CIRCULATORY SYSTEM

1. CIRCULATORY SYSTEM BLOOD

2. CIRCULATORY SYSTEM BLOOD HEART BLOOD VESSELS

3. FUNCTIONS OF BLOOD TRANSPORT PROTECTION REGULATION

4. FUNCTIONS OF BLOOD TRANSPORT OXYGEN (O2) CARBON DIOXIDE (CO2) NUTRIENTS WASTES HORMONES

5. FUNCTIONS OF BLOOD PROTECTION IMMUNE SYSTEM WHITE BLOOD CELLS ANTIBODIES CLOTTING SYSTEM PLATELETS FIBRINOGEN / FIBRIN

6. FUNCTIONS OF BLOOD REGULATION BODY TEMPERATURE pH WATER BALANCE ELECTROLYTE BALANCE

7. BLOOD COMPOSITION BLOOD IS COMPRISED OF TWO MAIN COMPONENTS: PLASMA FORMED ELEMENTS THESE COMPONENTS CAN BE SEPARATED BY CENTRIFUGATION

9. BLOOD COMPOSITION PLASMA (~55%) FORMED ELEMENTS BUFFY COAT (<1%) LEUKOCYTES PLATELETS RED BLOOD CELLS (~45%) THE FRACTION OF THE BLOOD VOLUME COMPRISED OF RED BLOOD CELLS IS TERMED THE HEMATOCRIT

10. PLASMA COMPOSITION WATER (~90%) SOLUTES (~10%) PROTEINS (~8%) OTHER COMPOUNDS (~2%) NUTRIENTS GASES WASTES HORMONES ELECTROLYTES

11. PLASMA PROTEINS MOST ABUNDANT PLASMA SOLUTE LIVER CAN PRODUCE 4 GRAMS OF PLASMA PROTEINS PER HOUR THREE MAJOR CATEGORIES ALBUMINS GLOBULINS FIBRINOGEN

12. PLASMA PROTEINS ALBUMINS ~60% OF PLASMA PROTEINS SMALL TRANSPORT LIPIDS, HORMONES, CALCIUM, ETC. BUFFER BLOOD pH CONTRIBUTE TO VISCOSITY & OSMOLARITY INFLUENCE BLOOD PRESSURE, BLOOD FLOW, AND FLUID BALANCE

13. PLASMA PROTEINS GLOBULINS ~36% OF PLASMA PROTEINS THREE SUBCLASSES ALPHA (a) BETA (b) GAMMA (g)

14. PLASMA PROTEINS GLOBULINS ALPHA (a) VARIOUS FUNCTIONS, ESPECIALLY TRANSPORT BETA (b) VARIOUS FUNCTIONS, ESPECIALLY TRANSPORT GAMMA (g) COMPONENTS OF IMMUNE SYSTEM PRODUCED BY PLASMA CELLS, WHICH ARE DESCENDED FROM WHITE BLOOD CELLS

15. PLASMA PROTEINS FIBRINOGEN ~4% OF PLASMA PROTEINS PRECURSOR OF FIBRIN INVOLVED IN BLOOD CLOTTING

16. PLASMA: NUTRIENTS SUGARS AMINO ACIDS FATS CHOLESTEROL PHOSPHOLIPIDS VITAMINS MINERALS

17. PLASMA: GASES OXYGEN (O2) REQUIRED FOR CELLULAR RESPIRATION CARBON DIOXIDE (CO2) PRODUCT OF CELLULAR RESPIRATION NITROGEN (N2) USUALLY PHYSIOLOGICALLY UNIMPORTANT WHY DO YOU THINK IT IS THERE?

18. PLASMA: WASTES NITROGENOUS WASTES PRODUCTS OF CATABOLISM (ESP: AMINO ACID CATABOLISM) MOST ABUNDANT IS UREA REMOVED FROM BLOOD BY KIDNEYS EXCRETED THROUGH URINE RATE OF REMOVAL BALANCES RATE OF PRODUCTION

19. PLASMA: ELECTROLYTES SODIUM (Na+) CALCIUM (Ca2+) POTASSIUM (K+) MAGNESIUM (Mg2+) CHLORIDE (Cl-) BICARBONATE (HCO3-) PHOSPHATE (HPO42-) SULFATE (SO42-)

20. PLASMA: ELECTROLYTES VARIOUS IONS SODIUM IS THE MOST PREVALENT INCREASE BLOOD OSMOLARITY AFFECT BLOOD VOLUME AFFECT BLOOD PRESSURE

21. FORMED ELEMENTS ERYTHROCYTES (RED BLOOD CELLS) LEUKOCYTES (WHITE BLOOD CELLS) PLATELETS (CELL FRAGMENTS)

23. ERYTHROCYTE FUNCTIONS CARRY O2 FROM LUNGS TO CELLS CARRY CO2 FROM CELLS TO LUNGS HOW DO O2 AND CO2 RELATE TO THE FUNCTIONS OF A CELL?

