Defective platelet production in Wdr1^rd/rd mice. (A) Thrombocytopenia in Wdr1^rd/rd mice at 7 weeks and 14 months of age. Individual male (■⁺/⁺, □ rd/rd) and female (●⁺/⁺, ○ rd/rd) mice are shown. Platelet counts for males at 7 weeks of age were Wdr1^+/+ 1460 (± 172) vs. Wdr1^rd/rd 271 (± 45); at 14 months of age Wdr1^+/+ 1892 (± 194) vs. Wdr1^rd/rd 417 (± 113). Platelet counts for females at 7 weeks of age were Wdr1^+/+ 1232 (± 202) vs. Wdr1^rd/rd 230 (± 37); at 14 months of age Wdr1^+/+ 1442 (± 123) vs. Wdr1^rd/rd 283 (± 73). Horizontal bars indicate the mean. (B) Elevated mean platelet volume in Wdr1^rd/rd mice. The platelet counts and MPV values shown in (A,B) were calculated in the same cohort of mice, aged specifically for the purpose. Data from unrelated C57BL/6 control animals bled on the same days as these mice indicate that machine drift over the intervening 12 months was primarily responsible for the decrease in baseline MPV observed. Horizontal bars indicate the mean. (C) Transmission electron microscopy of blood platelets. Platelets from Wdr1^rd/rd mice exhibit dramatic morphologic abnormalities characterized by increased size, loss of discoid shape, and the irregular distribution of granules and microtubule coil. (D) Platelet clearance rates are unaffected in Wdr1^rd/rd mice. N-hydroxysuccinimide-biotin was injected intravenously and the disappearance of labeled platelets and emergence of labeled platelets were measured twice daily. (E) Platelet production rates are markedly reduced in Wdr1^rd/rd mice. Absolute number of unlabeled platelets was calculated by multiplying % unlabeled platelets by total circulating platelet count at each time point. Data shown in panels D and E represent mean (± standard deviation); n equals 8 female mice per genotype (● ⁺/⁺, ○ rd/rd). Subsequent studies with male mice produced similar results (data not shown). The ordinate of panel E refers to the number of unlabeled platelets in the circulation. Because biotin labeling levels of between 72% and 96% were achieved, the data shown have been normalized to reflect the fact that a population of unlabeled platelets existed at time 0. Hence, the normalized mean platelet count shown at day 6 for wild-type mice is 754 (± 87) × 10⁹/L. Actual mean platelet counts at day 6 were 953 (± 81) × 10⁹/L, Wdr1^+/+; 287 (± 97) × 10⁹/L, Wdr1^rd/rd.