Volume 90 Number 5
Brief clinical and laboratory observations
Thus, patient L. M. appears to be a unique example of primary type I hyperlipoproteinemia in a patient with normal lipoprotein lipase activity. One other patient with typical type I hyperlipoproteinemia was initially reported as having normal post-heparin lipolytic activity; with the development of separate assays for the various components of post-heparin lipolytic activity, however, he was found to have a deficiency of protamine inactivated triglyceride lipase with a relative increase in the protamineresistant lipase. 4 The combination of findings in our patient suggest that primary type I hyperlipoproteinemia may represent a heterogeneous group of disorders, only one of which is associated with a deficiency of lipoprotein lipase activity.
3.
4.
5. 6.
7.
We thank Dr. Peter N. Herbert of The National Institutes of Health for his help in performing the triglyceride lipase enzyme assay.
8.
REFERENCES
9.
1. Fredrickson DS, and Levy RI: Familial hyperlipoproteinemia, In Stanbury JB, Wyngaarden JB, and Fredrickson DS, editors: Metabolic basis of inherited disease, New York, 1975, McGraw-Hill Book Company, Inc, pp 545614. 2, Harlan WR, Winesett PS, and Wasserman AJ: Tissue
Combined yon Willebrand disease and Hageman factor
deficiency George R. Buchanan, M.D., Daniel M. Green, M,D., and Robert I. Handin, M.D.,* Boston,
Mass. From the Division of Hematology-Oncology of the Department Of Medicine, Children's Hospital Medical Center, Division of Hematology, Department of Medicine, Peter Bent Brigham Hospital, and the Departments of Pediatrics and Medicine, Harvard Medical School Supported by United States Public Health Service Grant Nos. HL 05581, HL 17513, and HL 05392.
10.
779
lipoprotein lipase in normal individuals and in individuals with exogenous hypertriglyceridemia and the relationship of this enzyme to assimilation of fat, J Clin Invest 46:239, 1967. Schreibman PH, Arons DL, Saudek CD, and Arky RA: Abnormal lipoprotein lipase in familial exogenous hypertriglyceridemia, J Clin Invest 52:2075, 1973. Krauss RM, Levy RI, and Fredrickson DS: Selective measurement of two lipase activities in postheparin plasma from normal subjects and patients with hyperlipoproteinemia, J Clin Invest 54:1107, 1974. Motulsky AG: The genetic hyperlipidemias, N Engl J Med 294:823, 1976. Glueck CJ, Kaplan AP, Levy RL Greten H, Ga'alnick H, and Fredrickson DS: A new mechanism of exogenous hyperglyceridemia, Ann Intern Med 71:1051, 1969. Glueck CJ, Levy RI, Glueck HI, Gralnick HR, Greten H, and Fredrickson DS: Acquired type I hyperlipoproteinemia with systemic lupus erythematosus, dysglobulinemia and heparin resistance, Am J Med 47:318, 1969. Kessler JI, Kniffen JC, and Janowitz HD: Lipoprotein lipase inhibition in the hyperlipemia of acute alcoholic pancreatitis, N Engl J Med 269:943, 1963. Bierman EL, Bagdade JD, and Porte D: A concept of the pathogenesis of diabetic lipemia, Trans Assoc Am Physicians 79:348, 1966. Porte D, O'Hara DD, and Williams RH: The relation between postheparin lipolytic activity and plasma triglyceride in myxedema, Metabolism 15:107, 1966.
COMBtNAa'IONS of hemophilia A or yon Willebrand disease with other clotting factor deficiencies', '-' or with intrinsic platelet abnormalities 3~' have been observed but are probably chance events in most circumstances. Several patients have been described who have evidence of VWD and slightly decreased levels Of Factor XII (Hageman factor)." Unfortunately, family studies were not performed to document joint inheritance of the two defects. We describe a child who has both VWD and Hageman factor deficiency, with a similar defect in the patient's father, suggesting linked auiosomal dominant transmission of both disorders.
