Shortened platelet survival in cyanotic heart disease

Volume 87 Number 1

Brief clinical and laboratory observations

2. Scalinci N, quoted by Duke-Elder in Duke-Elder S, and Wybar KD: System of ophthalmology, The anatomy of the visual system, vol. 2, St. Louis, 1961, The C. V. Mosby Company. 3. Bistis J: La paralysie du sympathique dans l'rtiologie de l'hrtrrochromie, Arch d' Ophtalmol 32:569, 1928. 4. von Herrenschwand F: Ueber verschiedene arten yon heterochromia iridis, Klin Monatsbl Augenheilk 60:467, 1918. 5. Calhoun FP: Causes of heterochromia iridis with special reference to paralysis of the cervical sympathetic, Am J Ophthalmol 2:255, 1919. 6. Lazarescu D, and Lazarescu E.: Hrtrrochromie neurog~ne de l'iris et syndrome de Claude-Bernard-Horner, observation clinique et recherches experimentales, Ann Occul 170:767, 1933. 7. Passow A: Hornersyndrom, heterochromie und status dysraphicus, ein symptomenkomplex, Arch Augenheilk 107:1, 1933.

Shortened platelet survival in cyanotic heart disease J. Deane Waldman, M.D., Emily E. Czapek, M.D., Milton H. Paul, M.D.,* Allen D. Schwartz, M.D., Daniel L. Levin, M.D., and Susan Schindler, M.S., Chicago, Ill. THROMBOCYTOPENIA and abnormalities of the soluble coagulation system have been reported frequently in children with cyanotic heart disease. 1-8 Some authors 6-8 have considered these findings compatible with disseminated intravascular coagulopathy, but recent evidence does not support this conclusion. Our investigations were From the Divisions of Pediatric Cardiology (Willis J. Potts Children's Heart Center) and Pediatric Hematology, Northwestern University-McGaw Medical Center, The Children's Memorial Hospital Supported in part by Clinical Research Center contract MO-RR-O0199 and by grants from the Otho S.A. Sprague Memorial Institute, and the Griffin Cardiology Research Fund. Presented in part at the annual meeting of the Society for Pediatric Research, Washington, D.C., May 1-3, 1974. *Reprint address: Division of Cardiology, Children's Memorial Hospital, 2300 Children's Plaza, Chicago, IlL 60614.

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8. Mayou MS: Heterochromia iridis, associated with paralysis of the sympathetic in early life, Trans Ophthalmol Soc UK 30:196, 1910. 9. Mayou MS: Diseases of the nervous system. 2. Paralysis of the sympathetic (birth injury) with slight heterochromia iridis, Trans Ophthalmol Soc UK 36:411, I916. 10. StreiffJ: Ein neuer irisbefund bei fuchsscher heterochromie und weitere erganzungen zum heterochromieproblem, Klin Monatsbl Augenheilk 76:321, 1926. 11. Durham D: Congenital hereditary Horner's syndrome, Arch Ophthalmol 60:939, 1958. 12. Filler R, Traggis D, Jaffe N, and Vawter GF: Favorable outlook for children with mediastinal neuroblastoma, J Pediatr Surg 7:136, 1972. 13. Alfano JE: Ophthalmological aspects of neuroblastomatosis: a study of 53 verified cases, Trans Am Acad Ophthalmol Otolaryngol 72:830, 1968.

undertaken to evaluate hematologic responses to arterial unsaturation with particular attention to platelet survival. PATIENT

POPULATION

Twenty-one children were studied who had arterial oxygen unsaturation resulting from either cyanotic congenital heart defects or acyanotic congenital heart malformations with advanced p u l m o n a r y vascular disease and resultant secondary cyanosis. None had previously received autologous platelets, and all were in a stable clinical condition. The children ranged in age from nine months to 24 years; five were female and sixteen were male. Diagnoses included transposition of the great vessels (6), pseudotruncus (4), tetralogy of Fallot (3), advanced p u l m o n a r y vascular disease (2), truncus arteriosus (1), and other complex cyanotic lesions (5). Abbreviations used PT: prothrombin time aPTT: activated partial thromboplastin time FSP: fibrin split products PHL: platelet half-life DIC: disseminated intravascular coagulation

METHODS Three milliliters of blood were collected in 3.8% sodium citrate using a two-syringe technique and plastic containers throughout; the volume of anticoagulant was adjusted for the patient's hematocrit, using the formula: 45 Patient's hematocrit

• 0.05 m t = Volume of citrate.