24. ERYTHROCYTE QUANTITIES MEN: 4.6 – 6.2 MILLION/mL IN HEMATOCRIT 42 – 52 (% RBCs) WOMEN: 4.2 – 5.4 MILLION/mL HEMATOCRIT 37 – 48 (% RBCs) GENDER DIFFERENCES BASED ON: ANDROGENS INCREASE NUMBER MENSTRUAL LOSS DECREASES NUMBER BODY FAT (INVERSE RELATIONSHIP) FASTER CLOTTING IN MEN

25. ERYTHROCYTE STRUCTURE DISC SHAPED BICONCAVE 7.5 MICROMETER (mm) DIAMETER 2 MICROMETERS (mm) THICK

28. ERYTHROCYTE STRUCTURE PLASMA MEMBRANE PHOSPHOLIPID BILAYER GLYCOPROTEINS, GLYCOLIPIDS DETERMINE BLOOD TYPE ACTIN AND SPECTRIN ON INNER SURFACE RESILIENCE / DURABILITY / PLIABILITY

30. ERYTHROCYTE STRUCTURE PLASMA MEMBRANE HIGH SURFACE AREA:VOLUME RATIO RESULT OF BICONCAVE SHAPE INCREASES RATE OF GAS DIFFUSION INTO AND OUT OF CELLS

31. ERYTHROCYTE STRUCTURE CYTOPLASM LACKS ORGANELLES ESP: LACKS MITOCHONDRIA, NUCLEUS WHY IS THIS IMPORTANT? CANNOT REPAIR LIMITED LIFESPAN (~120 DAYS) CANNOT DIVIDE NEW CELLS FORMED IN BONE MARROW

32. ERYTHROCYTE STRUCTURE CYTOPLASM HEMOGLOBIN RED PIGMENT HIGH CONCENTRATION (33%) 280 MILLION MOLECULES PER CELL CARRIES MOST OF THE O2 CARRIES SOME OF THE CO2 PROTEIN & NON-PROTEIN COMPONENTS

33. HEMOGLOBIN PROTEIN COMPONENT 4 POLYPEPTIDES (HETEROTETRAMER) 2 a-GLOBIN PROTEINS 2 b-GLOBIN PROTEINS NON-PROTEIN COMPONENT 4 HEME GROUPS PORPHYRIN RING AND IRON ION IRON ION WITHIN HEME BINDS TO O2

36. ABO BLOOD TYPES DETERMINED BY SURFACE ANTIGENS GLYCOLIPIDS AND GLCOPROTEINS (SUGARS ON CELL SURFACE) GENETICALLY DETERMINED RECOGNIZED BY ANTIBODIES INDIVIDUALS POSSESS ANTIBODIES TO ANTIGENS THEY THEMSELVES DO NOT POSSESS RECOGNITION OF THESE ANTIGENS BY ANTIBODIES CAUSES CELL CLUMPING

38. ABO BLOOD TYPES DETERMINED BY GENE “I” THREE ALLELES IA IB i IA AND IB ARE CODOMINANT i IS RECESSIVE TO IA AND IB

39. ABO BLOOD TYPES THREE ALLELES OF “I” GENE INDIVIDUALS POSSESS TWO COPIES FOUR BLOOD TYPES A GENOTYPE IAIA OR IAi B GENOTYPE IBIB OR IBi AB GENOTYPE IAIB O GENOTYPE ii

40. ABO BLOOD TYPES ANTIBODIES TO A AND B ANTIGENS APPEAR SHORTLY AFTER BIRTH PRESENT FOR ENTIRE LIFE PRODUCED IN RESPONSE TO SIMILAR ANTIGENS ON INTESTINAL BACTERIA CROSS-REACT WITH A AND B ANTIGENS TERMED “ANTI-A” AND “ANTI-B” CAUSE OF TRANSFUSION REACTIONS