Abbreviations used VWD: von Willebrand disease PTT: activated partial thromboplastin time VIIIvwv: plasma levels of yon Willebrand factor VIIIAc~x: Factor VIII antigen
*Cancer Research Scholar, Massachusetts Division American
Cancer Society. Reprint address: George R. Buchanan, M.D.. Division of Hematologv-Oncology, Children"s Hospital Medical Center. 300 Longwood Ave., Boston, MA 02114.
CASE REPORT
Patient C.R. is a 6-year-old white girl who was noted to have a long activated partial thr0mboplastin time. There was no history
"78 0
Brief clinical and laboratory observations
The Journal of Pediatrics May 1977
Table I. Results of laboratory tests in Patient C.R. and her family
Normal range Prothrombin time PTT Platelet count Bleeding time Platelet retention VIII.~H~ Vlllvwv VllI~ Factor X1 Factor XII Fletcher factor Fitzgerald factor Platelet aggregation Platelet morphology Platelet adenosine diphosphate
Platelet adenosine triphosphate
Platelet serotonin uptake
11-14 seconds 25-35 seconds 150-450,000/~d 2t/2-8 minutes 20-80% 50-200% 60-180% 41-212% 50-150% 50-150% 1.7-3.6 ptmoles/10" platelets 4.8-84 btmoles/10'' platelets -
[
PatientC.R.
Sister
11.8 48 286,000 13 2 51 55 21 I0 t 6 Normal Normal Normal Normal 2.9
13.5 29 5 I25 79 52 56 83
Normal Normal
Father]Mother 11.7 32 201,000 5~/2 32 42 37 13.5 92 26 Normal Normal Normal Normal
12.2 29 283.000 7 170 179 89 76 115
Normal Normal
6.4
Normal
PTI = Partialthromboplastintime; Vlll~.r: Factor VIII coagulantactivity:VllIwvv:plasmalevelsof von Willebrandfactor; VIII,,x = Factor VIII antigen. of a bleeding disorder except for minimal bruising. She had never required surgical procedures and was in excellent health. There was also no history of abnormal bleeding in the patient's 9-yearold sister, either parent, or any other relative. MATERIALS AND METHODS Multiple tests of hemostatic function were performed on the patient and the members of her immediate family, all of whom refrained from taking medications for at least ten days prior to study. All screening tests were performed according to standard methods/Assays for Factors VIII, XI, and XII were performed by a one-stage technique using a modified PTT system containing congenitally deficient substrate plasmas/ Factors VIII and XII were assayed in three different laboratories. Fletcher factor (pre-kallikrein) was screened by measuring the PTT after prolonged kaolin incubation." Fletcher factor and Fitzgerald factor (high molecular weight kininogen)'" were kindly assayed by Dr. Allen P. Kaplan, National Institutes of Health, Bethesda, Md. Plasma levels of-von Willebrand factor were assayed according to the Ristocetin clumping method of Brinkhous and associates. '1 Factor VIII antigen was measured by electroimmunodiffusion using a commercially available anti-Factor VIII serum (Behring Diagnostics, Nutley, N J). The technique, which is a modification of the original method of Zimmerman and associates,"-' has been previously described. ':~ Platelet aggregation, platelet adenine nucleotides and platelet
scrotonin uptake were measured according to previously described methods/ RESULTS Results of representative laboratory studies are summarized in Table I. Most determinations were performed on two or three occasions. The patient consistently had an increased PTT, prolonged bleeding time, and reduced platelet retention in glass bead columns. Factor Vlll coagulant activity, VIIIAGx, and VIIlvwr were all decreased. These features are all consistent with VWD.' In addition, the patient had marked reduction in Factor XII coagulant activity, while other factors in the "contact system" (high molecular weight kininogen, pre-kallikrein, and Factor XI) were normal. Platelet aggregation in response to 25/,M epinephrine, 1.2 and 12/zM adenosine diphosphate, and 260 t~gm/ml collagen suspension was normal. The patient's father had a normal bleeding time and normal PTT but also had reduced values for VIH~,w. VllIvwr, VIIIAox, and Factor XII, findings consistent with mild von WiUebrand disease and concomitant Hageman trait. All studies performed on the patient's mother and sister were normal. DISCUSSION Rarely, VWD has been reported in association with intrinsic platelet abnormalities manifested by abnormal
