 1 S 2 Regular rhythm @ 60 Systolic murmur II/VI over LSB, No g,r u Lungs: CTA bilat., No w, c, r u Ext: No e, c, c

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

11 What’s missing?


13 Clinical Use

14 u >60.000 cardiac valve replacement/ year in the US u Mechanical valves: expected to last 20- 30 years u Tissue valves: u 30% of heterograft u 10-20% of homograft fail in 10-15 yrs Vongpatansin, et al. NEJM 1996

15 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)

16 Tissue Valves (Biologic) Heterograft Porcine 1- Carpentier-Edwards porcine 2- Medtronic-Hancock porcine 3- Biocor4- Intact 5- Mosaic Bovine Pericardial Carpentier-Edwards pericardial

17 Tissue Valves Homograft Cryopreserved aortic homograft Autograft Pulmonary autograft


19 Pathophysiology and mechanisms of Thrombosis u (+) Charged surfaces favor thrombus formation u (-) Charged surfaces : thromboresistant  Artificial surfaces with a net + charge: highly adsorptive of plasma proteins (& blood cells) e.g Fibrinogen (1st. Protein)

20 Virchow’s triad/ tetrad 1- Vascular endothelial surface abnormality 2- Stasis of blood flow 3- Abnormalities within circulating blood 4- Artificial surface

21 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)

22 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)


24 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)


26 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

27 Dream valve in Dreamland Ideal prosthetic valve: - Normal hemodynamic profile - Lives forever - Nonthrombogenic (Ideal valve … like Ideal husband Still DOES NOT EXIST)

28 Tissue-Engineered Heart Valve (TEHV) In Study... ÊWith human marrow stromal cells on the trileaflet heart valves fabricated from rapidly absorbable polymers  Hoerstrup SP, et al. Circ. 2002 ËCultivated 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

29 ÌAortic 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


31 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


33 Mechanical Valves I Expected long life span I Mechanical valve in another position IIaRenal failure, hemodialysis, hypercalcemia IIaRequiring warfarin for risk factors IIaAVR < 65 y, MVR < 70 y IIbThrombosed tissue valve replacement III CI or unwillingness to take warfarin ACC/AHA Guidelines 2001

34 Tissue Valves I CI or unwillingness to take warfarin IAVR > 65 y and no risk factors IIaAnticipated noncompliance with coumadin IIaMVR > 70 y and no risk factors IIbThrombosed mechanical valve replacement IIb< 65 y III Renal failure, hemodialysis, hypercalcemia III Growing adolescents ACC/AHA Guidelines 2003



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

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

39 Coumadin (Warfarin): How Farmers With Moldy Hay and An Attempt at Suicide Transformed the Face of Medicine u The name Warfarin was created from Wisconsin Alumni Research Foundation and the rin from the word coumarin u 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

40 u The farmer had with him a dead calf and a milk can of blood that would not coagulate u 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 u Link and his colleagues discovered that coumarin in the hay was being chemically transformed into dicoumarol

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

42 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

43  1941: Dicoumarol was patented and was therapeutically used as an anticoagulant

44 u 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

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

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

47 Rat Poison… or Wonder Drug?

48 u 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

49 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

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



53 u Warfarin is a vitamin K antagonist. It produces its anticoagulant effect by interfering with the vitamin K cycle u It interacts with the KO reductase enzyme so that vitamin KO cannot be recycled back to vitamin K u This leads to a depletion of vitamin KH 2, limiting the γ- carboxylation of the coagulation factors

54 Efficacy  1983: A system of standardising the PT in oral anticoagulant control was introduced by the World Health Organisation (WHO) u 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

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

56 Side Effects u Hemorrhage u Necrosis of the skin or other tissues u Purple Toes Syndrome

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

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

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

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

61  "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

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

63 Recommendations  From the 6th ACCP Consensus Conference

64 Management of Patients with Prosthetic Heart Valves u Anticoagulation  A) Mechanical Valves: Systemic embolization (Mitral valve 2 x risk of Aortic valve) u No anticoagulation: 4.0% per patient per year u Aspirin: 2.2% u Warfarin: 0.7 to 1.0% Cannegieter, SC et al. NEJM 1995

65 Mechanical Valves First 3 months: INR 2.5-3.5 After 3 months: u Aortic: Bileaflet or Medtronic Hall: INR 2-3 Risk Factor or other valves: INR 2.5-3.5 u Mitral:INR 2.5-3.5

66 B) Bioprosthetic Valves: u Major advantage is freedom from anticoagulation u 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

67 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

68 Warfarin + Aspirin Recommendations from the 6th Consensus Conference on Antithrombotic therapy: u Mechanical valve + thromboembolic event despite adequate anticoagulation u Caged ball or caged disk valve

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

70 PHV in Nonagenarians Study: u 35 (aged 90-<100 years old) had PHV between 1986 & 2000 u 30-day mortality: 17.1% u 2-year survival: 74.3% u No operative mortality

71 u 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

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

73 PHVs and Pregnancy u Mechanical PHVs: incidence of warfarin embroyopathy is low (average 3.9%) u 0-12 wks: unfractionated heparin u 13-38 wks: Warfarin OK u 39-40 wks: unfractionated heparin

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

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


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