44. Rh BLOOD TYPES DETERMINED BY SURFACE ANTIGENS UNRELATED TO ABO BLOOD TYPE GENETICALLY DETERMINED ALLELES OF THREE GENES C, c, D, d, E, e DD, Dd ARE Rh+ dd MAY BE Rh-, DEPENDING ON ALLELES OF OTHER GENES

45. Rh BLOOD TYPES ANTI-D ANTIBODIES NOT NORMALLY PRESENT PRESENT ONLY IN Rh- EXPOSED TO Rh+ FIRST EXPOSURE NOT PROBLEMATIC SECOND EXPOSURE PROBLEMATIC TRANSFUSION / PREGNANCY IMMUNE RESPONSE PREVENTABLE RhoGAM (Rh IMMUNE GLOBULIN)

47. OTHER BLOOD GROUPS > 100 OTHER BLOOD GROUPS USEFUL IN GENETIC / BIOCHEMICAL TESTING RARELY CAUSE TRANSFUSION REACTIONS

48. ERYTHROCYTE DISORDERS ANEMIA ERYTHROCYTE DEFICIENCY, OR HEMOGLOBIN DEFICIENCY THREE CLASSES INADEQUATE SYNTHESIS BLEEDING RBC DESTRUCTION

49. ERYTHROCYTE DISORDERS ANEMIA CONSEQUENCES OXYGEN DEPRIVATION (HYPOXIA) SHORTNESS OF BREATH REDUCED BLOOD OSMOLARITY WATER RETENTION IN TISSUES (EDEMA) REDUCED BLOOD VISCOSITY HEART BEATS FASTER CARDIAC FAILURE

50. ERYTHROCYTE DISORDERS SICKLE-CELL ANEMIA ~0.25% OF AFRICAN AMERICANS GENETICALLY DETERMINED ABERRANT b-GLOBIN ALLELE (HbS) SINGLE AMINO ACID SUBSTITUTION GLUTAMIC ACID (HbA) ? VALINE (HbS) CELLS SICKLE UNDER LOW OXYGEN MULTIPLE DELETERIOUS EFFECTS

53. ERYTHROCYTE DISORDERS SICKLE-CELL ANEMIA WHY IS THE FREQUENCY SO HIGH? MALARIA PREVALENT IN AFRICA Plasmodium PARASITE LIVES IN RBCs SURVIVES POORLY IN CELLS WITH HbS INDIVIDUALS WITH HbS LESS LIKELY TO DIE (HETEROZYGOTES MOST FIT) THUS, HbS PROVIDES PROTECTION

54. LEUKOCYTES 5,000 – 10,000 CELLS/mL FIVE TYPES: NEUTROPHILS 60 – 70 % 9 – 12 mM LYMPHOCYTES 25 – 33% 5 – 8 mM (most) MONOCYTES 3 – 8 % 12 – 15 mM EOSINOPHILS 2 – 4% 10 – 14 mM BASOPHILS <0.5 – 1% 8 – 10 mM

55. LEUKOCYTES GRANULOCYTES NEUTROPHILS EOSINOPHILS BASOPHILS AGRANULOCYTES LYMPHOCYTES MONOCYTES

56. LEUKOCYTES NEUTROPHILS HIGHLY MOBILE INCREASE IN RESPONSE TO BACTERIAL INFECTIONS KILLS BACTERIA PHAGOCYTOSIS CHEMICALLY (BURST LYSOSOMES)

57. LEUKOCYTES EOSINOPHILS INCREASE WITH ALLERGIES INCREASE WITH PARASITIC INFECTIONS PHAGOCYTOSIS ANTIGEN / ANTIBODY COMPLEXES ALLERGENS HYDROLYTIC ENZYME RELEASE RESPONSE TO HOOKWORM, TAPEWORM, ETC. TOO LARGE TO PHAGOCYTIZE

58. LEUKOCYTES BASOPHILS GENERALLY NOT PHAGOCYTIC AID OTHER LEUKOCYTES RELEASE HISTAMINE INCREASE BLOOD FLOW TO AREA RELEASE HEPARIN INHIBIT CLOTTING

59. LEUKOCYTES LYMPHOCYTES INCREASE IN IMMUNE RESPONSE SEVERAL SUBCLASSES VARIOUS IMMUNE FUNCTIONS ESP: SECRETE ANTIBODIES

