James J. Corrigan

Hemostatic markers in acute stroke.

To assess the time course of thrombosis and fibrinolysis after acute stroke, we measured concentrations of fibrinopeptide A (FpA), B-beta 1-42 peptide (B-beta 1-42), B-beta 15-42 peptide (B-beta 15-42), and crosslinked D-dimer (XDP) in 31 patients at varying times following acute ischemic stroke and in 13 neurologically stable patients with chronic strokes. FpA levels were markedly elevated during the first week after stroke and declined slowly during the first month. Mean FpA levels were not significantly elevated in chronic stroke patients. Mean XDP levels were slightly elevated during the first week and increased during the next 2 weeks after stroke. B-beta 1-42 and B-beta 15-42 levels were not elevated at any time following acute stroke. Our data suggest that fibrin formation greatly exceeds endogenous fibrinolysis during the acute phase of ischemic stroke. Endogenous fibrinolysis develops slowly following stroke. Prolonged elevation of FpA concentration suggests that thrombin activity and fibrin formation continue for up to 4 weeks in some patients with ischemic stroke.

Heparin therapy in bacterial septicemia

DISSEMINATED INTRAVASCULAR COAGULATION is an acquired coagulop~ithy characterized by intravascular c0nstimpt!on of certain plasma coagulation factors (fibrinogen; factors I1, V, and VHI) and platelets. DIC is frequently associated with a hemorrhagic diathesis and occasionally with microthrombosis) :~ In response to fibrin formation, the fibrinoiytic mechanism is activated and lyses the fibrin into soluble peptides called fibrinolyric split products or degradation products. In acute DIC, as occurs in septicemia, utilization of these coagulation factors and platelets far exceeds production rates in the majority of cases, yielding levels which fall below hemostatic minimums. These observations explain why other terms such as consumption coagulopathy, defibrination syndrome, and the intravascular coagulation-fibrinolytic syndrome have been used to describe DIC. Infections, particularly bacterial septicemia, play a significant roie in the pathogenesis of DIC? Heparin therapy in septicemic patienis with DIC has seemed logical since ~inticoagulants had been shown to be effective in DIC associated with oiher human diseases and in animal models. 7-9 However, the efficacy of heparin therapy for DIC in this clinical setting remains to be established. The purpose of this article is to review the known Changes in the hemostatic mechanism in patients with bacterial septicemia, and to analyze retrospectively 222

Iron and the exclusively breast-fed infant from birth to six months

This study was designed to determine whether normal, full-term, exclusively breast-fed infants develop iron deficiency anemia, as defined by hemoglobin or red blood cell indices more than two standard deviations below the age-specific mean, or depletion of iron stores, as defined by an abnormally low serum ferritin level. Thirty-three breast-fed infants were followed from birth to 6 months. Maternal blood and cord blood at delivery, and venous blood from the infants at 2, 4, and 6 months were analyzed for anemia as defined above. At 6 months of age, the mean hemoglobin concentration of these infants was slightly higher than the normal mean; four of 33 infants (12%) had a mean corpuscular volume greater than 2 SD below the reported normal mean; and two of 33 infants (6%) had a serum ferritin level less than 12 ng protein/ml. These data suggest that the infant who is exclusively breast-fed for the first 6 months of life is not at high risk for the development of iron deficiency anemia or the depletion of iron stores during that time.

Effect of polymyxin B sulfate on endotoxin activity in a gram-negative septicemia model.

Summary: The antiendotoxin effect of polymyxin B was investigated in experimentally induced septicemia in rabbits. The Pasteurella multocida organisms were sensitive to the antibacterial action of penicillin but not to polymyxin B. Animals pre-treated with polymyxin showed positive blood cultures and significantly reduced plasma endotoxin levels (Limulus test) with normal white blood cell and platelet counts when analyzed 6 hr after the injection of live organisms. Polymyxin therapy given after the animals had established septicemia-endotoxemia reduced the plasma endotoxin levels and improved the survival, but had no effect on the leukopenia and thrombocytopenia. The best survival data were obtained in rabbits who were treated with both penicillin and polymyxin. The data suggest that polymyxin is effective in neutralizing the endotoxic effects from live organisms and that the timing and perhaps duration of the polymyxin treatment is of critical importance. In addition, a modified Limulus lysate method was developed which showed that quantitative plasma endotoxin determination could be made more sensitive by prior heating of the plasma to remove the natural inhibitors.Speculation: This investigation and other reports have shown that polymyxin B sulfate neutralized endotoxin effects in animals given purified endotoxin, dead endotoxin-containing organisms, and gram-negative septicemic animals (3, 6, 8, 12–15). The antiendotoxin effect of the antibiotic appears to be separate from its antimicrobial effects. Because many of the manifestations of gram-negative septicemia in humans are reputed to be the result of endotoxemia, a clinical study focused on neutralization of the endotoxin effects would appear appropriate. The modified Limulus lysate test, as described in the report, was found to be accurate in measuring quantitative plasma endotoxin levels in small quantities of plasma by removal of the natural inhibitors by simply heating the plasma. The data also indicated that the lysate test sensitivity was directly related to the number of infectious organisms per milliliter of blood in the septicemic rabbit. Therefore, its sensitivity in humans could similarly be affected by the presence of inhibitors and the number of organisms. Because most human studies have failed to correlate the positivity of the test with the number of infecting organisms, these data would suggest that re-evaluation of its usefulness in clinical disease should be performed.

