SCREENING TESTS FOR BLEEDING DISORDERS

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1 THE AMERICAN JOURNAL OP CLINICAL PATHOLOGY Copyright 9 by The Williams & Wilkins Co. Vol., No. 5 Printed in U.S.A. SCREENING TESTS FOR BLEEDING DISORDERS PAUL DIDISHEIM, M.D. Department of Medicine, University of Utah College of Medicine, Salt Lake City, Utah The number and variety of diagnostic tests for bleeding disorders have increased at a distressingly rapid rate in recent years. This has led to confusion among many as to which tests should be performed in a given situation. The answer obviously depends on the situation, since the patient's past history of bleeding episodes, medications, family history of "bleeders," physical findings, and previous laboratory data are all helpful in the decision. To compare the sensitivity of various tests in different disorders, the accumulated experience of a diagnostic laboratory for hemorrhagic diseases was analyzed. PATIENTS The procedure for selecting patients for study was as follows. From the large number of patients with bleeding disorders seen in the Hematology Division, Department of Medicine, University of Utah Medical Center, a small proportion was referred or selected for further study in the coagulation laboratory because simple screening tests such as the prothrombin time and platelet count performed in other laboratories in the Medical Center did not sufficiently clarify the mechanism of bleeding, or because a particular research interest was evidenced in certain disease states. As a result most of the patients with thrombocytopenia from any cause were not studied further. A total of 53 patients were examined in the coagulation laboratory between August, 958, and May, 965. Although most were seen because of a significant hemorrhagic history, some were studied because they were asymptomatic relatives of "bleeders." Received June 25, 966. Dr. Didisheim's present address is Section of Clinical Pathology, Mayo Clinic, Rochester, Minnesota. This investigation was supported in part by Research Grants A-2625 and AM-89 from the National Institutes of Health, United States Public Health Service. 622 Results of some of these studies have been reported previously, 5 ' ' 8 ' " 2 but they are all included in the present study for statistical analysis. METHODS AND MATERIALS The following methods have been described previously: The platelet count; 6 bleeding time, quantitative clot retraction, platelet Factor 3 assay, in vivo platelet adhesiveness, and coagulation time in siliconized tubes; 8 tourniquet test (8 mm. Hg) and thromboplastin generation test; negative pressure capillary fragility; 2 prothrombin time, prothrombin consumption (serum prothrombin time), thrombin time (plasmathrombin clotting time), whole blood clot lysis time, and Factor V assay; 6 serum prothrombin time with soybean phosphatide; 8 and pro thrombin assay and assays for Factors VIII, IX, XI, and XII, fibrinogen, 2 and partial thromboplastin time. For the determination of coagulation time in glass tubes, 2 ml. of blood are delivered into each of two 3- by -mm. new glass tubes at 3 C. The first tube is tilted gently at -min. intervals, the time beginning after 5 min., until the tube can be inverted without the blood flowing; the second tube is then tilted in the same manner until it can be inverted without the blood flowing (end point). The euglobulin lysis time was measured at 3 C. on the imidazole-resuspended euglobulin precipitate of citrated plasma after clotting with human thrombin. No patient was considered to have an abnormality unless the average of two or more determinations on separate occasions gave an abnormal result. An "abnormality" was denned as a value that was beyond the 95 limits (mean ± 2 standard deviations) of results from a group of 2 or more healthy men and women. For the purpose of this study, a patient having signs of "hypercoagulability" by any of the tests performed was not considered to be "abnormal." Such signs include an abnormally Downloaded from by guest on 9 November 28

