Normal hematologic values and prevalence of anemia in children living on selected Pacific atolls.

The hematologic status of infants and children living on the small islands of the Pacific basin has been poorly documented. This report determines the normal ranges for hemoglobin (Hb) and mean corpuscular volume (MCV) for children residing on four of the small atolls of the Republic of the Marshall Islands in the archipelago of Micronesia. The difficulty in establishing normal hematologic values in pediatric populations is discussed and a methodology suggested that does not exclude any Hb value above the mean in determining the normal range for Hb. The study population was comprised of 563 Marshallese children representing approximately 3.4% of all children less than 16 years of age living in the Marshall Islands. The local prevalence of anemia and iron deficiency was also established.

Fibrinogen Irvine: a qualitatively abnormal fibrinogen associated with the predisposition to recurrent visceral and peripheral venous thrombosis.

A slow clotting dysfibrinogen with delayed anodal immunoelectrophoretic mobility and impaired fibrinopeptide A release has been identified in a patient with recurrent portal vein and deep venous thrombosis. Affected family members tested in the initial screening were asymptomatic. The proband's father died of pulmonary embolism at age 44 years and had mesenteric thrombosis at necropsy. The association of a plasma protein abnormality with visceral thrombosis is unusual and has never been observed previously with a dysfibrinogen. The qualitative abnormality is transmitted as an autosomal codominant and is tentatively designated, fibrinogen Irvine.

A practical heparin reduction algorithm: execution and operational characteristics.

A limited pilot study has been made of a newly devised heparin reduction algorithm (HRA). This formulation is a derivative of the alternative surveillance plan known as the activated partial thromboplastin time after heparin removal (aPTT/HR) scheme. Unlike the traditional plan, the HRA is the first approach to provide information about the individual and collective pharmacological effects of heparin and coumarins when the drugs are administered simultaneously. In this feasibility study the HRA was used without incident in six patients every 24 h to calculate the trend of the evolving anticoagulant effect of coumarin. The computations provided by a laboratory based data management group permitted the clinician to titrate precisely the withdrawal of heparin in response to the daily fluctuations in coumarin effect. In this way, the activated partial thromboplastin time could always be maintained within the desired therapeutic interval. Three divergent patient experiences are presented to demonstrate the operational characteristics and responsiveness of the new HRA plan.

Heritable alpha 2-macroglobulin deficiency in a patient with arterial thrombosis: alpha 2-macroglobulin deficiency Irvine.

A heritable deficiency in α(2)-macroglobulin (α(2)M) was identified in a 61-year-old man with arterial thrombosis. Plasma α(2)M levels among the patient's symptom-free relatives consistently ranged from 43 to 55 percent of laboratory mean-normal values. The new α(2)M variant displayed retarded anodal immunoelectrophoretic mobility when studied in plasma and serum. The affected members of this lineage showed no evidence of acquired or inherited thrombotic or consumptive derangements involving other plasma proteins. The significance of a possible causal association between α(2)M deficiency and the predisposition to arterial thrombosis is considered. The uncomplicated use of streptokinase and urokinase to treat the reference patient's arterial thrombosis is described. Recommendations are made for the adoption of a descriptive nomenclature. The new familial deficiency is tentatively designated α(2) (+)-macroglobulin deficiency Irvine.

Trials of commercial reagents in anion-exchange coagulation procedures: ortho diagnostics.

The suitability of Ortho Diagnostics one-stage prothrombin time (PT) reagent (Ortho Brain Thromboplastin) and activated partial thromboplastin (aPTT) reagent (Activated Thrombofax) has been evaluated for use in conjunction with the anion-exchange heparin removal maneuver. The PT/HR and aPTT/HR are tests used to follow the anticoagulant influence of coumarins when heparin also is being administered. After establishing a coumarin therapeutic range for Activated Thrombofax, a parallel trial was conducted with Ortho Brain Thromboplastin on coumarin-treated patient plasmas. Determinations also were made after heparin (0.2 mu/mL) was added and then removed by ECTEOLA microchromatography columns. Ortho Brain Thromboplastin was found to induce a shortening bias associated with a spurious improvement in the precision of tests run on anion-exchange treated plasmas that potentially could result in coumarin overdosage. The systematic error did not appear to result either from protracted incubation or the activation of prekallikrein, high molecular weight kininogen, Factor XI or XII. This reagent was found to perform appropriately with plasma not exposed to ECTEOLA. Activated Thrombofax gave reliable and reproducible results before and after heparin removal. This aPTT reagent could be used in the aPTT/HR anticoagulant surveillance scheme.