Volume 90 Number 5
platelet aggregation with epinephrine and collagen.*-~ 1~ Recently, Cramer and associates ~ reported nine of 39 patients with VWD to have decreased Factor XII activity. They suggested that these dual factor deficiencies were inherited jointly and proposed that the variants be named von Willebrand disease-San Diego. ~ Like our patient and her father, the patients in their series generally had few bleeding symptoms. However, deficiencies of Fletcher or Fitzgerald factors, which could also prolong the PTT, were not excluded in their patients. In addition, linkage of the VWD and Factor XII deficiency was not documented by inclusion of data from other family members. Hageman factor (Factor XII) deficiency is usually an autosomal recessive condition, although an autosomal dominant pattern of inheritance has been noted in some families. 1~ Our patient appears to have inherited both VWD and Hageman deficiency from her father, a finding consistent with a common defect causing impaired synthesis and/or function of both Factors VIII and XII, as has been proposed in the patients with von Willebrand disease-San Diego." Nevertheless, the findings may represent a chance occurrence of two unusual disorders in father and daughter. It is uncertain whether our patient is a heterozygote or a mildly affected homozygote for Hageman deficiency. The father's reduced Factor XII level suggests the former. However, there are probably multiple alleles for Factor XII synthesis 1'~and Patient C.R. may also have inherited an abnormal gene from her mother. The family described in this report renders support to the hypothesis of Cramer and co-workers ~ that a dual abnormality in both Factor XII and Factor VIII synthesis may be inherited jointly, since the patient and her father have both defects while the patient's mother and sister have neither. However, it seems inappropriate to designate combined VWD and Hageman deficiency as a new variant, i.e., von Willebrand disease-San Diego, which implies a defined structural change in the Factor VIII molecular complex leading to VWD. ~ The importance of this syndrome cannot even be assessed until more families with VWD are carefully studied for associated Factor XII deficiency. Although our patient had mild VWD, this condition was not the cause of her prolonged PTT, as the VII1AH~ level was not sufficiently reduced to affect this screening test. The PTT of her plasma could not be corrected by addition of Factor XII deficient plasma (data not included), and the Factor XII level was subsequently found to be 6%. Results of screening tests for coagulation must be scrutinized carefully, and when results of "definitive" factor assays do not explain the abnormal screening tests, further diagnostic studies must be carried out to
Brief cfnical and laboratory observations
78 1
exclude other coagulation abnormalities. Quantitative factor assays should always be performed in order to confirm the impression gained from the history and screening coagulation tests. We acknowledge the valuable technical assistance of Vera Martin, Sima Atefee, and Christine Holtkamp. We are indebted to Dr. Frank G. Emerling for referral of this patient and her family. REFERENCES
