Chylomicrons from patients with Type V hyperlipoproteinemia inhibit platelet function

Primary type V hyperlipoproteinemia was identified in two preadolescent children. The propositus (kindred N) was a 10-year-old girl with severely creamy plasma, lipemia retinalis, hypertriglyceridemia (triglyceride level, 6,800 mg/100 ml), and hypercholesterolemia (cholesterol level, 490 mg/100 ml). Her parents and an 8-year-old sister all had endogenous hypertriglyceridemia (type IV hyperlipoproteinemia). In kindred A, an 11-year-old boy had triglyceride levels as high as 1,100 mg/100 ml and recurrent abdominal pain. His father had type V hyperlipoproteinemia; his mother was normal. All three of his older teenage siblings had type IV hyperlipoproteinemia. The enzymatic activities of lipoprotein lipase (LPL), hepatic triglyceride lipase (HTL), and histaminase (H) were studied in postheparin plasma. The LPL level was low in the children and both parents in kindred N. LPL level in kindred A was normal, except for one child with type IV hyperlipoproteinemia. HTL level was normal to above normal in both kindreds. Most patients had a normal H level, but one parent (kindred N) had no preheparin H and very low levels of postheparin H. There was a strong correlation (r = 0.58, significant at < 1% level) between the release of LPL and H but not between HTL and H (r = 0.22). The mean (± 1 S.D.) levels of the enzymes were as follows: LPL, 2.8 ± 0.7 µmol/ml/hr in kindred N and 5.4 ± 2.2 µmol/ml/hr in kindred A; H, 13.4 ± 6.8 units/ml in kindred N and 22.0 ± 11.9 units/ml in kindred A; and HTL, 18.0 ± 7.1 µmol/ml/hr in kindred N and 14.9 ± 6.3 µmol/ml/hr in kindred A. The enzymatic activities of kindreds N and A were significantly different for LPL (P < .001) and H (.025 < P < .05) but not for HTL. All but one child had at least one high insulin level, which was accompanied by hyperglycemia in two children. The hypertriglyceridemia in all but one child was ameliorated on therapeutic diets. These data suggest that the genetic basis of the hypertriglyceridemia in these two families is different and that hyperchylomicronemia in childhood is not confined to the rare type I hyperlipoproteinemia.

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Distribution of cyclosporine in blood of a renal-transplant recipient with type V hyperlipoproteinemia.

Clinical Chemistry ◽

10.1093/clinchem/33.3.423 ◽

1987 ◽

Vol 33 (3) ◽

pp. 423-428 ◽

Cited By ~ 16

Author(s):

H L Verrill ◽

R E Girgis ◽

R E Easterling ◽

B S Malhi ◽

W F Mueller

Keyword(s):

Renal Transplant ◽

Plasma Lipids ◽

Kidney Tissue ◽

Therapeutic Drug ◽

Type V Hyperlipoproteinemia ◽

High Concentrations ◽

Stage Renal Disease ◽

End Stage ◽

Type V ◽

Severe Type

Abstract A patient with severe type V hyperlipoproteinemia and chronic end-stage renal disease received a renal transplant and therapy with cyclosporine. Concentrations of the drug in plasma as determined by liquid chromatography appeared extraordinarily high for the dose ingested. When we measured the drug in the plasma, plasma cleared by ultracentrifugation, leukocytes, erythrocytes, and whole blood, we found that the high concentrations of cyclosporine were associated with the chylomicrons that always were present in this patient's blood. Cyclosporine added directly to this patient's plasma was less associated with the plasma lipids. Isolated lymphocytes and kidney slices incubated with plasma from this patient bound no more drug than when incubated with nonhyperlipemic plasma containing cyclosporine at a normal therapeutic concentration. We conclude that the cyclosporine associated with the chylomicrons in this patient was not biologically available to either lymphocytes or kidney tissue. We strongly recommend the use of chylomicron-cleared plasma for therapeutic drug monitoring of cyclosporine in type V hyperlipoproteinemic patients.

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Inhibition of platelet function by A02131-1, a novel inhibitor of cGMP- specific phosphodiesterase, in vitro and in vivo

Blood ◽

10.1182/blood.v87.9.3758.bloodjournal8793758 ◽

1996 ◽

Vol 87 (9) ◽

pp. 3758-3767 ◽

Cited By ~ 7

Author(s):

SM Yu ◽

SY Tsai ◽

SC Kuo ◽

JT Ou

Keyword(s):

Platelet Function ◽

Platelet Rich Plasma ◽

Atp Release ◽

Camp Level ◽

Cgmp Level ◽

Prostaglandin D2 ◽

Type I ◽

Type V

The effect of A02131–1 [3-(5′-hydroxymethyl-2′-furyl)-1-benzyl thieno (3,2-c)pyrazole], a cGMP-specific phosphodiesterase (PDE) inhibitor, on platelet function was investigated. The compound was found to inhibit the aggregation of and adenosine triphosphate (ATP) release from human platelet-rich plasma and washed platelets that were induced by aggregation inducing drugs such as arachidonic acid (AA), collagen, U46619, platelet-activating factor (PAF), adenosine diphosphate (ADP) and A23187, and the inhibitory effect was concentration-dependent. A02131–1 also disaggregated the performed platelet aggregates induced by these inducers. Thromboxane B2 (TXB2) formations caused by collagen, PAF, ADP, and A23187 were inhibited by A02131–1 at concentrations that did not affect the AA-induced formation of TXB2 and prostaglandin D2 (PGD2). A02131–1 suppressed both the generation of inositol 1,4,5- triphosphate (IP3) and the increase of intracellular Ca2+ concentration stimulated by these aggregation inducers. A02131–1 was shown to increase the cAMP and cGMP levels in platelets and the extent was found to be dependent on concentration as well as time. A02131–1 increased the cAMP level much more slowly than the cGMP level. Activities of adenylate cyclase, guanylate cyclase, and PDEs (type I and III) were not altered by A02131–1. However, the activity of cGMP-specific PDE (type V) was inhibited by A02131–1. The antiplatelet aggregation activity and the effect on raising cAMP level of A02131–1 were both potentiated by prostaglandin E1 (PGE1). In the mouse tail bleeding test, A02131–1 was clearly shown to be more effective than dipyridamole in prolonging the tail bleeding time of conscious mice. These data indicate that A02131–1 is a cGMP-specific PDE (type V) inhibitor in human platelets.

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