Reduction of Platelet Thrombi in Cardiovascular Prostheses: Mechanical and

Tissue Heart Valves, Vascular Graft and Components of Heart Lung Machine

Mrinal K. Dewanjee, MSc, PhD, FAHA, FAIMBE

Mrinal K Dewanjee, PhD, FAHA, FAIMBENeurobiology, Neurodegeneration & Repair Laboratory, National Eye Institute, NIH, Bethesda, MD 20892, USA

In the absence of any tools or methods, the cardiovascular surgeons, neurologists, cardiologists could only speculate about the role of thrombi and emboli.

I made two major Algebraic equations that changed the world of thrombi and emboli on drug evaluation and reduction of thrombi on cardiovascular prostheses (CVPs: Mechanical and Tissue Heart Valves, Vascular Graft and Components of Heart Lung Machine) that also reduced mortality from platelet thrombi during cardiopulmonary bypass (CPB) procedure, essential for implantation of CVPs by continous measurements of thrombi: Non-invasive Imaging of thrombi in live animals and patients with a gamma camera and measurements of small amount of radioactivity with a gamma counter using In-111 tagged autologous platelets. Similar measurements were made for the clotting factors, fibrinogen, thrombin with I-125/123/131 labeled radionuclides. High shear rate in hollow-fiber fragmented platelets thus reducing their chance of thrombi and emboli in brain and other perfused organs during CPB and hemodialysis.

Cross-calibration of Gamma camera, Dose-calibrator and Gamma counter

Gamma camera could image large thrombi with large amount of radioactivity. Dose-calibrator measures large and medium amount of radioactivity (millicurie to microcurie). Small amount of radioactive thrombi is measured with a gamma counter (Counts per min: CPM). By cross-calibration, we could account for all platelets: Thrombi, Emboli and their fragments.The Equation, I developed, converted platelet-bound radioactive count into number of platelets. Mayo Clinic, NHLBI and Corporate sponsors supported my studies for 25 years.

Human Imaging

X-ray: CT Gamma ray: SPECT/CT MRI

Fused PET-CT-MRI

Ultrasound

Fluor-IR: Optical

?

Fusion ImagingCT: Structure/ResolutionPET/MRI: Function

3D Imaging of Organs by Miracle Machines of 21th Century

Indium chemistry is similar to that of a trivalent Cation, like Ferric ion: Fe3+

Best Best 111111InIn--complex for Cell Labelingcomplex for Cell LabelingMake platelets GLOW with RadiationMake platelets GLOW with Radiation

Quantification of platelet retention in aortocoronary femoral vein bypass graft in dogs treated with dipyridamole and aspirin. pg. 350-356. Circulation 69, No. 2, 350-356, 1984.Dewanjee, Mrinal K. Ph.D.; Tago, Mamoru M.D.; Josa, Miguel M.D.; Fuster, Valentin M.D.; Kaye, Michael P. M. D.

We used Idonne-125 for in vitro measurements and I-123 and I-131 for clotting factors: fibrinogen, thrombin and

other proteins.

Best Best 111111InIn--complex for Cell Labelingcomplex for Cell LabelingMake platelets GLOW with RadiationMake platelets GLOW with Radiation

Quantitation of Platelet Thrombi with 111In-platelets on stainless steel retainer for pyrolitic carbon disk, Dacron sewing ring, Teflon-felt-sutures and injured valve annulus in Medtronic Hall Valve Prostheses (22-mm, 24 hour after implantation)

in a Duroc-Yorkshire Pig model

Imaging Thrombus on Dacron Graft (15 yr. after Repair of Abdominal Aortic Aneurysm, 24 hr after IV

administration of 111In-platelets, 850 microcuries)

Dewanjee: Sem Nucl Med 14: 154-187,1984

Medtronic-Hall Single Disc Mechanical Heart ValveDisc opens and closes around the Central Pivot

Pig Model (24 hr)

Platelet Thrombi on Components of Mechanical Heart Valve (Pig Mitral annulus: 24 hr after heart valve implantation

(Medtronic-Hall Valve, Minneapolis, MN)

ECC: CPB, ECMO, Hemodialysis

Plasmapheresis

Extracorporeal Circuit for Blood Supply to Brain and other organs, when Heart and Lung are stopped/Bypasses for Repair and Oxygen is supplied by Artificial Lung

Open Heart Surgery-ECC: Roller Pumps (4)-Arterial Filter

Mitral and Aortic Heart valve replacement (Starr-Edwards)38-year old antiques Going Strong-73 year-old woman.