1. Robertson JG, and Trueman RG: Combined hemophilia and Christmas disease, Blood 24:281, 1964. 2. Smit-Sibinga CT, et al: Combined deficiency of factor V and factor VIII: Report of a family and genetic analysis, Br J Haematol 23:467, 1972. 3. WeissHJ: Abnormalities of factor Vlll and platelet aggregation-use of ristocetin in diagnosing the von Willebrand's syndrome, Blood 45:403, 1975. 4. Sultan Y, Bernal-Hoyos EJ, Levy-Toledano S, .leanneau C, and Caen JP: Dominant inherited familial Factor VIII deficiency (yon Willebrand's disease) associated with thrombocytopathic thrombocytopenia, Pathol Biol 22 (Suppl):27, 1974. 5. Dowling SV, Muntz RH, D'Souza S, and Ekhert H: Platelet release abnormality associated with a variant of von Willebrand's disease, Blood 47:265, 1976. 6. Cramer AD, Melaragno AJ, Phifer SJ, and Hougie C: Von Willebrand's disease San Diego, a new variant, Lancet 2:12. 1976. 7. Buchanan GR, and Handin RI: Platelet function in the Chediak-Higashi syndrome, Blood 47:941, 1976. 8. Hardisty RM: Bleeding disorders, Oxford, 1965, Blackwell Scientific publications. 9. Abildgaard C, and Harrison J: Fletcher factor deficiency: Family study and detection, Blood 43:641, 1974. 10. Waldman P, Abraham JP, Rebuck JW, Caldwetl J, Saito H, and Ramoff OD: Fitzgerald factor: a hitherto unrecognized coagulation factor, Lancet 1:949, 1975. 11. Brinkhous KM, Graham JE, Cooper HA, Allain JP, and Wagner RH: Assay of von Willebrand factor in von Willebrand's disease and hemophilia: Use of a macroscopic platelet aggregation test, Thromb Res 6:267, 1975. 12. Zimmerman TS, Ratnoff OD, and Powell AE: Immunologic differentiation of classic hemophilia (factor VIII deficiency) and yon Willebrand's disease, with observations on combined deficiencies of antihemophilic factor and proaccelerin (factor V) and an acquired circulating anticoagulant against antihemophilic factor, J Clin Invest 50:244, 1971. 13. Handin RI, Martin V, and Moloney WC: Antibodyinduced von Willebrand's disease. A newly defined inhibitor syndrome, Blood 48:393, 1976. 14. Hoyer LW: Von Willebrand's disease, in Spaet TH, editor: Progress in hemostasis and thrombosis, Vol 3, New York. 1976, Grune & Stratton, Inc., pp. 231-288. 15. Bennett B, Ratnoff OD, Holt JB, and Roberts HR: Hageman trait (factor XII deficiency): a probable second genotype inherited as an autosomal dominant characteristic, Blood 40:412, 1972. 16. Veltkamp JJ, Drion EF, and Loeliger EA: Detection of the carrier state in hereditary coagulation disorders II. Thromb Diath Haemorrh 19:403, 1968.
Brief clinical and laboratory observations
Thus, patient L. M. appears to be a unique example of primary type I hyperlipoproteinemia in a patient with normal lipoprotein lipase activity. One other patient with typical type I hyperlipoproteinemia was initially reported as having normal post-heparin lipolytic activity; with the development of separate assays for the various components of post-heparin lipolytic activity, however, he was found to have a deficiency of protamine inactivated triglyceride lipase with a relative increase in the protamineresistant lipase. 4 The combination of findings in our patient suggest that primary type I hyperlipoproteinemia may represent a heterogeneous group of disorders, only one of which is associated with a deficiency of lipoprotein lipase activity.
3.
4.
5. 6.
7.
We thank Dr. Peter N. Herbert of The National Institutes of Health for his help in performing the triglyceride lipase enzyme assay.
8.
REFERENCES
9.
1. Fredrickson DS, and Levy RI: Familial hyperlipoproteinemia, In Stanbury JB, Wyngaarden JB, and Fredrickson DS, editors: Metabolic basis of inherited disease, New York, 1975, McGraw-Hill Book Company, Inc, pp 545614. 2, Harlan WR, Winesett PS, and Wasserman AJ: Tissue
Combined yon Willebrand disease and Hageman factor
deficiency George R. Buchanan, M.D., Daniel M. Green, M,D., and Robert I. Handin, M.D.,* Boston,
Mass. From the Division of Hematology-Oncology of the Department Of Medicine, Children's Hospital Medical Center, Division of Hematology, Department of Medicine, Peter Bent Brigham Hospital, and the Departments of Pediatrics and Medicine, Harvard Medical School Supported by United States Public Health Service Grant Nos. HL 05581, HL 17513, and HL 05392.
10.