THE EFFECT OF VITAMIN E ON WARFARIN‐INDUCED VITAMIN K DEFICIENCY*

Vitamin K-deficient animals and humans developed a more severe coagulopathy when treated with vitamin E, which was due to further reduction in the vitamin K-dependent coagulation factors (II, VII, IX, and X). This phenomenon was not seen in normal vitamin K-sufficient animals or human subjects. The mechanism by which vitamin E causes this effect is not known. These coagulation factors are produced by the liver in precursor forms and are converted to functional proteins by a vitamin K-dependent reaction. Analysis of one of these coagulation factors, prothrombin (factor II), in plasma of vitamin K-deficient animals and humans treated with vitamin E was done in this study. The precursor of factor II is antigenically similar to biologically active factor II and can be activated to form thrombin by Echis carinatus venom. The data showed that functional factor II coagulant activity was reduced below base in warfarin-treated humans and animals given vitamin E. Factor II antigen as determined by electroimmunoassay in humans and factor II coagulant activity as measured using Echis venom in animals were unchanged and no different from untreated controls. The data suggest that vitamin E acts at the vitamin K-carboxylase step of carboxylation of precursor prothrombin and not in the synthesis of the precursor protein.

Factor II (prothrombin) levels in cord blood: Correlation of coagulant activity with immunoreactive protein

Hypoprothrombinemia occurs in newborn infants, but it is unclear whether this is the result of reduced production of Factor II precursor or a vitamin K deficient state. In this study, 76 cord blood specimens were analyzed for functional factor coagulant activity and levels of Factor II antigen as determined by electroimmunoassay. In 40 normal term infants, CA = 30% +/- 1.6 (mean +/- SEM) and Ag = 44% +/- 2.3; in 17 normal preterm infants CA = 30% +/- 1.0 and Ag = 31% +/- 4.2; and in 50 normal adults CA = 83 +/- 3 and Ag = 91 +/- 4. In the term infants the average ratio of CA:Ag was 0.90 and in the preterm infants 0.96, both values being similar to those in adults and suggesting underproduction of the precursor form. In 19 term infants who experienced complications of pregnancy and/or delivery, the ratio was 0.76; seven of these ratios were less than 0.70 (range 0.40 to 0.69). These data show that hypoprothrombinemia is common in infant cord blood and is most marked in preterm infants. In the normal infants the CA:Ag ratios were normal, suggesting that the hypoprothrombinemia is the result of reduced production of the protein and not of vitamin K deficiency. However, term infants with complications of labor and delivery had reduced CA:Ag ratios that were suggestive of vitamin K deficiency.

Eosinophilia in premature infants: Relationshipto weight gain†

Serial eosinophil counts were determined in 38 hospitalized, appropriately grown premature infants whose gestational ages ranged from 27 to 35 weeks. Absolute eosinophilia (greater than 700/mm3) was documented in 76% (29/38). Eosinophilia was mild (700 to 999/mm3) in 9, moderate (1,000 to 2,999/mm3) in 17, and marked (greater than or equal to 3,000/mm3) in 3 patients. The average time of onset was day 19. Peak eosinophilia was usually seen within one week of onset and lasted an average of 16 days. A consistent relationship (r = 0.86) was found between the day of peak eosinophilia (mean = day 27) and the day on which birthweight was regained (mean = day 22). No association was apparent between the occurrence or degree of eosinophilia and gestational age, birth stress, presence of umbilical catheter, parenteral alimentation solution, and time of beginning or type or oral feeds. The data suggest that eosinophilia is strongly associated with the establishment of an anabolic state.

Envenomation by the northern blacktail rattlesnake (Crotalus molossus molossus): report of two cases and the in vitro effects of the venom on fibrinolysis and platelet aggregation

In two cases of human envenomation by the northern blacktail rattlesnake (Crotalus molossus molossus) there was marked swelling and ecchymosis of the bitten extremity and thrombocytopenia and, in one case, hypofibrinogenemia. Treatment consisted of i.v. antivenin, crystalloid solution, fresh frozen plasma and cryoprecipitates, with recovery in each case. In vitro studies showed that the venom had fibrinolytic and platelet aggregating properties; a coagulant effect, although present, was much less marked.

Effects of oral diltiazem on platelet function: alone and in combination with “low dose” aspirin

The effects of 3 days of oral diltiazem, low dose aspirin (40 mg/day), and their combination on platelet function was studied in 5 normal subjects. Both drugs inhibited platelet aggregation and ATP release induced by collagen, epinephrine and threshold concentrations of ADP. Aspirin and diltiazem decreased thromboxane A2 generation during ADP induced aggregation by 94 percent and 53 percent respectively, however both agents inhibited aggregation similarly, which suggests that diltiazems anti-platelet effect was due to mechanisms other than inhibition of thromboxane metabolism alone. Combination therapy resulted in a partially additive inhibitory effect on ADP induced aggregation and thromboxane A2 generation. Two subjects had bleeding times over 15 minutes after receiving combination therapy.

Factor II (prothrombin) coagulant activity and immunoreactive protein: Detection of vitamin K deficiency and liver disease in patients with cystic fibrosis+

malnutri t ion or to the underlying metabolic defect of C F ? The data presented demonstrate that significant growth retardation occurs in CF despite normal plasma GH and SM concentrations, and suggest that the hypothalamicpituitary-sometomedin axis is intact in this disease. By these measurements, the growth failure of CF can be clearly distinguished from that of pure protein-calorie malnutrition, possibly because of preservation of adequate amino acid absorption in CF, despite impaired protein digestion. Severe hypoproteinemia is, in fact,