2 May 96 BLEEDING DISORDERS 623 TABLE DIAGNOSES OP PATIENTS IN WHOM AN ABNORMALITY OF HEMOSTASIS WAS FOUND Diagnosis Congenital coagulation defects Factor V Factor VIII Factor IX Factor XI Factor XII Von Willebnind's disease Hetcrozygotes for Factor IX deficiency Total Th rombocy t open i as Leukemias Idiopathic thrombocytopenic Familial Hepatic disease Aplastic anemia Myelofibrosis Total purpura Other defects Leukemias Myeloid metaplasia with or without myelofibrosis Thrombocytopathies other than above Dysproteincmias; multiple myeloma Other malignancies Total Miscellaneous Total No If) short clotting time in any test except the prothrombin consumption test; abnormally increased fibrinogen level, platelet count, or clot retraction; and abnormally prolonged fibrinolysis time by either the whole blood or euglobulin clot method. RESULTS Of the 53 patients examined, were excluded from the study because of insufficient or equivocal data or because of a thrombotic instead of a hemorrhagic history. Of the remaining 526 patients, 26 (39) had no demonstrable laboratory abnormality. Of these, 5 (6 ) had no significant bleeding or bruising symptoms. Of the remaining 9 who had a positive hemorrhagic history, despite negative laboratory findings, 25 were males and 2 were females. The diagnoses of the 32 patients in whom an abnormality was demonstrated are presented in Table. The relative frequency of abnormal test results in hemophilia (Factor VIII deficiency) is shown in Table 2. All patients were males. The partial thromboplastin time (PTT), thromboplastin generation test (TGT), and Factor VIII assay were abnormal in all patients tested. The prothrombin consumption test (PCT) and coagulation times in siliconized (CTS) or plain glass (CTG) tubes were abnormal in most patients, but were occasionally normal in patients with clinically mild hemophilia and Factor VIII levels greater than of normal. Several patients had prolonged bleeding times (BT); although their family histories were of the sex-linked pattern seen in hemophilia, studies were not carried out to determine whether their response to transfusions was characteristic of hemophilia or of von Willebrand's disease. 3 One TABLE 2 HEMOPHILIA (FACTOR VIII DEFICIENCY): RELA TIVE FREQUENCY OF ABNORMAL TEST RESULTS OF HEMOSTASIS IN 3 PATIENTS Partial thromboplastin time Thromboplastin generation test Factor VIII assay Prothrombin consumption test Coagulation time, silicone tube Coagulation time, glass tube Circulating anticoagulant Clot retraction Factor IX assay Prothrombin time Platelet count Whole blood clot lysis time Tourniquet test Abnormal Results Downloaded from by guest on 9 November 28

3 62 DIDISHEIM Vol. TABLE 3 FACTOR IX DEFICIENCY: RELATIVE FREQUENCY OF ABNORMAL TEST RESULTS OF HEMOSTASIS IN 2 PATIENTS Partial thromboplastin time Thromboplastin generation test Factor IX assay Prothrombin consumption test Coagulation time, silicone tube Coagulation time, glass tube Circulating anticoagulant Tourniquet test Clot retraction Factor VIII assay Prothrombin time Platelet count Whole blood clot lysis time Abnormal Result patient had a mild deficiency (3 ) of Factor IX in addition to a severe deficiency of Factor VIII (less than.). Other members of his family were not available for study; however, this patient had a circulating anticoagulant which may have been responsible for a spuriously low result in the Factor IX assay. In Table 3 are shown comparable results for Factor IX deficiency. All patients were males. Except for the Factor VIII and IX assays, the results are similar to those in Factor VIII deficiency. Again, the PTT, TGT, and specific assay are the most sensitive tests. The PCT, CTS, and CTG were occasionally normal in patients with mild degrees of deficiency (greater than of normal). No patient with a prolonged BT was seen. Only one patient who clearly fitted the criteria for Factor XI deficiency was seen. This patient did not come from Utah; he had previously been the subject of a report from another laboratory. 2 The findings in heterozygotes for Factor IX deficiency have been published. 2 Current data on the heterozygotes who had one or more abnormalities of hemostasis are summarized in Table. The Factor IX assay was abnormal in all of these. The TGT was much less sensitive. The defect in the TGT, when present, was always in the serum. Interestingly, the bleeding time and capillary fragility were abnormal in a significant proportion of cases. Prothrombin consumption, coagulation time in glass or silicone tubes, and other routine coagulation tests not listed were consistently normal. Two patients with acute promyelocytic leukemia were seen. They both had severe hypofibrinogenemia, a finding not observed in 86 patients with other forms of leukemia studied. These results have been published previously. Ten patients with established myelofibrosis, studied when their platelet counts were normal, comprise a separate report. 