779
lipoprotein lipase in normal individuals and in individuals with exogenous hypertriglyceridemia and the relationship of this enzyme to assimilation of fat, J Clin Invest 46:239, 1967. Schreibman PH, Arons DL, Saudek CD, and Arky RA: Abnormal lipoprotein lipase in familial exogenous hypertriglyceridemia, J Clin Invest 52:2075, 1973. Krauss RM, Levy RI, and Fredrickson DS: Selective measurement of two lipase activities in postheparin plasma from normal subjects and patients with hyperlipoproteinemia, J Clin Invest 54:1107, 1974. Motulsky AG: The genetic hyperlipidemias, N Engl J Med 294:823, 1976. Glueck CJ, Kaplan AP, Levy RL Greten H, Ga'alnick H, and Fredrickson DS: A new mechanism of exogenous hyperglyceridemia, Ann Intern Med 71:1051, 1969. Glueck CJ, Levy RI, Glueck HI, Gralnick HR, Greten H, and Fredrickson DS: Acquired type I hyperlipoproteinemia with systemic lupus erythematosus, dysglobulinemia and heparin resistance, Am J Med 47:318, 1969. Kessler JI, Kniffen JC, and Janowitz HD: Lipoprotein lipase inhibition in the hyperlipemia of acute alcoholic pancreatitis, N Engl J Med 269:943, 1963. Bierman EL, Bagdade JD, and Porte D: A concept of the pathogenesis of diabetic lipemia, Trans Assoc Am Physicians 79:348, 1966. Porte D, O'Hara DD, and Williams RH: The relation between postheparin lipolytic activity and plasma triglyceride in myxedema, Metabolism 15:107, 1966.
COMBtNAa'IONS of hemophilia A or yon Willebrand disease with other clotting factor deficiencies', '-' or with intrinsic platelet abnormalities 3~' have been observed but are probably chance events in most circumstances. Several patients have been described who have evidence of VWD and slightly decreased levels Of Factor XII (Hageman factor)." Unfortunately, family studies were not performed to document joint inheritance of the two defects. We describe a child who has both VWD and Hageman factor deficiency, with a similar defect in the patient's father, suggesting linked auiosomal dominant transmission of both disorders.
Abbreviations used VWD: von Willebrand disease PTT: activated partial thromboplastin time VIIIvwv: plasma levels of yon Willebrand factor VIIIAc~x: Factor VIII antigen
*Cancer Research Scholar, Massachusetts Division American
Cancer Society. Reprint address: George R. Buchanan, M.D.. Division of Hematologv-Oncology, Children"s Hospital Medical Center. 300 Longwood Ave., Boston, MA 02114.
CASE REPORT
Patient C.R. is a 6-year-old white girl who was noted to have a long activated partial thr0mboplastin time. There was no history
"78 0
Brief clinical and laboratory observations
The Journal of Pediatrics May 1977
Table I. Results of laboratory tests in Patient C.R. and her family
Normal range Prothrombin time PTT Platelet count Bleeding time Platelet retention VIII.~H~ Vlllvwv VllI~ Factor X1 Factor XII Fletcher factor Fitzgerald factor Platelet aggregation Platelet morphology Platelet adenosine diphosphate
Platelet adenosine triphosphate
Platelet serotonin uptake
11-14 seconds 25-35 seconds 150-450,000/~d 2t/2-8 minutes 20-80% 50-200% 60-180% 41-212% 50-150% 50-150% 1.7-3.6 ptmoles/10" platelets 4.8-84 btmoles/10'' platelets -
[
PatientC.R.