60. LEUKOCYTES MONOCYTES DIFFERENTIATE INTO MACROPHAGES PHAGOCYTOSIS OF PATHOGENS PHAGOCYTOSIS OF DEBRIS PRESENT ANTIGENS TO OTHER CELLS OF IMMUNE SYSTEM

61. PLATELETS 130,000 – 400,000 / mL NOT CELLS FRAGMENTS OF MEGAKARYOCYTES SMALL (2 – 4 mM DIAMETER) POSSESS VARIOUS ORGANELLES PSEUDOPODS AMOEBOID MOVEMENT PHAGOCYTOSIS

62. PLATELET FUNCTIONS SECRETE CLOTTING FACTORS SECRETE VASOCONSTRICTORS FORM TEMPORARY PLATELET PLUGS DISSOLVE OLD BLOOD CLOTS PHAGOCYTOSIS OF BACTERIA SECRETE CHEMICALS TO ATTRACT LEUKOCYTES TO SITES OF INFLAMMATION SECRETE GROWTH FACTORS

63. CONTROL OF BLEEDING HEMOSTASIS VASCULAR SPASM PLATELET PLUG FORMATION COAGULATION

66. CONTROL OF BLEEDING VASCULAR SPASM CONSTRICTION OF BROKEN VESSEL IMMEDIATE PROTECTION AGAINST BLEEDING MULTIPLE TRIGGERS

67. CONTROL OF BLEEDING TRIGGERS OF VASCULAR SPASM PAIN RECEPTORS ? NERVES ? BLOOD VESSELS CONSTRICT SMOOTH MUSCLE OF BLOOD VESSELS CONSTRICT PLATELETS RELEASE SEROTONIN (CHEMICAL VASOCONSTRICTOR)

68. CONTROL OF BLEEDING PLATELET PLUG FORMATION BLOOD VESSEL BROKEN COLLAGEN FIBERS EXPOSED PLATELETS BIND TO COLLAGE FIBERS FORM PSEUDOPODS ATTACH TO VESSEL AND OTHER PLATELETS CONTRACT AND PULL WALLS TOGETHER DEGRANULATION

69. CONTROL OF BLEEDING PLATELET PLUG FORMATION DEGRANULATION RELEASE OF COMPOUNDS TO VASOCONSTRICT ATTRACT PLATELETS STIMULATE DEGRANULATION PROMOTE AGGREGATION POSITIVE FEEDBACK

70. CONTROL OF BLEEDING COAGULATION (CLOTTING) MOST EFFECTIVE DEFENSE FIBRINOGEN ? FIBRIN ? POLYMER TWO REACTION PATHWAYS EXTRINSIC MECHANISM CLOTTING FACTORS FROM DAMAGED BLOOD VESSEL INTRINSIC MECHANISM CLOTTING FACTORS FROM BLOOD

71. CONTROL OF BLEEDING CLOTTING FACTORS PROCOAGULANTS PROTEINS PRODUCED IN LIVER INACTIVE ? ACTIVE EACH ACTIVATES THE NEXT REACTION CASCADE AMPLIFICATION AT EACH STEP POSITIVE FEEDBACK INVOLVED

73. CONTROL OF BLEEDING CLOT RETRACTION CLOT FORMED PLATELETS ADHERE TO FIBRIN PLATELETS CONTRACT PULLS EDGES OF BROKEN VESSEL TOGETHER PLATELETS SECRETE PDGF PLATELET-DERIVED GROWTH FACTOR STIMULATES MITOSIS FIBROBLASTS INVADE AND PRODUCE CONNECTIVE TISSUE

74. CONTROL OF BLEEDING CLOT DISSOLUTION FIBRINOLYSIS MULTIPLE STEPS POSITIVE FEEDBACK SIMILAR, IN REVERSE

76. CONTROL OF BLEEDING PREVENTION OF COAGULATION PLATELET REPULSION DILUTION AND BLOOD MOVEMENT ANTICOAGULANTS ANTITHROMBIN (LIVER) HEPARIN (BASOPHILS)

77. COAGULATION DISORDERS HEMOPHILIA DEFICIENCY IN A CLOTTING FACTOR CASCADE DISRUPTED CLOTTING DEFICIENCY

78. COAGULATION DISORDERS HEMOPHILIA A 83% OF ALL CASES FACTOR VIII DEFICIENCY SEX-LINKED, RECESSIVE 1/5,000 MALES AFFECTED TREATMENT BY PURIFIED FACTOR VIII HOW DID WE PURIFY FACTOR VIII? HOW DO WE PURIFY FACTOR VIII?