8 A prolonged bleeding time was the most frequent abnormality, being found in nine patients; this may have been related to the reduced adhesiveness of platelets that was seen in half of the patients studied. In addition to the group with myelofibrosis mentioned above, a number of other patients were seen who had evidence of an abnormality of platelet function (thrombocytopathy) or vascular function. They all had normal platelet counts at the time of study. Data on these patients are presented in Table 5. The criterion for the diagnosis of von Willebrand's disease was a prolonged bleeding time combined with a significant reduc- TABLE HETEROZYGOTES (CARRIERS) FOR FACTOR IX DEFICIENCY: RELATIVE FREQUENCY OF ABNORMAL TEST RESULTS OF HEMOSTASIS IN 5 PATIENTS WITH AT LEAST ONE ABNORMAL TEST RESULT Factor IX assay Thromboplastin generation test Capillary fragility Coagulation time, silicone tube Prothrombin consumption test Coagulation time, glass tube Abnormal Results 33 2 Downloaded from by guest on 9 November 28

4 May 96 BLEEDING DISORDERS 625 TABLE 5 RESULTS OF CERTAIN.HEMOSTATIC TESTS IN 2 PATIENTS WITH DISORDERS OF PLATELET OR VASCULAR FUNCTION OR BOTH* Patient No. Plat. BT TT Cap. frag CR SPT SPT-P Pit. F. 3 Pit. Ad. VIII IX Normal f Von Willebrtind's disease Prolonged BT only Primary thrombocytopiithy.secondary thrombocytopatliy (i a 8b [ min. - >5 >5t >5t >8t >3 8t 2* >3t 9t >9t >2f 9 lit 3t >m >5t st t >5{ 5.5 grade - 3t >t S S 6 5 sec * is* sec. 25-S (25F )t (3F5)t 5-25 t 25 3t ot It 22 5t 5t It It 5-5 3t 35t iot > S SS 8 2 > 52 > 5-5 * Plat. = platelets, X /cu. mm.; BT = bleeding time; TT = tourniquet test; Cap. frag. = negative pressure capillary fragility, number of petechiae;cr = clot retraction; SPT = serum prothrombin time; SPT-P = serum prothrombin time with soybean phosphatide; Pit. F. 3 = platelet Factor 3, percentage of normal; Pit. Ad. = platelet adhesiveness, ratio of adhesive to venous platelet count; VII, IX = assay for Factor VIII or IX, percentage of normal. f Mean ± 2 S.D. Abnormal values. After freeze-thawing of platelets. 8a and 8b = before and after treatment with chlorambucil, respectively. tion of the Factor VIII level. Three patients who definitely met this criterion were seen (Table 5). Patient 2 is the maternal uncle of patient ; patient 3 is unrelated. Patient, however, another maternal uncle of patient, had a prolonged bleeding time without depression of Factor VIII. Also, patient 5 is a brother of patient 3. Patients 6 and 3 are sisters; a third sister, not included in this report, had a bleeding time of 6.5 min. and a Factor VIII level that was of normal. There were no other known relationships among patients in Table 5. None of the patients in any of the categories had a known associated disorder, except those with secondary thrombocytopathy. Patients No. through had prolonged bleeding times despite normal platelet counts, normal clot retraction, and normal Downloaded from by guest on 9 November 28

5 626 DIDISHEIM Vol. TABLE THE RELATION OF CLOT RETRACTION TO THE PLATELET COUNT IN PATIENTS WITH TL I ROM BOC YTO PENT A Platelets per cu. mm. -9, 2-39, -59, (i-9, 8-99, -9, 2-39, Diminished Clot Retraction Factor VIII levels, and hence they do not meet the criteria for either von Willebrand's or Glanzmann's 3 disease. Patients No. 5 through had abnormally short serum prothrombin times; in one, correction of this abnormality was achieved with a soybean substitute for platelet phospholipid. Two of these patients had reduced platelet Factor 3 activity of platelets that were frozen and then thawed, and the other had reduced platelet adhesiveness; these were classified as having "primary thrombocytopathy." Patients No. 8 through 2 had reduced platelet adhesiveness in association with various disorders, and were categorized as having "secondary thrombocytopathy." Patient No. 8 had Waldenstrom's macroglobulinemia; the associated defect of platelet adhesiveness disappeared after weeks of treatment with chlorambucil, 8 mg. per day. Patient No. 9 had multiple myeloma; patient No. 2, chronic lymphocytic leukemia; patient No. 2, malignant reticuloendothelioma; and patients No. 22 through 2, refractory anemias of unknown origin. It is generally accepted that clot retraction is deficient in thrombocytopenia. Table 6 shows the correlation between the platelet count and clot retraction in patients with thrombocytopenia. Clot retraction was abnormal in only half of the patients, even when the platelet count was as low as 2, to, per cu. mm. Only when platelets were below this level was clot retraction usually abnormal. A prolonged bleeding time is also considered to be a hallmark of thrombocytopenia. Table shows the correlation