Sister
11.8 48 286,000 13 2 51 55 21 I0 t 6 Normal Normal Normal Normal 2.9
13.5 29 5 I25 79 52 56 83
Normal Normal
Father]Mother 11.7 32 201,000 5~/2 32 42 37 13.5 92 26 Normal Normal Normal Normal
12.2 29 283.000 7 170 179 89 76 115
Normal Normal
6.4
Normal
PTI = Partialthromboplastintime; Vlll~.r: Factor VIII coagulantactivity:VllIwvv:plasmalevelsof von Willebrandfactor; VIII,,x = Factor VIII antigen. of a bleeding disorder except for minimal bruising. She had never required surgical procedures and was in excellent health. There was also no history of abnormal bleeding in the patient's 9-yearold sister, either parent, or any other relative. MATERIALS AND METHODS Multiple tests of hemostatic function were performed on the patient and the members of her immediate family, all of whom refrained from taking medications for at least ten days prior to study. All screening tests were performed according to standard methods/Assays for Factors VIII, XI, and XII were performed by a one-stage technique using a modified PTT system containing congenitally deficient substrate plasmas/ Factors VIII and XII were assayed in three different laboratories. Fletcher factor (pre-kallikrein) was screened by measuring the PTT after prolonged kaolin incubation." Fletcher factor and Fitzgerald factor (high molecular weight kininogen)'" were kindly assayed by Dr. Allen P. Kaplan, National Institutes of Health, Bethesda, Md. Plasma levels of-von Willebrand factor were assayed according to the Ristocetin clumping method of Brinkhous and associates. '1 Factor VIII antigen was measured by electroimmunodiffusion using a commercially available anti-Factor VIII serum (Behring Diagnostics, Nutley, N J). The technique, which is a modification of the original method of Zimmerman and associates,"-' has been previously described. ':~ Platelet aggregation, platelet adenine nucleotides and platelet
scrotonin uptake were measured according to previously described methods/ RESULTS Results of representative laboratory studies are summarized in Table I. Most determinations were performed on two or three occasions. The patient consistently had an increased PTT, prolonged bleeding time, and reduced platelet retention in glass bead columns. Factor Vlll coagulant activity, VIIIAGx, and VIIlvwr were all decreased. These features are all consistent with VWD.' In addition, the patient had marked reduction in Factor XII coagulant activity, while other factors in the "contact system" (high molecular weight kininogen, pre-kallikrein, and Factor XI) were normal. Platelet aggregation in response to 25/,M epinephrine, 1.2 and 12/zM adenosine diphosphate, and 260 t~gm/ml collagen suspension was normal. The patient's father had a normal bleeding time and normal PTT but also had reduced values for VIH~,w. VllIvwr, VIIIAox, and Factor XII, findings consistent with mild von WiUebrand disease and concomitant Hageman trait. All studies performed on the patient's mother and sister were normal. DISCUSSION Rarely, VWD has been reported in association with intrinsic platelet abnormalities manifested by abnormal
Volume 90 Number 5
platelet aggregation with epinephrine and collagen.*-~ 1~ Recently, Cramer and associates ~ reported nine of 39 patients with VWD to have decreased Factor XII activity. They suggested that these dual factor deficiencies were inherited jointly and proposed that the variants be named von Willebrand disease-San Diego. ~ Like our patient and her father, the patients in their series generally had few bleeding symptoms. However, deficiencies of Fletcher or Fitzgerald factors, which could also prolong the PTT, were not excluded in their patients. In addition, linkage of the VWD and Factor XII deficiency was not documented by inclusion of data from other family members. Hageman factor (Factor XII) deficiency is usually an autosomal recessive condition, although an autosomal dominant pattern of inheritance has been noted in some families. 