78

Brief clinical and laboratory observations

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PLATELET HALF-LIFE (hours) Fig. 1. Platelet half-life (hours) compared with hematocrit (HCT; closed circles) and systemic arterial oxygen saturation (SAT; open circles). I. Correlation of platelet count and PHL in 21 cyanotic patients Table

l ee?l

( / m m 3)

> 80 hr

< 80 hr

> 150,000 < 150,000

8 patients 0 patients

10 patients 3 patients

Tests for prothrombin time and activated partial thromboplastin time, assays of factors V, VIII, and fibrinogen were performed by commonly used techniques. Fibrinogen/fibrin split products were measured using the tanned-red-cell hemagglutination inhibition technique on serum clotted with thrombin and collected in epsilonamino-caproic acid. Platelet survival times were determined by measuring the disappearance of ~lCr-labeled autologous platelets. Additional routine blood studies included hemoglobin and hematocrit (determined by centrifugation), at least three platelet counts (varying by not more than 10%), reticulocyte count, arterial blood gases, and routine measurements of hepatic function. Specimens of bone marrow were obtained in eight individuals. RESULTS General data. Hemoglobin concentrations varied between 14.6 and 23.6 gm/dl and arterial oxygen saturation ranged from 50% to 92% (mean 74.5%). There were no consistent abnormalities in platelet size noted. Adequate numbers of normal-appearing megakaryocytes were found in the eight bone marrow samples, including five from children with abnormal platelet survival times, one of whom was thrombocytopenic. Coagulation studies. Abnormalities of aPTT, levels of

factors V and VIII were found in only seven patients. There was no laboratory evidence of liver dysfunction in any patient with abnormalities of the soluble coagulation mechanism. Prothrombin time, fibrinogen level, and titer of FSP were normal in each patient. Platelet studies. Platelet survival times, expressed as the platelet half-life, in these 21 patients varied from 32 to 166 hours (normal for our laboratory is 80 to 130 hours). Eight patients had normal platelet half-lives of 90 hours or greater. Thirteen patients had shortened platelet survival times (32 to 75 hours); three of these had platelet counts less than 150,000/ram 3 and each had a markedly shortened platelet survival time. However, ten individuals had shortened PHL with normal platelet counts (Table I). COMMENT Our findings and those of others 1-~do not support the concept of disseminated intravascular coagulation in congenital heart disease with cyanosis under stable clinical conditions. None of our patients had abnormal prothrombin time, low level of fibrinogen, or elevated titer of FSP. Three children were thrombocytopenic and had no abnormalities of the soluble coagulation system. Sporadic coagulation abnormalities were found in nonthrombopenic individuals and, although we have no explanation for these findings, the pattern is not suggestive of DIC. Clearly, an alternative mechanism to DIC must be found to account for the low platelet count sometimes found in congenital heart disease with cyanosis. Our findings of shortened PHL in three thrombocytopenic children are in agreement with the work of Wedemeyer and Lewis 5 and Kummer and associates. ~However, in our series, ten patients with normal platelet count and cyanosis had shortened PHL. This implies that, although platelet survival is shortened, successful compensation by increased platelet production can be achieved. In this small patient population, no significant correlations were found between platelet half-life and the patient's age, hemodynamic values (pulmonary blood flow, pulmonary vascular resistance), or abnormalities of the soluble coagulation mechanism. Moderately significant relationships were noted (Fig. 1) when platelet halflife was correlated with systemic arterial oxygen saturation (P < 0.1) and with hematocrit value (p _< 0.01). All children with hematocrit values greater than 57% and six of seven children with oxygen saturation values below 71% had abnormal PHL. When, oxygen saturation was greater than 71% or hematocrit less than 57%, PHL was abnormally short in approximately half of the patients. Thus, while intense unsaturation and extreme erythrocytosis were almost always associated with abnormal

Volume 87 Number 1

platelet half-life, the presence of a more nearly normal oxygen saturation or hematocrit did not preclude a shortened platelet survival. Various therapeutic interventions have been proposed for cyanotic thrombocytopathy based on conflicting opinions as to pathogenesis. 2-4. . . . . Our study has shown abnormal platelet survival in cyanotic children, not due to DIC. A surprisingly high percentage (48%) with shortened PHL had normal platelet counts and may be considered to have a state of "compensated thrombocytolysis." However, shortened platelet survival could result from either intrinsic platelet abnormalities, or originally normal platelets damaged somewhere in the circulation. Until there is a deeper understanding of the mechanism of these abnormalities, therapeutic suggestions seem premature.