between the bleeding time and platelet count in thrombocytopenia. The bleeding time was usually prolonged even when the platelet count was as high as, to 39, per cu. mm. The tourniquet test is another test that is considered to reflect the degree of thrombocytopenia. Table also shows the correlation between the tourniquet test and the platelet count in thrombocytopenia. Even when the platelet count was below 2, per cu. mm., the tourniquet test was not always positive. How frequently are the bleeding time, clot retraction, and tourniquet test abnormal in patients with thrombocytopenia? Data on all patients with thrombocytopenia (less than, platelets per cu. mm.) are combined in Table 8. On the basis of these figures, as well as those in Tables 6 and, it appears that the bleeding time is the most sensitive to thrombocytopenia of the three tests; the next most sensitive is clot retraction, and the least sensitive is the tourniquet test. Fibrinogen deficiency may cause the TABLE THE RELATION OF THE BLEEDING TIME AND TOURNIQUET TEST TO THE PLATELET COUNT IN PATIENTS WITH THROMBOCYTOPENIA Platelets per cu. mm. -9, 2-59, -99, -39, No. of Patients 8 9 Prolonged Bleeding Time Positive Tourniquet TABLE 8 THE RELATIVE FREQUENCY OF ABNORMAL BLEED ING TIME, CLOT RETRACTION, AND TOURNI QUET TEST IN THROMBOCYTOPENIA Clot retraction Tourniquet test Abnormal Results Downloaded from by guest on 9 November 28

6 May 96 BLEEDING DISORDERS 62 prothrombin time to be prolonged. It may also cause a prolonged thrombin time. These two tests were compared with regard to their sensitivity to fibrinogen deficiency in 66 patients with fibrinogen levels below 5 mg. per ml. (Table 9). Results of both tests were regularly abnormal when the fibrinogen level was below 9 mg. In the intermediate range from 9 to 9 mg., the two tests appeared to be fairly comparable in their ability to reflect fibrinogen deficiency in a certain proportion of cases. Twenty patients with increased fibrinolytic activity were seen. Their diagnoses were: acute leukemia, eight patients; carcinoma of the prostate, four patients; chronic lymphocytic leukemia, two patients; and one patient each with bronchogenic carcinoma, chronic idiopathic thrombocytopenic purpura, systemic lupus erythematosus, infectious mononucleosis, acute surgical fibrinolysis, and no known associated disorder. The frequency of abnormal hemostatic tests in these patients is presented in Table. The euglobulin lysis time was more frequently abnormal than was the whole blood clot lysis time. Increased fibrinolytic activity was frequently present without an associated deficiency of fibrinogen or prothrombin or a prolonged prothrombin or thrombin time. Thrombocytopenia was generally present. Prothrombin consumption was abnormal only in those patients with thrombocytopenia; however, two patients with normal platelet counts and normal prothrombin consumptions nevertheless had prolonged bleeding times. TABLE 9 THE RELATION OP THE PHOTHKOMBIN TIME AND THROMBIN TIME TO THE FIBRINOGEN LEVEL IN GO PATIENTS Fibrinogen mg./loo ml Prolonged Times Prothrombin time 35 av. sec Thrombin time 5 av. sec > TABLE FIBRINOLYSIS: RELATIVE FREQUENCY OF ABNOU MAL TEST RESULTS OF HEMOSTASIS IN 2 PATIENTS Euglobulin lysis time Platelet count Whole blood clot lysis time Prothrombin consumption test Clot retraction Thrombin time Fibrinogen Prothrombin time Prothrombin assay Coagulation time, silicone tube Factors V, VIII, and IX Abnormal Results IS DISCUSSION It has been said that "normal" women tend to bleed or bruise more easily than "normal" men. Our data do not support this concept. Of 9 patients with significant bleeding or bruising tendencies, despite no abnormality that was detected by the screening tests which were performed, 25 were males. In both hemophilia and Factor IX deficiency, three tests were abnormal in every patient: the PTT, TGT, and specific assay for Factor VIII or IX. Other tests were abnormal with similar frequency in the two diseases. In both disorders a significant proportion of cases would have been missed if reliance had been placed on the coagulation time in glass or siliconized tubes, or on the prothrombin consumption test, as a screening procedure. In patients with a Factor VIII or IX level greater than of normal, these three tests frequently yield results within the normal range. 9 In the detection of heterozygotes for Factor IX deficiency, the specific assay for Factor IX was clearly the most sensitive of the tests performed. Approximately 8 of women known to be carriers were detected by this test. The genetic pattern of von Willebrand's disease has received much attention, 3 but Downloaded from by guest on 9 November 28