Inherited protein C deficiency and coumarin-responsive chronic relapsing purpura fulminans in a newborn infant.

A coumarin-responsive chronic relapsing purpura fulminans syndrome is described in a protein-C-deficient newborn infant. Episodes of acute disseminated intravascular coagulation (DIC) and cutaneous gangrene, which first appeared at age 11 h, were effectively controlled for 28 months with transfusions of fresh-frozen plasma. Cryoprecipitate and cryoprecipitate-poor plasma induced remissions as long as those induced by fresh-frozen plasma (less than or equal to 72 h). Coumarins sustained a cryoprecipitate-induced remission for 19 days: they were then electively discontinued and 17 h later the patient had an acute exacerbation of DIC with haemorrhaging. Family studies showed protein C levels of 31-40% in the subject's symptom-free mother and full and half brothers. DIC, the coumarin effect, and the inherited protein C abnormality appear to have contributed to the extremely low plasma levels (less than or equal to 6%) of protein C in the patient. This experience suggests that protein C deficiency may greatly compromise the ability of newborn infants to control consumptive disorders.

A structured approach to the management of purpura fulminans.

A 5-year-old boy with purpura fulminans (PF) was successfully managed with a protocol in which fresh frozen plasma (FFP) was administered, followed by a trial of certain therapeutic agents. This approach was based upon combined experience both with the reference patient and with a subject with a chronic form of PF. FFP controlled the acute disseminated intravascular coagulation in both instances and permitted venous antithrombotic drugs to be evaluated in safety. The PF syndrome in the index case was found to be heparin responsive, while the atypical case was coumarin responsive (heparin resistant). Initial administration of FFP was recommended rather than heparin in order to minimize the risk of hemorrhage while maintaining the likelihood of a swift response. When FFP is effective, a sequential trial should be undertaken with agents from the following categories: (1) venous antithrombotic, (2) antiplatelet, (3) antifibrinolytic, and (4) antiproteolytic. This process permits therapies to be thoroughly tested and used as investigative probes into the mechanisms of a particular case of PF. Should FFP prove ineffective, the list can serve as a guide for the investigation of various fastacting agents in the acute phases of disseminated intravascular coagulation. PF treatments are ranked in accordance with the number of positive outcomes in the literature.

Fibrinogen Seattle releases half the normal amount of fibrinopeptide B.

Fibrinogen Seattle, a clinically silent, slow-clotting dysfibrinogen, releases 50% of the normal amount of fibrinopeptide B as assessed by amino acid analysis. The reduced dysfibrin exhibited equal quantities of chains with B beta- and beta-charge mobility on polyacrylamide gel electrophoresis in 2 M urea at low pH. By these same techniques, the release of fibrinopeptide A was normal. Clots formed by repolymerizing the thrombin and batroxobin dysfibrin monomers showed a maximal turbidity that was lower than normal. Fibrinogen Seattle was indistinguishable from normal fibrinogen by radial immunodiffusion and immunoelectrophoresis. Degradation by plasmin and transamination by factor XIIIa were normal. The characteristics of fibrinopeptide release by fibrinogen Seattle distinguish it from other reported dysfibrinogens.

Use of activated partial thromboplastin time to monitor coumarin anticoagulation.