REFERENCES 1. Johnson CA, Abilgaard CF, and Schulman I: Absence of coagulation abnormalities in children with cyanotic congenital heart disease, Lancet 1:660, 1968. 2. Ekert H, Gilchrist GS, and Stanton R: Hemostasis in cyanotic congenital heart disease, J PEOXATR76:221, 1970.

The syndrome of aplasia cutis congenita with terminal, transverse defects of limbs Nina Seribanu, M.D., Washington, D: C.,

Brief clinical and laboratory observations

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3. I61ster NJ: Blood coagulation in children with cyanotic congenital heart disease, Acta Paediatr Scand 59:551, 1970. 4. Wedeymer AL, Edson JR, and Krivit W: Coagulation in cyanotic congenital heart disease, Am J Dis Child 124:656, 1972. 5. Wedemeyer A, and Lewis JH: Platelet survival studies in cyanotic cardiac patients (abstr.), J PEDIATR83:161, 1973. 6. Komp DM, and Sparrow AW: Polycythemia in cyanotic heart disease--a study of altered coagulation, J PEDIATR 76:231, 1970. 7. Ihenacho HNC, Breeze GR, Fletcher DJ, et al: Consumption coagulopathy in congenital heart disease, Lancet 1:231, 1973. 8. Dennis LH, Stewart JL, and Conrad ME: Heparin treatment of hemorrhagic diathesis in cyanotic congenital heart disease, Lancet 1:1088, 1967. 9. Kummer VH, Curtner HP, and Bucher U: Thrombocytopenic bei chronischen cot pulmonale und cyanotischen herzvitien, Schweiz Med Wochenschr 38:1334, 1964. 10. Maurer HM, and McCue CM: Correction of platelet dysfunction and bleeding in cyanotic congenital heart disease by simple red cell volume reduction (abstr.), Am Acad Pediatr. October 21, 1973. 11. Wedemeyer AL, and LewisJH: Improvement in hemostasis following phlebotomy in cyanotic patients with heart disease, J PEDIATg83:46, 1973.

proband's sister had only scalp defects. Farmer and Maxmen 3 described a sporadic case; this person, in addition to the association of aplasia curls congenita and terminal transverse defects, had dilated and tortuous scalp veins. Abbreviations used ACC: aplasia cutis congenita TTD: terminal transverse defects

and Samia A. Temtamy, M.B., B.Ch., D.C.H., Cairo, Egypt

IN 1945 ADAMS AND OLIVER 1 described eight affected individuals in three generations who had associated central skull and scalp defects a n d terminal transverse defects of the limbs. The proband had bilateral below-knee hemimelia and aphalangia of one hand associated with central skull and scalp defects; the father and three affected sibs had similar skull and scalp defects and terminal transverse defects at variable levels of the limbs. Kahn and Olmedo 2 reported one case of the same association; this patient also had curls marmorata. The

Supported by Grant No. MCT-O00925 -06 -0, Department of Health, Education and Welfare.

Recently we studied a patient who presented with central skull and scalp defects and TTD of the lower limbs. In addition he had curls marmorata and dilated and tortuous scalp veins. His mother is clinically normal, but his maternal aunt was said to have similar terminal transverse defects of the lower limbs (Fig. 1). One of the aunt's children, who died at 14 months of age, had cutis marmorata and dilated scalp veins. Our findings and previous reports suggest etiologic heterogeneity of ACC, of which ACC associated with TTD represents a distinct genetic entity.

CASE REPORT The proband, a 3-year-old white male, was the product of the first pregnancy of his mother, a 25-year-old unmarried woman. The pregnancy and delivery were uneventful; the birth weight was 5 pounds and 2 ounces. The congenital anomalies of the