7 62S DDSHEM Vol. remains to be explained satisfactorily. Data presented herein may be helpful in this regard (Table 5). Members of two families were studied. In one family (patients No., 2, and ), two patients exhibited the dual defect of prolonged bleeding time and reduced Factor VIII, considered by most to be pathognomonic of this disorder, and yet the third individual had only a prolonged bleeding time without the Factor VIII abnormality. In a second family (patients No. 3 and 5), a similar difference between two relatives was noted. A third family showed a different pattern: patients 6 and 3, sisters, had prolonged bleeding times without reduction of Factor VIII, whereas a third sister had a reduced Factor VIII level without a prolonged bleeding time. Although these variations may be attributable to true fluctuations in the patient or to inaccuracies of the tests, another explanation may be that "von Willebrand's disease" is caused by an abnormality in two closely linked autosomal genes, and that in a certain proportion of cases segregation occurs, thus causing the gene responsible for one or the other abnormality (but not both) to be inherited. 2 Several of the patients with "secondary thrombocytopathy" (Table 5) are of interest. In patients No. 8 and 9, the macroglobulin 9 and myeloma protein 23 may have been coating the platelets and thereby preventing them from adhering normally. Anemia may have influenced the result in patients 2 through 2, but is unlikely to have been the sole cause of the abnormalities observed. 8 The relative values of the bleeding time, tourniquet test, and clot retraction as screening tests for thrombocytopenia are indicated in Tables 6 through 8. The bleeding time is highly sensitive; the clot retraction and tourniquet tests are quite insensitive, and their performance for this purpose is probably wasted effort. A carefully performed platelet count 6 is not a difficult procedure and should be part of the routine battery of tests performed on patients suspected of having a hemostatic disorder. Screening tests for fibrinogen deficiency, in contrast, are highly sensitive. Significant fibrinogen deficiency (less than 9 mg. per ml.) was never seen unless both the prothrombin time and thrombin time were prolonged. Of the two tests evaluated for fibrinolysis, the euglobuhn lysis time appeared to be the more sensitive one. This has been the general experience in other laboratories. Since fibrinogen was frequently normal despite increased fibrinolytic activity, a normal prothrombin time, thrombin time, or fibrinogen assay is not sufficient evidence against the existence of a fibrinolytic state. The prolonged bleeding time, despite normal platelet count in two patients with fibrinolytic activity, suggests the possibility that circulating fibrinolysin may prolong the bleeding time by digesting fibrin at the site of hemostatic plug formation or by altering the platelet surface. Equally likely is the hypothesis that products of fibrinogen breakdown appearing in the circulation during the fibrinolytic state may have diminished the adhesive and aggregating properties of platelets,' 6 thus prolonging the bleeding time. Factor V and VIII deficiencies have been reported 22 as being part of the syndrome of "fibrinolytic purpura"; these defects did not occur in our experience (Table ). SUMMARY A review of the results of laboratory methods for detecting a bleeding state in 526 patients with various hemorrhagic disorders has led to the following conclusions. In hemophilia and Factor IX deficiency, the most sensitive tests are the partial thromboplastin time, thromboplastin generation test, and specific assays for Factor VIII or IX. Other technics, such as the determination of coagulation time in glass or silicone tubes or the prothrombin consumption test, are significantly less sensitive. In the detection of the heterozygous state for Factor IX deficiency, the specific assay for Factor IX is clearly the most sensitive of the methods tested. In two patients with acute promyelocytic leukemia, severe hypofibrinogenemia was a prominent feature. This was not seen in patients with other forms of leukemia who were studied. Downloaded from by guest on 9 November 28