The activated partial thromboplastin time after heparin removal (aPTT/HR) is an anionexchange procedure that permits the unobstructed monitoring of the progress of coumarin anticoagulation by removing interfering heparin. An all-intrinsic-pathway anticoagulant surveillance scheme based upon the aPTT/HR has been proposed and provisionally tested. The adoption of the new scheme will depend upon the identification of partial thromboplastins that are as predictable and reliable as the tissue thromboplastins in modern one-stage prothrombin times. In this study, the commercial APTT Reagent and Simplastin performed with equal sensitivity and specificity when evaluated by means of prothrombin group factor assays on coumarintreated subject plasmas. It is concluded that this commercial partial thromboplastin (1) is capable of being used for the purpose of following heparin, heparin plus coumarin, and coumarin anticoagulation; (2) is potentially able to identify more of the inherited and acquired derangements that can lead to anticoagulation-associated hemorrhage; and (3) is a universally available alternative to the traditional anticoagulant monitoring approach.

Normal coagulation findings, thrombocytopenia, and peripheral hemoconcentration in neonatal polycythemia.

The criteria used for partial plasma exchange transfusion in 32 of 42 polycythemic newborn infants with capillary hematocrits greater than or equal to 70% were a venous hematocrit greater than 65% and two or more clinical "symptoms," or a venous hematocrit greater than or equal to 70%. Coagulation tests performed on 20 infants before and after the partial plasma exchange transfusion were normal for age. Low platelet counts found in six of the 32 patients were associated with venous hematocrits of greater than or equal to 70%. In three patients the platelet counts (less than 100,000/microliters) increased to greater than or equal to 130,000/microliters after three days. In 20 of 32 infants in whom partial plasma exchange transfusions were performed, peripheral venous hematocrits prior to the exchange were 8.5% higher than umbilical venous hematocrits. Following treatment the venous hematocrits (umbilical and peripheral) did not show a statistically significant difference. Thus, the study revealed coagulation findings normal for age, thrombocytopenia in 20% of polycythemic infants, hemoconcentration, and a sluggish peripheral venous circulation.

Activated partial thromboplastin time after heparin removal (aPTT/HR) in a new scheme of anticoagulant monitoring.

Activated partial thromboplastin time after heparin removal (aPTT/HR), a test employing anion exchange chromatography, was devised as an alternative to the prothrombin time after heparin removal (PT/HR) to monitor simultaneous anticoagulation with heparin and coumarins. The potential utility of the aPTT/HR was assessed by performing parallel PTs and aPTTs on 62 consecutive plasmas from coumarin-treated outpatients. All samples had 0.2 units/ml of heparin added and then removed to see if the maneuver influenced therapeutic group assignment. In no instance did reassignment occur. A conditional Irwin-Fisher test (P = 0.000604) and a special multinomial trial analysis (P = 0.002) indicated that the aPTT would be at least comparable to the PT for following coumarin antithrombotic prophylaxis. Since the heparin removal procedure had no influence on therapeutic categorization, the same statistical proof could be applied to the relationship between aPTT/HR and PT/HR. This study indicates that the aPTT can be used to monitor all stages of heparin and /or coumarin anticoagulation.

Adult nephrotic syndrome and acquired coagulopathies: Hageman factor deficiency.

Analysis of tests of coagulation and fibrinolysis from 20 adult nephrotics prior to the onset of therapy disclosed that 40 percent had low factor XII levels. The mean factor XI was normal. The platelet count and fibrinogen concentration were elevated. The findings of this study on adults are similar to those of Honig and Lindley(21) in the nephrotic syndrome of childhood. Subjects with minimal change disease constituted a small (15 percent) but readily segregated subpopulation without evidence of fibrinolysis in association with low factor XII activity. Prolongation of the activated partial thromboplastin time corresponded in every instance with factor XII activities of ≤30 percent. Lengthening of the one stage prothrombin time was not directly attributable to factor deficiencies.

Changes of coagulation factors IX, VIII, VII, X, and V in nephrotic syndrome.