79. COAGULATION DISORDERS HEMOPHILIA B 15% OF ALL CASES FACTOR IX DEFICIENCY SEX-LINKED, RECESSIVE 1/30,000 MALES AFFECTED

80. BLOOD CELL PRODUCTION “HEMOPOIESIS” FORMS ALL SEVEN TYPES OF FORMED ELEMENTS OCCURS IN HEMOPOIETIC TISSUES E.G., BONE MARROW, THYMUS, ETC. INVOLVES DIVISION AND DIFFERENTIATION OF STEM CELLS

81. BLOOD CELL PRODUCTION STEM CELLS PLURIPOTENT CELLS UNDIFFERENTIATED CELLS ABLE TO DIVIDE AND DIFFERENTIATE INTO MULTIPLE TYPES OF CELLS NOT ALL ARE “TOTIPOTENT” (NOT FULLY DIFFERENTIATED) E.G., HEMOCYTOBLASTS (BLOOD) E.G., EMBRYONIC STEM CELLS

83. BLOOD CELL PRODUCTION YOLK SAC EARLIEST HEMOPOIETIC TISSUE PRODUCES STEM CELLS COLONIZE OTHER ORGANS BONE, LIVER, SPLEEN, THYMUS, ETC LIVER STOPS HEMOPOIESIS AT BIRTH SPLEEN STOPS ERYTHROPOIESIS SHORTLY AFTER BIRTH

84. BLOOD CELL PRODUCTION MYELOID HEMOPOIESIS OCCURS IN BONE MARROW FORMS ALL SEVEN FORMED ELEMENTS LYMPHOID HEMOPOIESIS OCCURS IN SEVERAL ORGANS THYMUS, TONSILS, LYMPH NODES, SPLEEN, INTESTINES, ETC. PRODUCES LYMPHOCYTES

85. BLOOD CELL PRODUCTION HEMOCYTOBLASTS STEM CELLS PLURIPOTENT DIFFERENTIATE INTO ALL FORMED ELEMENTS ERYTHROPOIESIS LEUKOPOIESIS THROMBOPOIESIS

86. ERYTHROCYTE PRODUCTION ERYTHROPOIESIS HEMOCYTOBLASTS DEVELOP RECEPTORS FOR EPO (ERYTHROPOIETIN) NO LONGER PLURIPOTENT “PROERYTHROBLASTS” PROERYTHROBLAST ? ERYTHROBLAST STIMULATED BY EPO ERYTHROBLAST DIVIDE, PRODUCE HEMOGLOBIN NUCLEUS DEGENERATES “RETICULOCYTE”

87. ERYTHROCYTE PRODUCTION ERYTHROPOIESIS RETICULOCYTE STILL HAS ER FOR 1 – 2 DAYS BONE MARROW ? BLOODSTREAM RETICULOCYTE ? ERYTHROCYTE LOSS OF E.R. ~1% OF CIRCULATING RBCs ARE RETICULOCYTES

88. ERYTHROCYTE PRODUCTION ERYTHROCYTE HOMEOSTASIS MAINTAINED BY NEGATIVE FEEDBACK DROP IN RBC COUNT LESS OXYGEN IN BLOOD (HYPOXEMIA) KIDNEYS INCREASE EPO OUTPUT ERYTHROPOIESIS STIMULATED INCREASE IN RBC COUNT (3 – 4 DAYS)

89. ERYTHROCYTE PRODUCTION ERYTHROCYTE HOMEOSTASIS WHY IS IT HARD TO PLAY BALL IN DENVER? HIGHER ALTITUDE LESS OXYGEN IN AIR LESS OXYGEN IN BLOOD (HYPOXEMIA) KIDNEYS INCREASE EPO OUTPUT ERYTHROPOIESIS STIMULATED INCREASE IN RBC COUNT

91. ERYTHROCYTE PRODUCTION IRON METABOLISM NECESSARY MICRONUTRIENT COMPONENT OF HEMOGLOBIN DAILY IRON LOSS MEN: 0.9 MG/DAY WOMEN: 1.7 MG/DAY 5 – 20+ MG REQUIRED/DAY (ONLY A FRACTION IS ABSORBED)