8 May 96 BLEEDING DISORDERS 629 In myelofibrosis, the bleeding time was prolonged in 9 of patients despite normal platelet counts. This may have been related to the reduced platelet adhesiveness seen in half of the patients studied. The bleeding time (Ivy, modified) and the platelet adhesiveness test emerge as valuable technics for the detection of hemostatic abnormalities in a miscellaneous group of disorders, in addition to von Willebrand's disease and myelofibrosis, and in a number of patients without other known disorders. Of the three tests commonly considered to reflect thrombocytopenia, the bleeding time appears to be far more sensitive than the tourniquet test or clot retraction. Not every patient with thrombocytopenia has a prolonged bleeding time, however. The prothrombin time and thrombin time are about equally sensitive to significant fibrinogen deficiency. The laboratory evaluation of a suspected bleeding disorder should include the following tests: the platelet count, bleeding time (Ivy), prothrombin time, partial thromboplastin time, and euglobulin lysis time. Platelet adhesiveness by the in vivo method appears to be a promising additional test which may occasionally be abnormal despite a normal bleeding time. Coagulation times in glass or silicone tubes, prothrombin consumption, clot retraction, tourniquet test, and negative pressure capillary fragility, as performed in this laboratory, are less sensitive than the above tests and, therefore, have limited usefulness as screening tests. The thromboplastin generation test, its modification for the assay of platelet Factor 3 activity, and specific plasma clotting factor assays can usually be reserved for patients in whom an abnormality has been found by one of the screening procedures recommended above, and when more specific diagnostic information is desired. Acknowledgments. Dr. M. M. Wintrobe and Dr. G. E. Cartwright made it possible to study the patients comprising this report. Dr. C. A. Owen, Jr., made valuable suggestions in preparing the manuscript. The study of patient J. L., with Factor XI deficiency, was made possible by Dr. S. I. Rapaport. Miss Dorothy L. Bunting gave expert technical assistance. REFERENCES. Alexander, B.: Thrombin and precursors.. Estimation of plasma prothrombin by the one-stage method. In: Tocantins, L. M.: The Coagulation of Blood: Methods of Study. New York, Grime & Stratton, Inc., 955, pp Barrow, E. M., and Graham, J. B.: von Willebrand's disease. In: Moore, C. V., and Brown, E. B.: Progress in Hematology, vol., New York, Grime & Stratton, Inc., 96, pp Barrow, E. M., Heindel, C. C, Roberts, IT. R., and Graham, J. B.: Heterozygosity and homozygosity in von Willebrand's disease. Proc. Soo. Exp. Biol. & Med., 8: GS- 8, 95.. Biggs, R., and Macfarlane, R. G.: Human Blood Coagulation and Its Disorders, Ed. 2. Springfield,., Charles C Thomas, Publisher, Bithell, T. C, Didisheim, P., Cartwright, G. E., and Wintrobe, M. M.: Thrombocytopenia inherited as an autosomal dominant trait. Blood, 25: 23-2, 95.. Brecher, G., and Cronkite, E. P.: Morphology and enumeration of human blood platelets. J. Appl. Physiol., 8: 35-3, 95.. Didisheim, P.: Hageman factor deficiency (Hageman trait): case report and review of the literature. Arch. Int. Med., : -, Didisheim, P., and Bunting, D.: Abnormal platelet function in myelofibrosis. Am. J. Clin. Path.,,5: 5-53, Didisheim, P., and Lewis, J. IT.: Congenital disorders of the mechanism for coagulation of blood. Pediatrics, 22: 8-93, 95S.. Didisheim, P., Pizzuto, J., and Bunting, D. L.: An improved assay for factor IX (PTC, Christmas factor). In: Brinkhous, K. M.: International Conference on Hemophilia, Washington, D. C, 93, The Hemophilias. Chapel Hill, University of North Carolina Press, 96, pp Didisheim, P., Trombold, J. S., Vandervoort, R. L. E., and Mibashan, R. S.: Acute promyelocytic leukemia with fibrinogen and factor V deficiencies. Blood, 2S: -2S, Didisheim, P., and Vandervoort, R. L. E.: Detection of carriers for factor IX (PTC) deficiency. Blood, 2: 5-55, Friedman, L. L., Bowie, E. J. W., Thompson, J. IT., Jr., Brown, A. L., Jr., and Owen, C. A., Jr.: Familial Glanzmann's thrombasthenia. Proc. Staff Meet. Mayo Clin., 39: 98-98, 9.. Hellem, A. J., Borchgrevink, C. F., and Amos, S. B.: The role of red cells in haemostasis: the relation between haematocrit, bleeding time and platelet adhesiveness. Brit. J. ITaemat., : 2-5, Kowalski, E., Kopec, M., and Wegrzynowicz, Z.: Influence of fibrinogen degradation products (FDP) on platelet aggregation, adhesiveness and viscous metamorphosis. Thromb. Diath. Haemorrh., : -23, 93.. Lewis, J. IT., and Didisheim, P.: Differential diagnosis and treatment in hemorrhagic clis- Downloaded from by guest on 9 November 28

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