1~ Our patient appears to have inherited both VWD and Hageman deficiency from her father, a finding consistent with a common defect causing impaired synthesis and/or function of both Factors VIII and XII, as has been proposed in the patients with von Willebrand disease-San Diego." Nevertheless, the findings may represent a chance occurrence of two unusual disorders in father and daughter. It is uncertain whether our patient is a heterozygote or a mildly affected homozygote for Hageman deficiency. The father's reduced Factor XII level suggests the former. However, there are probably multiple alleles for Factor XII synthesis 1'~and Patient C.R. may also have inherited an abnormal gene from her mother. The family described in this report renders support to the hypothesis of Cramer and co-workers ~ that a dual abnormality in both Factor XII and Factor VIII synthesis may be inherited jointly, since the patient and her father have both defects while the patient's mother and sister have neither. However, it seems inappropriate to designate combined VWD and Hageman deficiency as a new variant, i.e., von Willebrand disease-San Diego, which implies a defined structural change in the Factor VIII molecular complex leading to VWD. ~ The importance of this syndrome cannot even be assessed until more families with VWD are carefully studied for associated Factor XII deficiency. Although our patient had mild VWD, this condition was not the cause of her prolonged PTT, as the VII1AH~ level was not sufficiently reduced to affect this screening test. The PTT of her plasma could not be corrected by addition of Factor XII deficient plasma (data not included), and the Factor XII level was subsequently found to be 6%. Results of screening tests for coagulation must be scrutinized carefully, and when results of "definitive" factor assays do not explain the abnormal screening tests, further diagnostic studies must be carried out to
Brief cfnical and laboratory observations
78 1
exclude other coagulation abnormalities. Quantitative factor assays should always be performed in order to confirm the impression gained from the history and screening coagulation tests. We acknowledge the valuable technical assistance of Vera Martin, Sima Atefee, and Christine Holtkamp. We are indebted to Dr. Frank G. Emerling for referral of this patient and her family. REFERENCES
1. Robertson JG, and Trueman RG: Combined hemophilia and Christmas disease, Blood 24:281, 1964. 2. Smit-Sibinga CT, et al: Combined deficiency of factor V and factor VIII: Report of a family and genetic analysis, Br J Haematol 23:467, 1972. 3. WeissHJ: Abnormalities of factor Vlll and platelet aggregation-use of ristocetin in diagnosing the von Willebrand's syndrome, Blood 45:403, 1975. 4. Sultan Y, Bernal-Hoyos EJ, Levy-Toledano S, .leanneau C, and Caen JP: Dominant inherited familial Factor VIII deficiency (yon Willebrand's disease) associated with thrombocytopathic thrombocytopenia, Pathol Biol 22 (Suppl):27, 1974. 5. Dowling SV, Muntz RH, D'Souza S, and Ekhert H: Platelet release abnormality associated with a variant of von Willebrand's disease, Blood 47:265, 1976. 6. Cramer AD, Melaragno AJ, Phifer SJ, and Hougie C: Von Willebrand's disease San Diego, a new variant, Lancet 2:12. 1976. 7. Buchanan GR, and Handin RI: Platelet function in the Chediak-Higashi syndrome, Blood 47:941, 1976. 8. Hardisty RM: Bleeding disorders, Oxford, 1965, Blackwell Scientific publications. 9. Abildgaard C, and Harrison J: Fletcher factor deficiency: Family study and detection, Blood 43:641, 1974. 10. Waldman P, Abraham JP, Rebuck JW, Caldwetl J, Saito H, and Ramoff OD: Fitzgerald factor: a hitherto unrecognized coagulation factor, Lancet 1:949, 1975. 11. Brinkhous KM, Graham JE, Cooper HA, Allain JP, and Wagner RH: Assay of von Willebrand factor in von Willebrand's disease and hemophilia: Use of a macroscopic platelet aggregation test, Thromb Res 6:267, 1975. 12. Zimmerman TS, Ratnoff OD, and Powell AE: Immunologic differentiation of classic hemophilia (factor VIII deficiency) and yon Willebrand's disease, with observations on combined deficiencies of antihemophilic factor and proaccelerin (factor V) and an acquired circulating anticoagulant against antihemophilic factor, J Clin Invest 50:244, 1971. 13. Handin RI, Martin V, and Moloney WC: Antibodyinduced von Willebrand's disease. A newly defined inhibitor syndrome, Blood 48:393, 1976. 14. Hoyer LW: Von Willebrand's disease, in Spaet TH, editor: Progress in hemostasis and thrombosis, Vol 3, New York. 1976, Grune & Stratton, Inc., pp. 231-288. 15. Bennett B, Ratnoff OD, Holt JB, and Roberts HR: Hageman trait (factor XII deficiency): a probable second genotype inherited as an autosomal dominant characteristic, Blood 40:412, 1972. 16. Veltkamp JJ, Drion EF, and Loeliger EA: Detection of the carrier state in hereditary coagulation disorders II. Thromb Diath Haemorrh 19:403, 1968.