Thrombus on Pericardial Tissue heart valve in Calf and young patients calcifies.

SE Mech Ball-in-a-

Cage Valves

Calf (Holstein) Model for Tissue Heart Valve (Pericardium-Sweet heart piece) CalcificationBoth Aortic and mitral valve prostheses calcified after 2 years (10 yr old boy at Mayo Clinic)

Tissue engineering for spontaneous endothelial cell coverage of pericardial tissue heart valve (explant from a calf at 60 days). Leaflets were conjugated with

Aminodiphosphonate and assembled at Shiley, Inc. (Dewanjee ASAIO 32: 24,1986)

Mapping of regional platelet thrombi on five segments of CABG and enhancing of graft patency from 75% to 95% with aspirin-

Persantine therapy (Dewanjee et al. Circ 69: 350, 1984)

Quantitation of Universal Parameter for Platelet-Fibrinogen Organization in Thrombus

CABG Patency by Platelet-inhibitors(Dewanjee et al. Circulation 69:350, 1984)

MRI (1.5 Tesla, Picker Inc., Univ. of Miami, Radiology) of Pig Brain Swelling after Cardiopulmonary Bypass (~3 hr) Higher TNFα during CPB

Cholesterol Deposition on Canine CABG (Dewanjee 1982): Why we should use Statin Early after Surgery or Vessel Wall

Injury!

Mathematical Models for the Calculation of Human Platelet Survival Times. Dewanjee MK, et. al. Mayo Clinic Proc 61: 327-336, 1986.

Schematic representation of a platelet showing the different platelet organelles. Besides the membrane systems, i.e., Open Canalicular System (OCS) and Dense Tubular System (DTS), and Mitochondria, the three specific granules are easily identified. Dense granules (d –G, CaPO4) are the smallest with an intense opaque dense core surrounded by a clear space. Platelets provide a rich sources for a rapid access for a variety of growth factors

IV Infusion of In-111 tagged PMN Neutrophils in a Pig Model: Transient Margination-Lung

LUNG

LIVER

SPLEEN

Hello Michael and Chris,

As I walk around the Bldg. 10 South entry, I was intrigued by your impressive assembly of cardiovascular prostheses (CVPs), their history of developments and the heart lung-machine used to implant the CVPs. My mother, a pious Hindu woman told me I have no right to kill animals, especially holy cows, I used to evaluate the calcification of tissue heart valves, unless I solve the puzzle of arterial thrombi. I am proud to keep the promise I made during her visit in 1980.

I was lucky to face the challenge of measurement of thrombi and emboli in animal models and patients for the last 25 years (1976-2000) working with best cardiologists, thoracic surgeons, pathologists, hematologists and pharmacologists at Mayo Clinic, Univ. of Miami, FL and UIUC Urbana-Champaign, IL.

Dr. Nina Braunwald's student, Dr. Jerry Kaiser helped to me set up the Cardiovascular Surgery Lab at Miami (1987-1996), after I left Mayo Clinic.

I hope, you could use some of figures, I developed in collaboration withe the bioengineers at Baxter, Medtronics and Bjork-Shiley to improve blood flow, deliver oxygen and reduce thrombi. The corporations are very generous to provide with hundreds of heart valves, circuits for heart-lung machine and drugs, gratis to resolve their problems and patients.

If you have any question, I will be glad to assist.

Thanks. Mrinal