92. ERYTHROCYTE PRODUCTION IRON METABOLISM ABSORBED AS Fe2+ (FERROUS ION) BINDS TO TRANSFERRIN (b-GLOBULIN) TRAVELS TO VARIOUS TISSUES EXCESS BINDS TO APOFERRITIN TO FORM FERRITIN (STORAGE COMPLEX)

94. ERYTHROCYTE DEATH CELL COMPONENTS DETERIORATE SPECTRIN, MEMBRANE CANNOT REPAIR NO NUCLEUS, NO RIBOSOMES PASS THROUGH SMALL CAPILLARIES ESPECIALLY IN SPLEEN “ERYTHROCYTE GRAVEYARD” HEMOLYSIS RUPTURE OF ERYTHROCYTES

95. ERYTHROCYTE DEATH HEMOLYSIS MEMBRANE FRAGMENTS DIGESTED BY MACROPHAGES LIVER, SPLEEN HEMOGLOBIN MACROPHAGE SEPARATES HEME FROM GLOBIN

96. ERYTHROCYTE DEATH HEMOLYSIS GLOBIN (MACROPHAGE) HYDROLYZED INTO AMINO ACIDS HEME (MACROPHAGE) IRON SEPARATED FROM PORPHYRIN RING

97. ERYTHROCYTE DEATH HEMOLYSIS IRON RELEASED INTO BLOOD BINDS TO TRANSFERRIN RECYCLED

98. ERYTHROCYTE DEATH HEMOLYSIS PORPHYRIN RING ? BILIVERDIN ? BILIRUBIN (BILE PIGMENTS) RELEASED INTO BLOOD COMBINES WITH ALBUMIN LIVER REMOVES BILIRUBIN SECRETES INTO BILE GALLBLADDER DISCHARGES INTO SMALL INTESTINE BACTERIA CONVERT INTO UROBILINOGEN BROWN COLOR OF FECES

99. LEUKOCYTE PRODUCTION LEUKOPOIESIS HEMOCYTOBLASTS DEVELOP RECEPTORS FOR VARIOUS CSFs (COLONY STIMULATING FACTORS) CSFs PRODUCED BY LYMPHOCYTES AND MACROPHAGES DIFFERENT CSFs STIMULATE PRODUCTION OF DIFFERENT LEUKOCYTE TYPES E.G., BACTERIAL INFECTION ? CSF1 ? ? NEUTROPHILS E.G., ALLERGY ? CSF2 ? ? EOSINOPHILS

100. LEUKOCYTE PRODUCTION LEUKOPOIESIS HEMOCYTOBLASTS DEVELOP INTO: B PROGENITORS BECOME B-LYMPHOCYTES T PROGENITORS BECOME T-LYMPHOCYTES GRANULOCYTE-MACROPHAGE COLONY-FORMING UNITS BECOME GRANULOCYTES AND MONOCYTES

101. LEUKOCYTE PRODUCTION LEUKOPOIESIS GRANULOCYTES AND MONOCYTES STORED IN BONE MARROW UNTIL NEEDED LYMPHOCYTES BEGIN DEVELOPMENT IN BONE MARROW SOME COMPLETE DEVELOPMENT IN THYMUS MATURE LYMPHOCYTES COLONIZE OTHER ORGANS SPLEEN, LYMPH NODES, ETC.

102. PLATELET PRODUCTION THROMBOPOIESIS HEMOCYTOBLASTS DEVELOP RECEPTORS FOR THROMBOPOIETIN NO LONGER PLURIPOTENT “MEGAKARYOBLAST” MEGAKARYOBLAST ? MEGAKARYOCYTE STIMULATED BY THROMBOPOIETIN DNA REPLICATION WITHOUT DIVISION GIGANTIC CELL (~100 mM DIAMETER) MULTILOBED NUCLEUS RESIDES ON BONE MARROW, LUNGS

103. PLATELET PRODUCTION THROMBOPOIESIS MEGAKARYOCYTE INFOLDINGS OF PLASMA MEMBRANE SMALL FRAGMENTS BREAK OFF PLATELETS PLATELETS MANY STORED IN SPLEEN LIFESPAN ~ 4 DAYS