Plasma procoagulant activities of factors IX, VIII, VII, IX, and V were determined in 21 adult patients with nephrotic syndrome of diverse etiologies. The studies were performed during the initial presentation and prior to institution of any therapy. Procoagulant activities of all these coagulation factors were found to be markedly elevated in a majority of the tested patients. Elevated factor VIII and factor V plasma procoagulant activities demonstrated in this study are in agreement with earlier investigations. None of our patients exhibited acquired factor IX deficiency, a publicized complication of nephrotic syndrome. Instead, the prevalent abnormality was increased plasma factor IX activity in these patients. Our results also suggest that previously reported increased combined factor VII-X activity in nephrotic syndrome is due to elevation of both factor VII and factor X activities.

Prothrombin time after heparin removal. Application to monitoring simultaneous anticoagulation with heparin and coumarins.

Coumarin-anticoagulated plasmas from 31 subjects comprising two study groups were passed through epichlorohydrin triethanolamine cellulose (ECTEOLA) chromatography columns. Group I plasmas, which were run with nothing added, had mean prothrombin times of 21.6 +/- 5.4 sec prior to and 22.4 +/- 5.6 sec following exposure to these columns (r = 0.9449; t = 1.8307, P less than 0.100). The mean prothrombin time for Group II, 18.2 +/- 4.9 sec, lengthened with 5 u/ml heparin to 35.5 +/- 16.2 sec, and returned to 19.2 +/- 5.0 (r = 0.9763) after chromatography. Therefore, it appears that coumarin anticoagulation had no significant influence upon the capacity of ECTEOLA effectively to remove heparin in therapeutic doses. This means that virtually all prothrombin time reagent systems can be employed to monitor concurrent heparin and coumarin anticoagulation. In addition, quality control of the combined technic is simpler, and the technic more sensitive to low levels of fibrinogen and factor V.

Fibrinogen Seattle: a qualitatively abnormal fibrinogen in a patient with tetralogy of Fallot.

A dysfibrinogen was detected in the plasma of a 14-year-old asymptomatic Caucasian boy who had tetralogy of Fallot. The mutant molecular species could be traced through four generations in an autosomal dominant type of inheritance pattern. Nine of 14 family members were found to have the coagulopathy. Following laboratory and clinical evaluation, the proband underwent radical repair of the cardiac defect without incident. This variant is tentatively designated fibrinogen Seattle pending further characterization.

Complement consumption in acute disseminated intravascular coagulation without antecedent immunopathology.

Complement component C3, component C4, and total hemolytic complement CH50 were measured in blood from ten patients with acute disseminated intravascular coagulation (aDIC) syndromes. The study group was selected on the basis of history to exclude antecedent immunologic, infectious, or hepatic disease. The mortality rate was high (90%), the average duration of illness short (8.5 days), and the utilization of blood products extensive. The behaviors of C3 and C4 were found to be analogous to fibrinogen, plasminogen, antiplasmin, and platelets. CH50 activity paralled C3 and C4, as well as results of the soluble coagulation factor screening tests. It is concluded that serum complement is consumed as part of the multisystem dysfunction, aDIC, and that in conjunction with traditional indicators it may be utilized to gauge the severity of this syndrome.

A solid-phase radioassay for the quantitative determination of antiplasmin activity in human plasma.

The caseinolytic activity of one CTA (Committe on Thrombolytic Agents) unit of human plasmin is inhibited by a series of plasma dilutions containing antiplasmin. Then neutralization of the standard plasmin by increasing amounts of antiplasmin shows a steeper linear decrease of plasmin activity betwwen 1.0 and 0.5 CTA units and a much smaller further inactivation below 0.5 CTA units. It is thought that the standard plasmin is partially damaged at the antiplasmin combining site during the purification procedrue and might be responsible for the differences in plasmin-antiplasmin neutralization in the standard curve. Using the steeper slope of the plasmin neutralization curve, an average of 8.6 +/- 1.0 CTA units plasmin neutralizing activity per ml human plasma was found in 36 healthy donors. The difficulty of obtaining 'native' standard plasmin with full antiplasmin combining capacity represents the main problem of a reproducible reliable antiplasmin assay.